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Sample records for active specific immunotherapy

  1. Antigen-specific active immunotherapy for ovarian cancer

    NARCIS (Netherlands)

    Leffers, N.; Daemen, T.; Helfrich, W.; Boezen, H. M.; Cohlen, B. J.; Melief, Cornelis; Nijman, H. W.

    2010-01-01

    BACKGROUND: Despite advances in chemotherapy, prognosis of ovarian cancer remains poor. Antigen-specific active immunotherapy aims to induce a tumour-antigen-specific anti-tumour immune responses as an alternative treatment for ovarian cancer. OBJECTIVES: To assess feasibility of antigen-specific ac

  2. Allergen Specific Immunotherapy

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    Şükrü Çekiç

    2015-04-01

    Full Text Available Allergen specific immunotherapy (SIT is the only treatment that can provide a cure for allergic disorders. This treatment is based on development of immune tolerance by exposure to allergen in repetitive and increasing doses. It is tertiary to avoidance of allergen and pharmacotherapy. Allergens used for immunotherapy, must be confirmed by skin prick test or specific IgE and must be applied in supervision of allergy specialists. Studies show that immunotherapy, improve asthma symptoms, decreases drug consumption, prevent development of asthma in rhinitis patients and reduce new sensitizations. Common side effects diminished with the usage of standardized allergen solutions. It is contraindicated in severe asthma. Though it is recommended to avoid immunotherapy in patients using beta blockers and ACE inhibitors, immunotherapy can be considered in mandatory situations regarding possible benefits and harms. Most common ways of administration are subcutaneous and sublingual; new methods such as epicutaneous and intralymphatic injections are currently being studied.

  3. Allergen-specific immunotherapy

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    Moote William

    2011-11-01

    Full Text Available Abstract Allergen-specific immunotherapy is a potentially disease-modifying therapy that is effective for the treatment of allergic rhinitis/conjunctivitis, allergic asthma and stinging insect hypersensitivity. However, despite its proven efficacy in these conditions, it is frequently underutilized in Canada. The decision to proceed with allergen-specific immunotherapy should be made on a case-by-case basis, taking into account individual patient factors such as the degree to which symptoms can be reduced by avoidance measures and pharmacological therapy, the amount and type of medication required to control symptoms, the adverse effects of pharmacological treatment, and patient preferences. Since this form of therapy carries the risk of anaphylactic reactions, it should only be prescribed by physicians who are adequately trained in the treatment of allergy. Furthermore, injections must be given under medical supervision in clinics that are equipped to manage anaphylaxis. In this article, the authors review the indications and contraindications, patient selection criteria, and the administration, safety and efficacy of allergen-specific immunotherapy.

  4. From "magic bullets" to specific cancer immunotherapy.

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    Riether, Carsten; Schürch, Christian; Ochsenbein, Adrian F

    2013-01-23

    The immune system is able to specifically target antigen-expressing cancer cells. The promise of immunotherapy was to eliminate cancer cells without harming normal tissue and, therefore, with no or very few side effects. Immunotherapy approaches have, for several decades, been tested against several tumours, most often against malignant melanoma. However, although detectable immune responses have regularly been induced, the clinical outcome has often been disappointing. The development of molecular methods and an improved understanding of tumour immunosurveillance led to novel immunotherapy approaches in the last few years. First randomised phase III trials proved that immunotherapy can prolong survival of patients with metastatic melanoma or prostate cancer. The development in the field is very rapid and various molecules (mainly monoclonal antibodies) that activate the immune system are currently being tested in clinical trials and will possibly change our treatment of cancer. The ultimate goal of any cancer therapy and also immunotherapy is to cure cancer. However, this depends on the elimination of the disease originating cancer stem cells. Unfortunately, cancer stem cells seem resistant to most available treatment options. Recent developments in immunotherapy may allow targeting these cancer stem cells specifically in the future. In this review, we summarise the current state of immunotherapy in clinical routine and the expected developments in the near future.

  5. New visions in specific immunotherapy in children

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    Halken, Susanne; Lau, Susanne; Valovirta, Erkka

    2008-01-01

    Specific immunotherapy is indicated for confirmed immunoglobulin E-mediated airway diseases using standardized allergen products with documented clinical efficacy and safety. For decades the subcutaneous route of administration (SCIT) has been the gold standard. Recently, the sublingual...

  6. Allergen specific immunotherapy in nasobronchial allergy.

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    Joshi S

    2003-12-01

    Full Text Available BACKGROUND: More than one antigen has been used for immunotherapy of allergic disorders. So far less than five antigens have been employed with variable results. AIM: To evaluate effect of multiple antigens up to six in the immunotherapy of nasobronchial allergy. SETTING AND DESIGN: Based on clinical history, symptoms present for at least 3 years with set criteria of immunomodulation for asthma and rhinitis: documented IgE mediated asthma and rhinitis, failure in allergen avoidance and moderate to severe clinical manifestations. MATERIAL AND METHODS: Five hundred cases of various allergic disorders attending allergy clinic of Bombay hospital were screened. Allergen specific immunotherapy was initiated in 131 subjects (56 -rhinitis and 75 asthma with prior consent. Patients suffering from allergic disorders secondary to diseases or drug therapy were excluded. Multiple allergen immunotherapy was given at specific intervals up to a period of one year. Allergen extracts were prepared as per standard technique. For statistical analysis "students′t test" was used. RESULTS AND CONCLUSIONS: Significant improvement in PEFR, reduction in skin sensitivity to allergens used in immunotherapy formulation and symptomatic relief without any untoward reaction show that multiple allergen immunotherapy is as effective as monoallergen immunotherapy in nasobronchial allergy.

  7. Active Immunotherapy of Cancer.

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    Chodon, Thinle; Koya, Richard C; Odunsi, Kunle

    2015-01-01

    Clinical progress in the field of cancer immunotherapy has been slow for many years but within the last 5 years, breakthrough successes have brought immunotherapy to the forefront in cancer therapy. Promising results have been observed in a variety of cancers including solid tumors and hematological malignancies with adoptive cell therapy using natural host tumor infiltrating lymphocytes, host cells that have been genetically engineered with antitumor T-cell receptors or chimeric antigen receptors, immune checkpoint inhibitors like anti-CTLA-4, anti-PD-1 or PD-L1 monoclonal antibodies and oncolytic virus-based immunotherapy. However, most treatment modalities have shown limited efficacy with single therapy. The complex nature of cancer with intra- and inter-tumor antigen and genomic heterogeneity coupled with the immune suppressive microenvironment emphasizes the prospect of personalized targeted immunotherapy to manipulate the patient's own immune system against cancer. For successful, robust and long-lasting cure of cancer, a multi-modal approach is essential, combining anti-tumor cell therapy with manipulation of multiple pathways in the tumor microenvironment to ameliorate tumor-induced immunosuppression.

  8. Recombinant allergens for allergen-specific immunotherapy: 10 years anniversary of immunotherapy with recombinant allergens.

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    Valenta, Rudolf; Linhart, B; Swoboda, I; Niederberger, V

    2011-06-01

    The broad applicability of allergen-specific immunotherapy for the treatment and eventually prevention of IgE-mediated allergy is limited by the poor quality and allergenic activity of natural allergen extracts that are used for the production of current allergy vaccines. Today, the genetic code of the most important allergens has been deciphered; recombinant allergens equalling their natural counterparts have been produced for diagnosis and immunotherapy, and a large panel of genetically modified allergens with reduced allergenic activity has been characterized to improve safety of immunotherapy and explore allergen-specific prevention strategies. Successful immunotherapy studies have been performed with recombinant allergens and hypoallergenic allergen derivatives and will lead to the registration of the first recombinant allergen-based vaccines in the near future. There is no doubt that recombinant allergen-based vaccination strategies will be generally applicable to most allergen sources, including respiratory, food and venom allergens and allow to produce safe allergy vaccines for the treatment of the most common forms of IgE-mediated allergies.

  9. [Scleroderma related to specific immunotherapy. A report of a case].

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    Morfín Maciel, Blanca María; Castillo Morfín, Blanca María

    2009-01-01

    It has been described two main phenotypes of helper T cells. On activation, the immune system develops the most effective Th response. Whereas Th1 cells promote cell-mediate immunity against intracellular pathogens and an over expression could favor autoimmune diseases; Th2 cells develop humoral immunity against extracellular pathogens promoting allergic response. Normally, the two profiles coexist in the same individual with different grades of expression. Recently, it has been described a new subset: Th17, which is related to tissue injury in autoimmune diseases. Then, allergic and autoimmune diseases result from an unbalanced response of the immune system. Allergen-specific immunotherapy is the only curative treatment of a specific allergy, which leads to a life-long tolerance against allergens. There are no controlled studies about the effectiveness or risks associated with allergen-specific immunotherapy in patients with autoimmune disorders. On the other hand, scleroderma is an autoimmune chronic systemic disorder of unknown etiology characterized by excess collagen deposition in the skin and viscera, along with vascular injury. We report a girl with allergic asthma and with a second degree family history of systemic sclerosis who developed localized scleroderma during allergen specific immunotherapy. Because allergy vaccination alter the balance between effector and regulatory T-cell populations, which regulate immune tolerance, a positive family history of autoimmunity in first or second degree, could be a contraindication for allergen-specific immunotherapy.

  10. Local Nasal Specific Immunotherapy for Allergic Rhinitis

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    Passalacqua Giovanni

    2006-09-01

    Full Text Available Abstract The possibility of producing local hyposensitization by administering allergens via mucosal routes was envisaged at the beginning of 1900, and local nasal immunotherapy has been extensively studied since the 1970s. Presently, there are 21 randomized controlled trials being conducted with the most common allergens, consistently showing the clinical efficacy of local nasal immunotherapy for rhinitis. Other advantages are that it has an optimal safety profile and can be self-administered at home by the patient. Moreover, there are several data from animal models and from humans that confirm the immunomodulatory effect of intranasally administered antigens. On the other hand, local nasal immunotherapy seems to be effective only on rhinitis symptoms and requires a particular technique of administration. For these reasons, its clinical use is progressively declining in favour of the sublingual route although nasal immunotherapy is validated in official documents and remains a viable alternative to injection.

  11. Mechanisms of allergen-specific immunotherapy

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    Fujita Hiroyuki

    2012-01-01

    Full Text Available Abstract Allergen-specific immunotherapy (allergen-SIT is a potentially curative treatment approach in allergic diseases. It has been used for almost 100 years as a desensitizing therapy. The induction of peripheral T cell tolerance and promotion of the formation of regulatory T-cells are key mechanisms in allergen-SIT. Both FOXP3+CD4+CD25+ regulatory T (Treg cells and inducible IL-10- and TGF-β-producing type 1 Treg (Tr1 cells may prevent the development of allergic diseases and play a role in successful allergen-SIT and healthy immune response via several mechanisms. The mechanisms of suppression of different pro-inflammatory cells, such as eosinophils, mast cells and basophils and the development of allergen tolerance also directly or indirectly involves Treg cells. Furthermore, the formation of non-inflammatory antibodies particularly IgG4 is induced by IL-10. Knowledge of these molecular basis is crucial in the understanding the regulation of immune responses and their possible therapeutic targets in allergic diseases.

  12. Immune-Checkpoint Blockade and Active Immunotherapy for Glioma

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    Ahn, Brian J. [Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 (United States); Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Pollack, Ian F. [Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 (United States); Okada, Hideho, E-mail: okadah@upmc.edu [Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 (United States); Brain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 (United States); Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 (United States); Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213 (United States)

    2013-11-01

    Cancer immunotherapy has made tremendous progress, including promising results in patients with malignant gliomas. Nonetheless, the immunological microenvironment of the brain and tumors arising therein is still believed to be suboptimal for sufficient antitumor immune responses for a variety of reasons, including the operation of “immune-checkpoint” mechanisms. While these mechanisms prevent autoimmunity in physiological conditions, malignant tumors, including brain tumors, actively employ these mechanisms to evade from immunological attacks. Development of agents designed to unblock these checkpoint steps is currently one of the most active areas of cancer research. In this review, we summarize recent progresses in the field of brain tumor immunology with particular foci in the area of immune-checkpoint mechanisms and development of active immunotherapy strategies. In the last decade, a number of specific monoclonal antibodies designed to block immune-checkpoint mechanisms have been developed and show efficacy in other cancers, such as melanoma. On the other hand, active immunotherapy approaches, such as vaccines, have shown encouraging outcomes. We believe that development of effective immunotherapy approaches should ultimately integrate those checkpoint-blockade agents to enhance the efficacy of therapeutic approaches. With these agents available, it is going to be quite an exciting time in the field. The eventual success of immunotherapies for brain tumors will be dependent upon not only an in-depth understanding of immunology behind the brain and brain tumors, but also collaboration and teamwork for the development of novel trials that address multiple layers of immunological challenges in gliomas.

  13. Immune-Checkpoint Blockade and Active Immunotherapy for Glioma

    Directory of Open Access Journals (Sweden)

    Brian J. Ahn

    2013-11-01

    Full Text Available Cancer immunotherapy has made tremendous progress, including promising results in patients with malignant gliomas. Nonetheless, the immunological microenvironment of the brain and tumors arising therein is still believed to be suboptimal for sufficient antitumor immune responses for a variety of reasons, including the operation of “immune-checkpoint” mechanisms. While these mechanisms prevent autoimmunity in physiological conditions, malignant tumors, including brain tumors, actively employ these mechanisms to evade from immunological attacks. Development of agents designed to unblock these checkpoint steps is currently one of the most active areas of cancer research. In this review, we summarize recent progresses in the field of brain tumor immunology with particular foci in the area of immune-checkpoint mechanisms and development of active immunotherapy strategies. In the last decade, a number of specific monoclonal antibodies designed to block immune-checkpoint mechanisms have been developed and show efficacy in other cancers, such as melanoma. On the other hand, active immunotherapy approaches, such as vaccines, have shown encouraging outcomes. We believe that development of effective immunotherapy approaches should ultimately integrate those checkpoint-blockade agents to enhance the efficacy of therapeutic approaches. With these agents available, it is going to be quite an exciting time in the field. The eventual success of immunotherapies for brain tumors will be dependent upon not only an in-depth understanding of immunology behind the brain and brain tumors, but also collaboration and teamwork for the development of novel trials that address multiple layers of immunological challenges in gliomas.

  14. Specific immunotherapy for renal cell carcinoma

    NARCIS (Netherlands)

    Bleumer, I.

    2006-01-01

    Despite the fact that evaluation of cytokine-based therapies for mRCC shows that a subset of patients react favourable to immunotherapy, significant side effects do occur. With the increased knowledge of tumor-immunology, the recognition of immunogenic tumor proteins and antibodies, new treatment op

  15. EAACI: A European Declaration on Immunotherapy. Designing the future of allergen specific immunotherapy.

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    Calderon, Moises A; Demoly, Pascal; Gerth van Wijk, Roy; Bousquet, Jean; Sheikh, Aziz; Frew, Anthony; Scadding, Glenis; Bachert, Claus; Malling, Hans J; Valenta, Rudolph; Bilo, Beatrice; Nieto, Antonio; Akdis, Cezmi; Just, Jocelyne; Vidal, Carmen; Varga, Eva M; Alvarez-Cuesta, Emilio; Bohle, Barbara; Bufe, Albrecht; Canonica, Walter G; Cardona, Victoria; Dahl, Ronald; Didier, Alain; Durham, Stephen R; Eng, Peter; Fernandez-Rivas, Montserrat; Jacobsen, Lars; Jutel, Marek; Kleine-Tebbe, Jörg; Klimek, Ludger; Lötvall, Jan; Moreno, Carmen; Mosges, Ralph; Muraro, Antonella; Niggemann, Bodo; Pajno, Giovanni; Passalacqua, Giovanni; Pfaar, Oliver; Rak, Sabina; Senna, Gianenrico; Senti, Gabriela; Valovirta, Erkka; van Hage, Marianne; Virchow, Johannes C; Wahn, Ulrich; Papadopoulos, Nikolaos

    2012-10-30

    Allergy today is a public health concern of pandemic proportions, affecting more than 150 million people in Europe alone. In view of epidemiological trends, the European Academy of Allergy and Clinical Immunology (EAACI) predicts that within the next few decades, more than half of the European population may at some point in their lives experience some type of allergy.Not only do allergic patients suffer from a debilitating disease, with the potential for major impact on their quality of life, career progression, personal development and lifestyle choices, but they also constitute a significant burden on health economics and macroeconomics due to the days of lost productivity and underperformance. Given that allergy triggers, including urbanization, industrialization, pollution and climate change, are not expected to change in the foreseeable future, it is imperative that steps are taken to develop, strengthen and optimize preventive and treatment strategies.Allergen specific immunotherapy is the only currently available medical intervention that has the potential to affect the natural course of the disease. Years of basic science research, clinical trials, and systematic reviews and meta-analyses have convincingly shown that allergen specific immunotherapy can achieve substantial results for patients, improving the allergic individuals' quality of life, reducing the long-term costs and burden of allergies, and changing the course of the disease. Allergen specific immunotherapy not only effectively alleviates allergy symptoms, but it has a long-term effect after conclusion of the treatment and can prevent the progression of allergic diseases.Unfortunately, allergen specific immunotherapy has not yet received adequate attention from European institutions, including research funding bodies, even though this could be a most rewarding field in terms of return on investments, translational value and European integration and, a field in which Europe is recognized as a

  16. EAACI: A European Declaration on Immunotherapy. Designing the future of allergen specific immunotherapy

    Directory of Open Access Journals (Sweden)

    Calderon Moises A

    2012-10-01

    Full Text Available Abstract Allergy today is a public health concern of pandemic proportions, affecting more than 150 million people in Europe alone. In view of epidemiological trends, the European Academy of Allergy and Clinical Immunology (EAACI predicts that within the next few decades, more than half of the European population may at some point in their lives experience some type of allergy. Not only do allergic patients suffer from a debilitating disease, with the potential for major impact on their quality of life, career progression, personal development and lifestyle choices, but they also constitute a significant burden on health economics and macroeconomics due to the days of lost productivity and underperformance. Given that allergy triggers, including urbanization, industrialization, pollution and climate change, are not expected to change in the foreseeable future, it is imperative that steps are taken to develop, strengthen and optimize preventive and treatment strategies. Allergen specific immunotherapy is the only currently available medical intervention that has the potential to affect the natural course of the disease. Years of basic science research, clinical trials, and systematic reviews and meta-analyses have convincingly shown that allergen specific immunotherapy can achieve substantial results for patients, improving the allergic individuals’ quality of life, reducing the long-term costs and burden of allergies, and changing the course of the disease. Allergen specific immunotherapy not only effectively alleviates allergy symptoms, but it has a long-term effect after conclusion of the treatment and can prevent the progression of allergic diseases. Unfortunately, allergen specific immunotherapy has not yet received adequate attention from European institutions, including research funding bodies, even though this could be a most rewarding field in terms of return on investments, translational value and European integration and, a field in

  17. An epitope common to gangliosides O-acetyl-GD3 and GD3 recognized by antibodies in melanoma patients after active specific immunotherapy.

    Science.gov (United States)

    Ravindranath, M H; Morton, D L; Irie, R F

    1989-07-15

    active specific immunotherapy of melanoma.

  18. Does allergen-specific immunotherapy induce contact allergy to aluminium?

    Science.gov (United States)

    Netterlid, Eva; Hindsén, Monica; Siemund, Ingrid; Björk, Jonas; Werner, Sonja; Jacobsson, Helene; Güner, Nuray; Bruze, Magnus

    2013-01-01

    Persistent, itching nodules have been reported to appear at the injection site after allergen-specific immuno-therapy with aluminium-precipitated antigen extract, occasionally in conjunction with contact allergy to aluminium. This study aimed to quantify the development of contact allergy to aluminium during allergen-specific immunotherapy. A randomized, controlled, single-blind multicentre study of children and adults entering allergen-specific immunotherapy was performed using questionnaires and patch-testing. A total of 205 individuals completed the study. In the 3 study groups all subjects tested negative to aluminium before allergen-specific immunotherapy and 4 tested positive after therapy. In the control group 4 participants tested positive to aluminium. Six out of 8 who tested positive also had atopic dermatitis. Positive test results were found in 5/78 children and 3/127 adults. Allergen-specific immunotherapy was not shown to be a risk factor for contact allergy to aluminium. Among those who did develop aluminium allergy, children and those with atopic dermatitis were more highly represented.

  19. Allergen-specific immunotherapy and risk of autoimmune disease

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    Linneberg, Allan; Madsen, Flemming; Skaaby, Tea

    2012-01-01

    After 100 years of experience with allergen-specific immunotherapy (SIT), an issue that is still unresolved is whether SIT can act as a trigger of, or as a risk factor for, autoimmune disease. We searched the literature for evidence on this topic.......After 100 years of experience with allergen-specific immunotherapy (SIT), an issue that is still unresolved is whether SIT can act as a trigger of, or as a risk factor for, autoimmune disease. We searched the literature for evidence on this topic....

  20. SPECIFIC IMMUNOTHERAPY AND CELLULAR IMMUNITY IN PATIENTS WITH CERVICAL CANCER

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    D. K. Kenbaeva

    2013-01-01

    Full Text Available Cellular mechanisms are quite important immunological components of tumor surveillance, being, however, most vulnerable to influence of different adverse factors, including surgery-associated stress and ionizing radiation. Our study was aimed for assessing specific effects of immunotherapy upon indices of cellular immunity in patients with cervical cancer. Eighty-eight patients with cervical cancer (clinical stage I-IIA, Т1аN0M0-T2aN0M0, who underwent appropriate surgery (for IA stage, or a combined treatment, including surgery gamma-ray teletherapy (IB, IIA stages are under study. The patients were distributed in two groups, depending on the therapy applied. Group 1 included patients subjected to surgical treatment plus and radiation therapy, Group 2 included those patients who were treated according to this protocol, with addition of a specific immunotherapy. Contents of T cells and various CD subpopulations of T-lymphocytes were identified by immunofluorescence techniques. Among patients with cervical cancer at clinical stages IA, IB, IIA, a reliable decrease in cellular immunity indices was registered, both after surgery, and during combined treatment. Introduction of specific immunotherapy to the conventional treatment schedule was associated with increase of cellular immune indices, and, in first line, the antineoplastic mechanisms (e.g., NK’s and NKT cell contents. One should point to a relatively low efficiency of this immunotherapy in combined treatment of patients with cervical cancer at IIA stage.

  1. Seed-based oral vaccines as allergen-specific immunotherapies.

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    Takaiwa, Fumio

    2011-03-01

    Plant-based vaccines have advantages over conventional vaccines in terms of scalability, lack of requirement for cold chain logistics, stability, safety, cost-effectiveness and needle-free administration. In particular, when antigen is expressed in seeds, high production is possible and immunogenicity is not lost even if stocked at ambient temperature for several years. Induction of immune tolerance (desensitization) to allergen is a principle strategy for controlling allergic diseases, and is generally carried out by subcutaneous injection. Seed-based oral administration offers a straightforward and inexpensive alternative approach to deliver vaccines effectively to the GALT without loss of activity. Consumption of transgenic seeds containing modified hypo-allergenic tolerogen or T-cell epitope peptides derived from allergens has no or very few severe side effects and can induce immune tolerance leading to reduction of allergen-specific IgE production, T-cell proliferation and release of histamine. Suppression of allergen-specific clinical symptoms results. Thus, seed-based allergy vaccines offer an innovative and convenient allergen-specific immunotherapeutic approach as an alternative to conventional allergen-specific immunotherapy.

  2. Personalized approaches to active immunotherapy in cancer.

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    Ophir, Eran; Bobisse, Sara; Coukos, George; Harari, Alexandre; Kandalaft, Lana E

    2016-01-01

    Immunotherapy is emerging as a promising anti-cancer curative modality. However, in contrast to recent advances obtained employing checkpoint blockade agents and T cell therapies, clinical efficacy of therapeutic cancer vaccines is still limited. Most vaccination attempts in the clinic represent "off-the shelf" approaches since they target common "self" tumor antigens, shared among different patients. In contrast, personalized approaches of vaccination are tailor-made for each patient and in spite being laborious, hold great potential. Recent technical advancement enabled the first steps in the clinic of personalized vaccines that target patient-specific mutated neo-antigens. Such vaccines could induce enhanced tumor-specific immune response since neo-antigens are mutation-derived antigens that can be recognized by high affinity T cells, not limited by central tolerance. Alternatively, the use of personalized vaccines based on whole autologous tumor cells, overcome the need for the identification of specific tumor antigens. Whole autologous tumor cells could be administered alone, pulsed on dendritic cells as lysate, DNA, RNA or delivered to dendritic cells in-vivo through encapsulation in nanoparticle vehicles. Such vaccines may provide a source for the full repertoire of the patient-specific tumor antigens, including its private neo-antigens. Furthermore, combining next-generation personalized vaccination with other immunotherapy modalities might be the key for achieving significant therapeutic outcome.

  3. Immunotherapy

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    ... that will trigger an immune response. What's more, cancer cells may also suppress immunity, which may contribute to the immune system's failure to recognize cancer cells as foreign invaders. Immunotherapy is based on ...

  4. A Review of Allergy and Allergen Specific Immunotherapy

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    Katayoon Bidad

    2011-03-01

    Full Text Available Since 20th  century, when allergy was defined, an ongoing attempt for discovering the mechanisms underlying it and its treatment began. Defining allergens as well as cells such as regulatory T-cells and characterizing the antibodies involved in the pathogenesis (including blocking antibodies have helped very much towards a better understanding of the immunologic process.However, Allergen specific immunotherapy (SIT, as a specific curative treatment for allergy also dates back to the beginning of the previous century and has progressed considerably during these years. SIT similar to natural immunomodulation, directs the immune response towards tolerance.New strategies in this field, such as using recombinant allergens, T- and B-cell-epitope- containing peptides, and DNA vaccination have shown promising results. Sublingual immunotherapy, although not yet  FDA-approved, as an alternative  strategy in SIT  has demonstrated efficacy as well as safety.Furthermore, allergen extracts, their standardization and their modification have also been the focus of much research. Undoubtedly, specific immunotherapy is proven to be an efficacious  method  to  treat  allergy,  so  its  cost-effectiveness  should  be  estimated  in developing countries in order to include it in the country's health priorities. Informing physicians about the new anti-vaccination movement is also crucial.

  5. Food allergy to apple and specific immunotherapy with birch pollen

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    Hansen, Kirsten Skamstrup; Khinchi, Marianne Søndergaard; Skov, Per Stahl

    2004-01-01

    Conflicting results concerning the effect of specific pollen immunotherapy (SIT) on allergy to plant foods have been reported. The aim of this study was to investigate the effect of SIT using a birch pollen extract on food allergy with focus on allergy to apple. Seventy-four birch pollen......-allergic patients were included in a double-blind, double-dummy, and placebo-controlled comparison of sublingual-swallow (SLIT) and subcutaneous (SCIT) administration of a birch pollen extract. Sixty-nine percent of these patients reported allergy to apple. The clinical reactivity to apple was evaluated by open....... Therefore, oral allergy syndrome (OAS) to apple should not be considered as a main criterion for selecting patients for birch pollen immunotherapy at present....

  6. Tumor-Associated Antigens for Specific Immunotherapy of Prostate Cancer

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    Kiessling, Andrea [Biologics Safety and Disposition, Preclinical Safety, Translational Sciences, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Werk Klybeck, Klybeckstraße 141, Basel CH-4057 (Switzerland); Wehner, Rebekka [Institute of Immunology, Medical Faculty, University of Technology Dresden, Fetscherstraße 74, Dresden 01307 (Germany); Füssel, Susanne [Department of Urology, Medical Faculty, University of Technology Dresden, Fetscherstraße 74, Dresden 01307 (Germany); Bachmann, Michael [Institute of Immunology, Medical Faculty, University of Technology Dresden, Fetscherstraße 74, Dresden 01307 (Germany); Wirth, Manfred P. [Department of Urology, Medical Faculty, University of Technology Dresden, Fetscherstraße 74, Dresden 01307 (Germany); Schmitz, Marc, E-mail: marc.schmitz@tu-dresden.de [Institute of Immunology, Medical Faculty, University of Technology Dresden, Fetscherstraße 74, Dresden 01307 (Germany)

    2012-02-22

    Prostate cancer (PCa) is the most common noncutaneous cancer diagnosis and the second leading cause of cancer-related deaths among men in the United States. Effective treatment modalities for advanced metastatic PCa are limited. Immunotherapeutic strategies based on T cells and antibodies represent interesting approaches to prevent progression from localized to advanced PCa and to improve survival outcomes for patients with advanced disease. CD8{sup +} cytotoxic T lymphocytes (CTLs) efficiently recognize and destroy tumor cells. CD4{sup +} T cells augment the antigen-presenting capacity of dendritic cells and promote the expansion of tumor-reactive CTLs. Antibodies mediate their antitumor effects via antibody-dependent cellular cytotoxicity, activation of the complement system, improving the uptake of coated tumor cells by phagocytes, and the functional interference of biological pathways essential for tumor growth. Consequently, several tumor-associated antigens (TAAs) have been identified that represent promising targets for T cell- or antibody-based immunotherapy. These TAAs comprise proteins preferentially expressed in normal and malignant prostate tissues and molecules which are not predominantly restricted to the prostate, but are overexpressed in various tumor entities including PCa. Clinical trials provide evidence that specific immunotherapeutic strategies using such TAAs represent safe and feasible concepts for the induction of immunological and clinical responses in PCa patients. However, further improvement of the current approaches is required which may be achieved by combining T cell- and/or antibody-based strategies with radio-, hormone-, chemo- or antiangiogenic therapy.

  7. Specific immunotherapy by the sublingual route for respiratory allergy

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    Incorvaia Cristoforo

    2010-11-01

    Full Text Available Abstract Specific immunotherapy is the only treatment able to act on the causes and not only on the symptoms of respiratory allergy. Sublingual immunotherapy (SLIT was introduced as an option to subcutaneous immunotherapy (SCIT, the clinical effectiveness of which is partly counterbalanced by the issue of adverse systemic reactions, which occur at a frequency of about 0.2% of injections and 2-5% of the patients and may also be life-threatening. A large number of trials, globally evaluated by several meta-analyses, demonstrated that SLIT is an effective and safe treatment for allergic rhinitis and allergic asthma, severe reactions being extremely rare. The application of SLIT is favored by a good compliance, higher than that reported for SCIT, in which the injections are a major factor for noncompliance because of inconvenience, and by its cost-effectiveness. In fact, a number of studies showed that SLIT may be very beneficial to the healthcare system, especially when its effectiveness persists after treatment withdrawal because of the induced immunologic changes.

  8. Clinical Outcomes of Specific Immunotherapy in Advanced Pancreatic Cancer: A Systematic Review and Meta-Analysis

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    Jiang Chen

    2017-01-01

    Full Text Available Specific immunotherapies, including vaccines with autologous tumor cells and tumor antigen-specific monoclonal antibodies, are important treatments for PC patients. To evaluate the clinical outcomes of PC-specific immunotherapy, we performed a systematic review and meta-analysis of the relevant published clinical trials. The effects of specific immunotherapy were compared with those of nonspecific immunotherapy and the meta-analysis was executed with results regarding the overall survival (OS, immune responses data, and serum cancer markers data. The pooled analysis was performed by using the random-effects model. We found that significantly improved OS was noted for PC patients utilizing specific immunotherapy and an improved immune response was also observed. In conclusion, specific immunotherapy was superior in prolonging the survival time and enhancing immunological responses in PC patients.

  9. Perspectives on allergen-specific immunotherapy in childhood

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    Calderon, M A; Gerth van Wijk, R; Eichler, I;

    2012-01-01

    This article is the result of consensus reached by a working group of clinical experts in paediatric allergology as well as representatives from an ethical committee and the European Medicine Agency (EMA). The manuscript covers clinical, scientific, regulatory and ethical perspectives on allergen......-specific immunotherapy in childhood. Unmet needs are identified. To fill the gaps and to bridge the different points of view, recommendations are made to researchers, to scientific and patient organizations and to regulators and ethical committees. Working together for the benefit of the community is essential....... The European Academy of Allergy and Clinical Immunology (EAACI) serves as the platform of such cooperation....

  10. Allergen-specific immunotherapy: from therapeutic vaccines to prophylactic approaches.

    Science.gov (United States)

    Valenta, R; Campana, R; Marth, K; van Hage, M

    2012-08-01

    Immunoglobulin E-mediated allergies affect more than 25% of the population. Allergen exposure induces a variety of symptoms in allergic patients, which include rhinitis, conjunctivitis, asthma, dermatitis, food allergy and life-threatening systemic anaphylaxis. At present, allergen-specific immunotherapy (SIT), which is based on the administration of the disease-causing allergens, is the only disease-modifying treatment for allergy. Current therapeutic allergy vaccines are still prepared from relatively poorly defined allergen extracts. However, with the availability of the structures of the most common allergen molecules, it has become possible to produce well-defined recombinant and synthetic allergy vaccines that allow specific targeting of the mechanisms of allergic disease. Here we provide a summary of the development and mechanisms of SIT, and then review new forms of therapeutic vaccines that are based on recombinant and synthetic molecules. Finally, we discuss possible allergen-specific strategies for prevention of allergic disease.

  11. The clinical-immunological analysis of a specific and combined immunotherapy of patients with cervical cancer

    Directory of Open Access Journals (Sweden)

    D. K. Kenbayeva

    2012-01-01

    Full Text Available Research objective is the comparative assessment of efficiency of two various ways of an immunotherapy of patients with cervical cancer. 57 patients with cervical cancer, the III stages, distributed on 3 groups – combined radiotherapy, a combination of a radiotherapy and specific immunotherapy, and also a radiotherapy, specific and adaptive immunotherapy are surveyed. Clinical efficiency of treatment was estimated by means of primary tumor regression and 3-year survival rate. The scheme of combined immunotherapy was shown to possess the most clinical efficiency. Positive dynamics of cell immunity indicators was accompanied to clinical efficiency of treatment.

  12. Enhancing Cancer Immunotherapy Via Activation of Innate Immunity.

    Science.gov (United States)

    Goldberg, Jacob L; Sondel, Paul M

    2015-08-01

    Given recent technological advances and advances in our understanding of cancer, immunotherapy of cancer is being used with clear clinical benefit. The immunosuppression accompanying cancer itself, as well as with current cancer treatment with radiation or chemotherapy, impairs adaptive immune effectors to a greater extent than innate effector cells. In addition to being less suppressed, innate immune cells are capable of being enhanced via immune-stimulatory regimens. Most strategies being investigated to promote innate immune responses against cancer do not require complex, patient-specific, ex vivo cellular or molecular creation of therapeutic agents; thus they can, generally, be used as "off the shelf" therapeutics that could be administered by most cancer clinics. Successful applications of innate immunotherapy in the clinic have effectively targeted components of the innate immune response. Preclinical data demonstrate how initiation of innate immune responses can lead to subsequent adaptive long-term cancer immunity. We hypothesize that integration of innate immune activation strategies into combination therapies for cancer treatment will lead to more effective and long-term clinical benefit.

  13. Specific allergen immunotherapy attenuates allergic airway inflammation in a rat model of Alstonia scholaris pollen induced airway allergy.

    Science.gov (United States)

    Datta, Ankur; Moitra, Saibal; Hazra, Iman; Mondal, Somnath; Das, Prasanta Kumar; Singh, Manoj Kumar; Chaudhuri, Suhnrita; Bhattacharya, Debanjan; Tripathi, Santanu Kumar; Chaudhuri, Swapna

    2016-01-01

    Pollen grains are well established to be an important cause of respiratory allergy. Current pharmacologic therapies for allergic asthma do not cure the disease. Allergen specific immunotherapy is the only treatment method which re-directs the immune system away from allergic response leading to a long lasting effect. The mechanism by which immunotherapy achieves this goal is an area of active research world-wide. The present experimental study was designed to develop an experimental model of allergic lung inflammation based on a relevant human allergen, Alstonia scholaris pollen, and to establish the immunological and cellular features of specific allergen immunotherapy using this same pollen extract. Our results revealed that Alstonia scholaris pollen sensitization and challenge causes eosinophilic airway inflammation with mucin hypersecretion. This is associated with increased total IgE, increased expression of FcɛRI on lung mast cells and increased levels of IL-4, IL-5 & IL-13 as confirmed by ELISA, in-situ immunofluorescence and FACS assay. Allergen specific immunotherapy reduced airway inflammation and also decreased total IgE level, FcɛRI expression, IL-4, IL-5 & IL-13 levels. It was further noted that the reduction of these levels was more by intra-nasal route than by intra-peritoneal route. Thus we present a novel animal model of Alstonia scholaris pollen allergic disease and specific allergen immunotherapy which will pave the way towards the development of better treatment modalities.

  14. The blocking activity of birch pollen-specific immunotherapy-induced IgG4 is not qualitatively superior to that of other IgG subclasses

    DEFF Research Database (Denmark)

    Ejrnaes, Anne M; Bødtger, Uffe; Larsen, Jørgen N;

    2004-01-01

    blocking activity was found in the purified IgG4 fraction. There was no significant difference in the binding avidities (1/K(d)) measured in the two IgG fractions. Thus, it appears that SIT-induced specific IgG4 contributes to the IgG blocking of allergen binding to IgE in a simple quantitative manner...

  15. Harnessing mechanistic knowledge on beneficial versus deleterious IFN-I effects to design innovative immunotherapies targeting cytokine activity to specific cell types

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    Marc eDALOD

    2014-10-01

    Full Text Available Type I interferons (IFN-I were identified over 50 years ago as cytokines critical for host defense against viral infections. IFN-I promote antiviral defense through two main mechanisms. First, IFN-I directly reinforce or induce de novo in potentially all cells the expression of effector molecules of intrinsic antiviral immunity. Second, IFN-I orchestrate innate and adaptive antiviral immunity. However, IFN-I responses can be deleterious for the host in a number of circumstances, including secondary bacterial or fungal infections, several autoimmune diseases, and, paradoxically, certain chronic viral infections. We will review the proposed nature of protective versus deleterious IFN-I responses in selected diseases. Emphasis will be put on the potentially deleterious functions of IFN-I in human immunodeficiency virus type 1 (HIV-1 infection, and on the respective roles of IFN-I and IFN-III in promoting resolution of hepatitis C virus (HCV infection. We will then discuss how the balance between beneficial versus deleterious IFN-I responses is modulated by several key parameters including i the subtypes and dose of IFN-I produced, ii the cell types affected by IFN-I and iii the source and timing of IFN-I production. Finally we will speculate how integration of this knowledge combined with advanced biochemical manipulation of the activity of the cytokines should allow designing innovative immunotherapeutic treatments in patients. Specifically, we will discuss how induction or blockade of specific IFN-I responses in targeted cell types could promote the beneficial functions of IFN-I and/or dampen their deleterious effects, in a manner adapted to each disease.

  16. Harnessing Mechanistic Knowledge on Beneficial Versus Deleterious IFN-I Effects to Design Innovative Immunotherapies Targeting Cytokine Activity to Specific Cell Types.

    Science.gov (United States)

    Tomasello, Elena; Pollet, Emeline; Vu Manh, Thien-Phong; Uzé, Gilles; Dalod, Marc

    2014-01-01

    Type I interferons (IFN-I) were identified over 50 years ago as cytokines critical for host defense against viral infections. IFN-I promote anti-viral defense through two main mechanisms. First, IFN-I directly reinforce or induce de novo in potentially all cells the expression of effector molecules of intrinsic anti-viral immunity. Second, IFN-I orchestrate innate and adaptive anti-viral immunity. However, IFN-I responses can be deleterious for the host in a number of circumstances, including secondary bacterial or fungal infections, several autoimmune diseases, and, paradoxically, certain chronic viral infections. We will review the proposed nature of protective versus deleterious IFN-I responses in selected diseases. Emphasis will be put on the potentially deleterious functions of IFN-I in human immunodeficiency virus type 1 (HIV-1) infection, and on the respective roles of IFN-I and IFN-III in promoting resolution of hepatitis C virus (HCV) infection. We will then discuss how the balance between beneficial versus deleterious IFN-I responses is modulated by several key parameters including (i) the subtypes and dose of IFN-I produced, (ii) the cell types affected by IFN-I, and (iii) the source and timing of IFN-I production. Finally, we will speculate how integration of this knowledge combined with advanced biochemical manipulation of the activity of the cytokines should allow designing innovative immunotherapeutic treatments in patients. Specifically, we will discuss how induction or blockade of specific IFN-I responses in targeted cell types could promote the beneficial functions of IFN-I and/or dampen their deleterious effects, in a manner adapted to each disease.

  17. Recent Advance in Antigen-Specific Immunotherapy for Acute Myeloid Leukemia

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    Norimitsu Kadowaki

    2011-01-01

    Full Text Available Relapse after chemotherapy is inevitable in the majority of patients with acute myeloid leukemia (AML. Thus, it is necessary to develop novel therapies that have different antileukemic mechanisms. Recent advances in immunology and identification of promising leukemia-associated antigens open the possibilities for eradicating minimal residual diseases by antigen-specific immunotherapy after chemotherapy. Several methods have been pursued as immunotherapies for AML: peptide vaccines, granulocyte-macrophage colony-stimulating factor-secreting tumor vaccines, dendritic cell vaccines, and adoptive T cell therapy. Whereas immunogenicity and clinical outcomes are improving in these trials, severe adverse events were observed in highly avid engineered T cell therapies, indicating the importance of the balance between effectiveness and side effects in advanced immunotherapy. Such progress in inducing antitumor immune responses, together with strategies to attenuate immunosuppressive factors, will establish immunotherapy as an important armament to combat AML.

  18. Allergen specificity is relevant for immunotherapy prescription in polysensitised children

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    Ciprandi Giorgio

    2012-09-01

    Full Text Available Abstract The sensitization to more allergens, such as polysenitization, is becoming a frequent characteristic of allergic patients, since the childhood. However, this phenomenon is considered an obstacle to prescribe immunotherapy by many doctors. This study investigated the relevance of polysensitization in a cohort of allergic children and evaluated the number of allergen extracts prescribed for these children. There are allergens that are frequent, but not prescribed. This issue should be matter of adequate debate for Italian paediatricians.

  19. Antigen-Specific Immunotherapy against Allergic Rhinitis: The State of the Art

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    Takashi Fujimura

    2010-01-01

    Full Text Available Allergic rhinitis is the most prevalent type I allergy in industrialized countries. Pollen scattering from trees or grasses often induces seasonal allergic rhinitis, which is known as pollinosis or hay fever. The causative pollen differs across different areas and times of the year. Impaired performance due to pollinosis and/or medication used for treating pollinosis is considered to be an important reason for the loss of concentration and productivity in the workplace. Antigen-specific immunotherapy is an only available curative treatment against allergic rhinitis. Subcutaneous injection of allergens with or without adjuvant has been commonly used as an immunotherapy; however, recently, sublingual administration has come to be considered a safer and convenient alternative administration route of allergens. In this review, we focus on the safety and protocol of subcutaneous and sublingual immunotherapy against seasonal allergic rhinitis. We also describe an approach to selecting allergens for the vaccine so as to avoid secondary sensitization and adverse events. The biomarkers and therapeutic mechanisms for immunotherapy are not fully understood. We discuss the therapeutic biomarkers that are correlated with the improvement of clinical symptoms brought about by immunotherapy as well as the involvement of Tr1 and regulatory T cells in the therapeutic mechanisms. Finally, we focus on the current immunotherapeutic approach to treating Japanese cedar pollinosis, the most prevalent pollinosis in Japan, including sublingual immunotherapy with standardized extract, a transgenic rice-based edible vaccine, and an immunoregulatory liposome encapsulating recombinant fusion protein.

  20. Specific immunotherapy (SIT in the treatment of allergic rhinitis

    Directory of Open Access Journals (Sweden)

    Gorenoi, Vitali

    2010-03-01

    Full Text Available Scientific background: Allergic rhinitis (AR exhibits a prevalence of approx. 20% in Germany and causes enormous costs in the health care system. Specific immunotherapy (SIT is considered to be the only potentially causal therapy for AR and mainly administered by two routes, subcutaneous (SCIT and sublinguale (SLIT. SIT promises a reduction of symptoms and the need for medication in patients with AR. Research questions: The question arises, to what extent is SIT effective and cost effective in the treatment of AR and which ethical-social and legal aspects have to be considered regarding its application. Methods: The literature search was accomplished in the electronic data bases MEDLINE, EMBASE etc. in February 2008. The medical evaluation was based on systematic reviews of blinded, randomised controlled studies (RCT. The economic evaluation included health-economic studies on the basis of RCT. Additionally, it was also searched for publications explicitly addressing ethical-social and legal aspects of the use of SIT. Results: Medical evaluationTwo reviews on SCIT and three on SLIT were included in the medical evaluation. For the evaluation of SIT with grass pollen results for short and medium-term effects are considered from several studies, for SIT with other seasonal allergens (e. g. tree pollen and with house dust mite allergens from clearly fewer studies and for SIT with other perennial allergens only from a few. The reviews report a significant reduction of the symptom and medication score in favour of SCIT with seasonal allergens and recognise the effectiveness at least for grass pollen allergens. Also for other seasonal allergens SCIT is appraised as effective. The reviews about SLIT determine a significant reduction of the symptom and the medication score in favour of SLIT vs. placebo in short and medium term follow-up in evaluations across all allergens. The subgroup analyses show a significant reduction of the symptom and medication

  1. Engineered cytotoxic T lymphocytes with AFP-specific TCR gene for adoptive immunotherapy in hepatocellular carcinoma.

    Science.gov (United States)

    Sun, Longhao; Guo, Hao; Jiang, Ruoyu; Lu, Li; Liu, Tong; He, Xianghui

    2016-01-01

    Alpha-fetoprotein (AFP) is overexpressed in hepatocellular carcinoma (HCC) and could serve as a tumor-associated antigen (TAA) and potential target for adoptive immunotherapy. However, low frequency and severe functional impairment of AFP-specific T cells in vivo hamper adoptive infusion. TAA-specific T cell receptor (TCR) gene transfer could be an efficient and reliable alternation to generate AFP-specific cytotoxic T lymphocytes (CTLs). Autologous dendritic cells (DC) pulsed with AFP158-166 peptides were used to stimulate AFP-specific CTLs. TCR α/β chain genes of AFP-specific CTLs were cloned and linked by 2A peptide to form full-length TCR coding sequence synthesized into a lentiviral vector. Nonspecific activated T cells were engineered by lentivirus infection. Transgenetic CTLs were evaluated for transfection efficiency, expression of AFP158-166-specific TCR, interferon (IFN)-γ secretion, and specific cytotoxicity toward AFP+ HCC cells in vitro and in vivo. Flow cytometry revealed the AFP158-166-MHC-Pentamer positive transgenetic CTLs was 9.86 %. The number of IFN-γ secretion T cells and the specific cytotoxicity toward HpeG2 in vitro and in tumor-bearing NOD/SCID mice were significantly raised in transgenetic CTLs than that of AFP158-166-specific CTLs obtained by peptide-pulsed DCs or control group. TCR gene transfer is a promising strategy to generate AFP158-166-specific CTLs for the treatment of HCC.

  2. Optimizing complement-activating antibody-based cancer immunotherapy: a feasible strategy?

    Directory of Open Access Journals (Sweden)

    Maio Michele

    2004-06-01

    Full Text Available Abstract Passive immunotherapy with monoclonal antibodies (mAb targeted to specific tumor-associated antigens is amongst the most rapidly expanding approaches to biological therapy of cancer. However, until now a limited number of therapeutic mAb has demonstrated clinical efficacy in selected neoplasia. Results emerging from basic research point to a deeper characterization of specific biological features of neoplastic cells as crucial to optimize the clinical potential of therapeutic mAb, and to identify cancer patients who represent the best candidates to antibody-based immunotherapy. Focus on the tissue distribution and on the functional role of membrane complement-regulatory proteins such as Protectin (CD59, which under physiologic conditions protects tissues from Complement (C-damage, might help to optimize the efficacy of immunotherapeutic strategies based on C-activating mAb.

  3. Evaluation of effectiveness of specific subcutaneous immunotherapy for patients with allergic rhinitis and asthma

    Directory of Open Access Journals (Sweden)

    Mohammad Reza Zandkarimi

    2013-06-01

    Full Text Available Background: Allergen immunotherapy involves the administration of gradually increasing quantities of specific allergens to patients with IgE-mediated conditions until a dose is reached that is effective in reducing disease severity from natural exposure. This study evaluated the clinical efficacy of immunotherapy with extracts of common aeroallergens North-East of Iran in asthma and allergic rhinitis. Material and Methods: In this prospective study 156 cases were chosen randomley. The mean age of patients was 37 years (range 5-65 years. The patients with mild to moderate asthma and allergic rhinitis and history of atopy were selected for immunotherapy when they showed no effective response to medical treatment.Immunotherapy materials were made from common aeroallergens in north-eastern region of Iran by Dome Hollister US company. Immunotherapy schedule for injection of the extract with vial dilution of 1:10000pg was one injection every week for ten weeks and one injection with dilution of 1:1000pg every other week for the other ten weeks and one injection monthly from dilution of 1:100pg for two years. Results: One hundred twenty (77% of cases had allergic rhinitis 29(18.5% cases had allergic asthma and 7(4.5% cases were mixed. Mean age of patients were 37 years old. 48(30.8% cases were male. Analysis of efficacy of treatment showed that immunotherapy significantlyimproved the signs and symptoms of all the groups. In allergic rhinitis group 84(70% cases completely improved, 22(18.4% patients moderately responded and no response to immunotherapy was observed in 14(11.6% patients. In allergic asthma group, 22(75% cases completely improved 4(13.6% cases moderately responded and no response to immunotherapy was detected in 3(11.4% cases. In mixed group, 3(42.8% cases completely improved, 3(42.8% cases moderately responded and no response was observed in 1(14.4% case. Conclusion: Specific allergen immunotherapy for patients with allergic persistent

  4. Potential for novel MUC1 glycopeptide-specific antibody in passive cancer immunotherapy

    DEFF Research Database (Denmark)

    Madsen, Caroline B; Wandall, Hans H; Pedersen, Anders Elm

    2013-01-01

    MUC1 is an important target for antibodies in passive cancer immunotherapy. Antibodies against mucin glycans or mucin peptide backbone alone may give rise to cross reactivity with normal tissues. Therefore, attempts to identify antibodies against cancer-specific MUC1 glycopeptide epitopes havebeen...... made. We recently demonstrated that a monoclonal antibody against the immunodominant Tn-MUC1 (GalNAc-α-MUC1) antigen induced ADCC in breast cancer cell lines, suggesting the feasibility of targeting combined glycopeptide epitopes in future passive cancer immunotherapy....

  5. Future perspectives in target-specific immunotherapies of myasthenia gravis.

    Science.gov (United States)

    Dalakas, Marinos C

    2015-11-01

    Myasthenia gravis (MG) is an autoimmune disease caused by complement-fixing antibodies against acetylcholine receptors (AChR); antigen-specific CD4+ T cells, regulatory T cells (Tregs) and T helper (Th) 17+ cells are essential in antibody production. Target-specific therapeutic interventions should therefore be directed against antibodies, B cells, complement and molecules associated with T cell signaling. Even though the progress in the immunopathogenesis of the disease probably exceeds any other autoimmune disorder, MG is still treated with traditional drugs or procedures that exert a non-antigen specific immunosuppression or immunomodulation. Novel biological agents currently on the market, directed against the following molecular pathways, are relevant and specific therapeutic targets that can be tested in MG: (a) T cell intracellular signaling molecules, such as anti-CD52, anti-interleukin (IL) 2 receptors, anti- costimulatory molecules, and anti-Janus tyrosine kinases (JAK1, JAK3) that block the intracellular cascade associated with T-cell activation; (b) B cells and their trophic factors, directed against key B-cell molecules; (c) complement C3 or C5, intercepting the destructive effect of complement-fixing antibodies; (d) cytokines and cytokine receptors, such as those targeting IL-6 which promotes antibody production and IL-17, or the p40 subunit of IL-12/1L-23 that affect regulatory T cells; and (e) T and B cell transmigration molecules associated with lymphocyte egress from the lymphoid organs. All drugs against these molecular pathways require testing in controlled trials, although some have already been tried in small case series. Construction of recombinant AChR antibodies that block binding of the pathogenic antibodies, thereby eliminating complement and antibody-depended-cell-mediated cytotoxicity, are additional novel molecular tools that require exploration in experimental MG.

  6. Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAFV600E melanoma

    Science.gov (United States)

    Hu-Lieskovan, Siwen; Mok, Stephen; Moreno, Blanca Homet; Tsoi, Jennifer; Faja, Lidia Robert; Goedert, Lucas; Pinheiro, Elaine M.; Koya, Richard C.; Graeber, Thomas; Comin-Anduix, Begoña; Ribas, Antoni

    2016-01-01

    Combining immunotherapy and BRAF targeted therapy may result in improved antitumor activity with the high response rates of targeted therapy and the durability of responses with immunotherapy. However, the first clinical trial testing the combination of the BRAF inhibitor vemurafenib and the CTLA-4 antibody ipilimumab was terminated early due to substantial liver toxicities. MEK inhibitors can potentiate the MAPK inhibition in BRAF mutant cells, while potentially alleviating the unwanted paradoxical MAPK activation in BRAF wild type cells that lead to side effects when using BRAF inhibitors alone. However, there is the concern of MEK inhibitors being detrimental to T cell functionality. Using a mouse model of syngeneic BRAFV600E driven melanoma, we tested whether addition of the MEK inhibitor trametinib would enhance the antitumor activity of combined immunotherapy with the BRAF inhibitor dabrafenib. Combination of dabrafenib and trametinib with pmel-1 adoptive cell transfer (ACT) showed complete tumor regression, increased T cell infiltration into tumors and improved in vivo cytotoxicity. Single agent dabrafenib increased tumor-associated macrophages and T regulatory cells (Tregs) in tumors, which decreased with the addition of trametinib. The triple combination therapy resulted in increased melanosomal antigen and MHC expression, and global immune-related gene up-regulation. Given the up-regulation of PD-L1 seen with dabrafenib and/or trametinib combined with antigen-specific ACT, we tested combination of dabrafenib, trametinib with anti-PD1 therapy in SM1 tumors, and observed superior anti-tumor effect. Our findings support the testing of triple combination therapy of BRAF and MEK inhibitors with immunotherapy in patients with BRAFV600E mutant metastatic melanoma. PMID:25787767

  7. Specific IgG and its subclass antibodies after immunotherapy with gynandropsis gynandra

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    Latha G

    2005-01-01

    Full Text Available Background : About 10 to 15 % of the Indian population is known to suffer from major allergic disorders such as Asthma, Rhinitis, Atopic Dermatitis and Urticaria. Aeroallergens play a major role in the pathogenesis of respiratory allergic diseases. Among the aeroallergens, pollens are major causative agents. The predominance of pollen allergens necessitate the need to assess the specific immunotherapy (SIT in allergic patients. Objective : To evaluate the effect of immunotherapy based on the presence of IgG and its subclass antibodies towards whole pollen antigen of Gynandropsis gynandra (G.gynandra and its fractions. Material and Methods : A study was conducted in 30 bronchial asthma patients on immunotherapy, by assessing the levels of IgG and its subclasses specific to G. gynandra pollen. Results : There was a significant increase in IgG and its subclass antibodies to whole pollen antigen and its fractions i.e.> 90kD, 46-37kD and 36-32kD after the course of IT. Conclusion : The use of peptide fractions may be more appropriate instead of the whole pollen antigen to test the effect of immunotherapy.

  8. Basophil activation test in the diagnosis and monitoring of mastocytosis patients with wasp venom allergy on immunotherapy

    NARCIS (Netherlands)

    Bidad, Katayoon; Nawijn, Martijn C.; van Oosterhout, Antoon J. M.; van der Heide, Sicco; Oude Elberink, Joanne N. G.

    2014-01-01

    Background There is need for an accurate diagnostic test in mastocytosis patients with wasp venom allergy (WVA) and monitoring of these patients during immunotherapy (IT). In this study, we aimed to evaluate sensitivity and specificity of the Basophil Activation Test (BAT) as a diagnostic and monito

  9. Tolerance induction after specific immunotherapy with pollen allergoids adjuvanted by monophosphoryl lipid A in children.

    Science.gov (United States)

    Rosewich, M; Schulze, J; Eickmeier, O; Telles, T; Rose, M A; Schubert, R; Zielen, S

    2010-06-01

    Specific immunotherapy (SIT) is a well-established and clinically effective treatment for allergic diseases. A pollen allergoid formulated with the T helper type 1 (Th1)-inducing adjuvant monophosphoryl lipid A (MPL) facilitates short-term SIT. Little is known about mechanisms of tolerance induction in this setting. In a prospective study, 34 patients allergic to grass pollen (25 male, nine female, median age 10.2 years) received a total of 44 SIT courses (20 in the first, 24 in the second) with MPL-adjuvanted pollen allergoids. Immunogenicity was measured by levels of specific immunoglobulin G (IgG(grass)) and IgG4(grass) by antibody blocking properties on basophil activation, and by induction of CD4(+), CD25(+) and forkhead box P3 (FoxP3(+)) regulatory T cells (T(reg)). Specific IgG and IgG4 levels increased only slightly in the first year of SIT. In the second year these changes reached significance (P adjuvant MPL needs at least two courses to establish tolerance.

  10. Aluminium in allergen-specific subcutaneous immunotherapy--a German perspective.

    Science.gov (United States)

    Kramer, Matthias F; Heath, Matthew D

    2014-07-16

    We are living in an "aluminium age" with increasing bioavailability of the metal for approximately 125 years, contributing significantly to the aluminium body burden of humans. Over the course of life, aluminium accumulates and is stored predominantly in the lungs, bones, liver, kidneys and brain. The toxicity of aluminium in humans is briefly summarised, highlighting links and possible causal relationships between a high aluminium body burden and a number of neurological disorders and disease states. Aluminium salts have been used as depot-adjuvants successfully in essential prophylactic vaccinations for almost 100 years, with a convincing positive benefit-risk assessment which remains unchanged. However, allergen-specific immunotherapy commonly consists of administering a long-course programme of subcutaneous injections using preparations of relevant allergens. Regulatory authorities currently set aluminium limits for vaccines per dose, rather than per treatment course. Unlike prophylactic vaccinations, numerous injections with higher proportions of aluminium-adjuvant per injection are applied in subcutaneous immunotherapy (SCIT) and will significantly contribute to a higher cumulative life dose of aluminium. While the human body may cope robustly with a daily aluminium overload from the environment, regulatory cumulative threshold values in immunotherapy need further addressing. Based on the current literature, predisposing an individual to an unusually high level of aluminium, such as through subcutaneous immunotherapy, has the potential to form focal accumulations in the body with the propensity to exert forms of toxicity. Particularly in relation to longer-term health effects, the safety of aluminium adjuvants in immunotherapy remains unchallenged by health authorities - evoking the need for more consideration, guidance, and transparency on what is known and not known about its safety in long-course therapy and what measures can be taken to prevent or

  11. Tolerance induction in hemophilia A animal models: battling inhibitors with antigen-specific immunotherapies.

    Science.gov (United States)

    Adair, Patrick; Su, Yan; Scott, David W

    2013-05-01

    Hemophilia A is an X-linked recessive bleeding disorder due to either a lack of or greatly reduced activity in the blood coagulation protein factor VIII (FVIII), due to mutations in the F8 gene. This poses significant challenges for FVIII replacement therapy since hemophilic patients are not immunologically tolerant to the protein. Thus, a proportion of patients who receive plasma-derived or recombinant FVIII replacement therapy develop anti FVIII neutralizing antibodies, known as "inhibitors." These patients require long-term regimens of high dose FVIII administration, which has varying success rates and prohibitive costs. Therefore, therapeutics for tolerance induction in such patients with inhibitors are desired. In this review, we address the current progress of immunotherapies for inducing FVIII specific tolerance in animal models of hemophilia A. Specifically we discuss the beneficial effects of B-cell depletion on immune tolerance induction (ITI), B-cell mediated gene therapy, antigen-coupled lymphocyte therapy, and regulatory T-cell epitopes (Tregitopes).

  12. Extra-thymically induced T regulatory cell subsets: the optimal target for antigen-specific immunotherapy

    Science.gov (United States)

    Verhagen, Johan; Wegner, Anja; Wraith, David C

    2015-01-01

    Antigen-specific immunotherapy aims to selectively restore tolerance to innocuous antigens in cases of autoimmune or allergic disease, without the need for general immune suppression. Although the principle of antigen-specific immunotherapy was discovered more than a century ago, its clinical application to date is limited, particularly in the control of autoimmunity. This has resulted mainly from a lack of in-depth understanding of the underlying mechanism. More recently, the differentiation of extra-thymically induced T regulatory (Treg) cell subsets has been shown to be instrumental in peripheral tolerance induction. Two main types of inducible Treg cells, interleukin-10-secreting or Foxp3+, have now been described, each with distinct characteristics and methods of therapeutic induction. It is crucial, therefore, to identify the suitability of either subset in the control of specific immune disorders. This review explores their natural function, the known mechanisms of therapeutic differentiation of either subset as well as their in vivo functionality and discusses new developments that may aid their use in antigen-specific immunotherapy, with a focus on autoimmune disease. PMID:25716063

  13. Specific immunotherapy with mugwort pollen allergoid reduce bradykinin release into the nasal fluid

    Science.gov (United States)

    Grzanka, Alicja; Jawor, Barbara; Czecior, Eugeniusz

    2016-01-01

    Introduction A pathomechanism of allergic rhinitis is complex. A neurogenic mechanism seems to play a significant role in this phenomenon. Aim The evaluation of influence of specific immunotherapy of mugwort pollen allergic patients on the bradykinin concentration in the nasal lavage fluid. Material and methods The study included 22 seasonal allergic rhinitis patients. Thirty persons with monovalent allergy to mugwort pollen, confirmed with skin prick tests and allergen-specific immunoglobulin E, underwent a 3-year-long allergen immunotherapy with the mugwort extract (Allergovit, Allergopharma, Germany). The control group was composed of 9 persons with polyvalent sensitivity to pollen, who were treated with pharmacotherapy. Before the allergen-specific immunotherapy (AIT) and in subsequent years before the pollen seasons, a provocation allergen test with the mugwort extract was performed, together with collection of nasal fluids, where bradykinin concentration was determined according to Proud method. Results There were similar levels of bradykinin in both groups at baseline prior to therapy (AIT group: 584.0 ±87.2 vs. controls 606.3 ±106.5 pg/ml) and changes after allergen challenge 1112.4 ±334.8 vs. 1013.3 ±305.9 pg/ml as well. The bradykinin concentration in nasal lavage fluid after mugwort challenge in 1 year was lower in the AIT group (824.1 ±184.2 pg/ml vs. 1000.4 ±411.5 pg/l; p < 005) with a further significant decrease after the 2nd and 3rd year of specific immunotherapy. Significant reduction of symptoms and medications use was observed in hyposensitized patients. Conclusions A decreased level of bradykinin as a result of AIT suggests that some of the symptomatic benefits of AIT may be related to the reduced release of bradykinin into nasal secretions. These values correlate with clinical improvement within the course of treatment. PMID:27605897

  14. Lung-derived innate cytokines: new epigenetic targets of allergen-specific sublingual immunotherapy

    Directory of Open Access Journals (Sweden)

    Abbas Pishdadian

    2016-01-01

    Full Text Available Objective(s:Sublingual allergen-specific immunotherapy is a safe and effective method for treatment of IgE-mediated respiratory allergies; however, the underlying mechanisms are not fully understood. This study was planned to test whether sublingual immunotherapy (SLIT can exert epigenetic mechanisms through which the airway allergic responses can be extinguished. Materials and Methods:BALB/c mice were sensitized intraperitoneally and challenged intranasally. Then, they received sublingual treatment with recombinant Che a 2 (rChe a 2, a major allergen of Chenopodium album. After SLIT, allergen-specific antibodies in sera, cytokine profiles of spleen cell cultures, mRNA and protein expression of lung-derived IL-33, IL-25, and TSLP (thymic stromal lymphopoietin, and histone modifications of these three genes were assessed. Results:Following Immunotherapy, systemic immune responses shifted from Th2 to Th1 profile as demonstrated by significant decrease in IgE and IL-4 and substantial increase in IgG2a and IFN-γ. At local site, mRNA and protein levels of lung-derived pro-inflammatory cytokines IL-33 and TSLP were markedly down-regulated following SLIT that was associated with marked enrichment of trimethylated lysine 27 of histone H3 at promoter regions of these two cytokines. Conclusion:In our study, sublingual immunotherapy with recombinant allergen effectively attenuated allergic immune responses, at least partly, by induction of distinct histone modifications at specific loci. Additionally, the lung-derived pro-allergic cytokines IL-33 and TSLP could be promising mucosal candidates for either monitoring allergic conditions or therapeutic approaches.

  15. Specific IgE response to different grass pollen allergen components in children undergoing sublingual immunotherapy

    Directory of Open Access Journals (Sweden)

    Marcucci Francesco

    2012-06-01

    Full Text Available Abstract Background Grass pollen is a major cause of respiratory allergy worldwide and contain a number of allergens, some of theme (Phl p 1, Phl p 2, Phl p 5, and Phl 6 from Phleum pratense, and their homologous in other grasses are known as major allergens. The administration of grass pollen extracts by immunotherapy generally induces an initial rise in specific immunoglobulin E (sIgE production followed by a progressive decline during the treatment. Some studies reported that immunotherapy is able to induce a de novo sensitisation to allergen component previously unrecognized. Methods We investigated in 30 children (19 males and 11 females, mean age 11.3 years, 19 treated with sublingual immunotherapy (SLIT by a 5-grass extract and 11 untreated, the sIgE and sIgG4 response to the different allergen components. Results Significant increases (p  Conclusions These findings confirm that the initial phase of SLIT with a grass pollen extract enhances the sIgE synthesis and show that the sIgE response concerns the same allergen components which induce IgE reactivity during natural exposure.

  16. Regulatory T cells as immunotherapy

    Directory of Open Access Journals (Sweden)

    Benjamin David Singer

    2014-02-01

    Full Text Available Regulatory T cells (Tregs suppress exuberant immune system activation and promote immunologic tolerance. Because Tregs modulate both innate and adaptive immunity, the biomedical community has developed intense interest in using Tregs for immunotherapy. Conditions that require clinical tolerance to improve outcomes—autoimmune disease, solid organ transplantation, and hematopoietic stem cell transplantation—may benefit from Treg immunotherapy. Investigators have designed ex vivo strategies to isolate, preserve, expand, and infuse Tregs. Protocols to manipulate Treg populations in vivo have also been considered. Barriers to clinically feasible Treg immunotherapy include Treg stability, off-cell effects, and demonstration of cell preparation purity and potency. Clinical trials involving Treg adoptive transfer to treat graft versus host disease preliminarily demonstrated the safety and efficacy of Treg immunotherapy in humans. Future work will need to confirm the safety of Treg immunotherapy and establish the efficacy of specific Treg subsets for the treatment of immune-mediated disease.

  17. Allergen-specific immunotherapy provides immediate, long-term and preventive clinical effects in children and adults: the effects of immunotherapy can be categorised by level of benefit -the centenary of allergen specific subcutaneous immunotherapy

    Directory of Open Access Journals (Sweden)

    Jacobsen Lars

    2012-04-01

    Full Text Available Abstract Allergen Specific Immunotherapy (SIT for respiratory allergic diseases is able to significantly improve symptoms as well as reduce the need for symptomatic medication, but SIT also has the capacity for long-term clinical effects and plays a protective role against the development of further allergies and symptoms. The treatment acts on basic immunological mechanisms, and has the potential to change the pathological allergic immune response. In this paper we discuss some of the most important achievements in the documentation of the benefits of immunotherapy, over the last 2 decades, which have marked a period of extensive research on the clinical effects and immunological background of the mechanisms involved. The outcome of immunotherapy is described as different levels of benefit from early reduction in symptoms over progressive clinical effects during treatment to long-term effects after discontinuation of the treatment and prevention of asthma. The efficacy of SIT increases the longer it is continued and immunological changes lead to potential long-term benefits. SIT alone and not the symptomatic treatment nor other avoidance measures has so far been documented as the therapy with long-term or preventive potential. The allergic condition is driven by a subset of T-helper lymphocytes (Th2, which are characterised by the production of cytokines like IL-4, and IL-5. Immunological changes following SIT lead to potential curative effects. One mechanism whereby immunotherapy suppresses the allergic response is through increased production of IgG4 antibodies. Induction of specific IgG4 is able to influence the allergic response in different ways and is related to immunological effector mechanisms, also responsible for the reduced late phase hyperreactivity and ongoing allergic inflammation. SIT is the only treatment which interferes with the basic pathophysiological mechanisms of the allergic disease, thereby creating the potential for

  18. Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAFV600E melanoma

    OpenAIRE

    Hu-Lieskovan, Siwen; Mok, Stephen; Moreno, Blanca Homet; Tsoi, Jennifer; Faja, Lidia Robert; Goedert, Lucas; Pinheiro, Elaine M.; Koya, Richard C; Graeber, Thomas; Comin-Anduix, Begoña; Ribas, Antoni

    2015-01-01

    Combining immunotherapy and BRAF targeted therapy may result in improved antitumor activity with the high response rates of targeted therapy and the durability of responses with immunotherapy. However, the first clinical trial testing the combination of the BRAF inhibitor vemurafenib and the CTLA-4 antibody ipilimumab was terminated early due to substantial liver toxicities. MEK inhibitors can potentiate the MAPK inhibition in BRAF mutant cells, while potentially alleviating the unwanted para...

  19. Glucocorticoid-independent modulation of GR activity: Implications for immunotherapy.

    Science.gov (United States)

    Hapgood, Janet P; Avenant, Chanel; Moliki, Johnson M

    2016-09-01

    Pharmacological doses of glucocorticoids (GCs), acting via the glucocorticoid receptor (GR) to repress inflammation and immune function, remain the most effective therapy in the treatment of inflammatory and immune diseases. Since many patients on GC therapy exhibit GC resistance and severe side-effects, much research is focused on developing more selective GCs and combination therapies, with greater anti-inflammatory potency. GCs mediate their classical genomic transcriptional effects by binding to the cytoplasmic GR, followed by nuclear translocation and modulation of transcription of target genes by direct DNA binding of the GR or its tethering to other transcription factors. Recent evidence suggests, however, that the responses mediated by the GR are much more complex and involve multiple parallel mechanisms integrating simultaneous signals from other receptors, both in the absence and presence of GCs, to shift the sensitivity of a target cell to GCs. The level of cellular stress, immune activation status, or the cell cycle phase may be crucial for determining GC sensitivity and GC responsiveness as well as subcellular localization of the GR and GR levels. Central to the development of new drugs that target GR signaling alone or as add-on therapies, is an in-depth understanding of the molecular mechanisms of GC-independent GR desensitization, priming and activation of the unliganded GR, as well as synergy and cross-talk with other signaling pathways. This review will discuss the information currently available on these topics and their relevance to immunotherapy, as well as identify unanswered questions and future areas of research.

  20. Design of tumour-specific immunotherapies using dendritic cells – analyses of IL15-DC

    OpenAIRE

    Al-Mahdi, Rania Ali Muhsen

    2009-01-01

    Immunotherapy of malignancies aims at activating the patient’s own immune system to fight the tumour affecting the patient. Even though the use of dendritic cells (DC) has shown promising results, the DC vaccination strategy needs improvement, as only few relevant clinical responses could be documented so far. Aim: In this study, the standard protocol to generate monocyte derived DC using GM-CSF and IL-4 was compared to the use of GM-CSF and IL-15. Methods: Monocytes were isolated by plastic ...

  1. The Yin and Yang aspects of IL-27 in induction of cancer-specific T-cell responses and immunotherapy.

    Science.gov (United States)

    Li, Ming-Song; Liu, Zhenzhen; Liu, Jin-Qing; Zhu, Xiaotong; Liu, Zhihao; Bai, Xue-Feng

    2015-01-01

    Accumulating evidences from animal studies have indicated that both endogenous and exogenous IL-27, an IL-12 family of cytokine, can increase antitumor T-cell activities and inhibit tumor growth. IL-27 can modulate Treg responses, and program effector T cells into a unique T-effector stem cell (TSEC) phenotype, which enhances T-cell survival in the tumor microenvironment. However, animal studies also suggest that IL-27 induces molecular pathways such as IL-10, PD-L1 and CD39, which may downregulate tumor-specific T-cell responses. In this review paper, we will discuss the Yin and Yang aspects of IL-27 in the induction of tumor-specific T-cell responses, and the potential impacts of these functions of IL-27 in the design of cancer immunotherapy.

  2. Current issues on sublingual allergen-specific immunotherapy in children with asthma and allergic rhinitis

    Directory of Open Access Journals (Sweden)

    Živković Zorica

    2016-01-01

    Full Text Available In 1993 the European Academy of Allergy and Clinical Immunology was the first official organization to recognize that sublingual administration could be “promising route” for allergic desensitization. A few years later, the World Health Organization recommended this therapy as “a viable alternative to the injection route in adults.” The first meta-analysis showed sublingual allergen specific immunotherapy (SLIT effectiveness for allergic rhinitis and another study showed SLIT can actually help prevent the development of asthma both in adults and in children. The main goal of this review article is to present insight into the most up-to-date understanding of the clinical efficacy and safety of immunotherapy in the treatment of pediatric patients with allergic rhinitis and asthma. A literature review was performed on PubMed from 1990 to 2015 using the terms “asthma,” “allergic rhinitis,” “children,” “allergen specific immune therapy.” Evaluating data from double-blind placebo-controlled randomized clinical trials (DB-PC-RCTs, the clinical efficacy (assessed as the reduction of symptom score and the need of rescue medicament of SLIT for allergic rhinitis and allergic asthma, has been confirmed in various meta-analysis Outcomes such as rhinoconjunctivitis score and medication scores, combined scores, quality of life, days with severe symptoms, immunological endpoints, and safety parameters were all improved in the SLIT-tablet compared with placebo group. SLIT safety has been already proven in many DB-PC-RCTs and real-life settings. In accordance with all of the above mentioned, the goals for future trials and studies are the development of comprehensive guidelines for clinical practice on immunotherapy, embracing all the different potential participants. The importance of allergen immunotherapy is of special relevance in the pediatric age, when the plasticity and modulability of the immune system are maximal, and when

  3. Cancer immunotherapy

    DEFF Research Database (Denmark)

    Cairns, Linda; Aspeslagh, Sandrine; Anichini, Andrea

    2016-01-01

    This report covers the Immunotherapy sessions of the 2016 Organisation of European Cancer Institutes (OECI) Oncology Days meeting, which was held on 15th-17th June 2016 in Brussels, Belgium. Immunotherapy is a potential cancer treatment that uses an individual's immune system to fight the tumour....... In recent years significant advances have been made in this field in the treatment of several advanced cancers. Cancer immunotherapies include monoclonal antibodies that are designed to attack a very specific part of the cancer cell and immune checkpoint inhibitors which are molecules that stimulate...... or block the inhibition of the immune system. Other cancer immunotherapies include vaccines and T cell infusions. This report will summarise some of the research that is going on in this field and will give us an update on where we are at present....

  4. Developments in allergen-specific immunotherapy: from allergen extracts to allergy vaccines bypassing allergen-specific immunoglobulin E and T cell reactivity.

    Science.gov (United States)

    Focke, M; Swoboda, I; Marth, K; Valenta, R

    2010-03-01

    Allergen-specific immunotherapy (SIT) is the only specific and disease-modifying approach for the treatment of allergy but several disadvantages have limited its broad applicability. We argue that the majority of the possible disadvantages of SIT such as unwanted effects, poor efficacy and specificity as well as inconvenient application are related to the poor quality of natural allergen extracts, which are the active ingredients of all currently available allergy vaccines. Because of the progress made in the field of molecular allergen characterization, new allergy vaccines based on recombinant allergens, recombinant hypoallergenic allergen derivatives and allergen-derived T cell peptides have entered clinical testing and hold promise to reduce the side-effects and to increase the specificity as well as the efficacy of SIT. Here, we present a refined immunotherapy concept, which is based on the use of peptides derived from allergen surfaces that exhibit reduced, allergen-specific IgE as well as T cell reactivity. These peptides when fused to non-allergenic carriers give rise to allergen-specific protective IgG responses with T cell help from a non-allergenic carrier molecule. We summarize the experimental data demonstrating that such peptide vaccines can bypass allergen-specific IgE as well as T cell activation and may be administered at high doses without IgE- and T cell-mediated side-effects. Should these peptide vaccines prove efficacious and safe in clinical trials, it may become possible to develop convenient, safe and broadly applicable forms of SIT as true alternatives to symptomatic, drug-based allergy treatment.

  5. 特异性免疫治疗新进展%New Progress of Specific Immunotherapy

    Institute of Scientific and Technical Information of China (English)

    龚舒; 代继宏; 符州

    2011-01-01

    特异性免疫治疗(SIT)作为目前唯一可能根治变应性疾病的治疗方法,不仅可以减轻过敏症状,减少用药,还可阻止自然病程的进展,预防新变应原的产生.近年来舌下SIT因其良好的安全性、有效性和易操作性已在欧洲各国广泛开展.标准化的变应原制剂在国内外逐步应用,已取代非标准化制剂.然而无论是皮下注射还是舌下含服方法,其具体有效剂量、治疗方案、治疗疗程尚待规范统一.随着对其作用机制的不断深入研究,以及以重组变应原为主的新制剂的研发,SIT的应用范围将会进一步扩大,更好地用于变应性疾病的治疗.%Specific immunotherapy(SIT) ,as the only treatment which can treat the underlying cause of the allergic disease ,it is not only able to reduce symptoms and needs for medication, but also prevent the progression of the allergic disease and the development of new sensitivities. During this last decade,sublingual immunotherapy has been widely used in European countries because of its excellent safety, efficacy and comphance. And the introducing of the standardized allergen products is another progress,which allow to replace the non - standardized allergen extracts. However, for both subcutaneous immunotherapy and sublingual immunotherapy, the optimal dosage, the duration and the scheme of the therapy still need to be standardized. The advances in understanding the mechanisms of SIT and the development of the new vaccine such as recombinant allergens will result in more widespread clinical use of SIT,and may allow to be better serve for the management of allergic disease.

  6. Immunotherapy with Allergen Peptides

    Directory of Open Access Journals (Sweden)

    Larché Mark

    2007-06-01

    Full Text Available Specific allergen immunotherapy (SIT is disease-modifying and efficacious. However, the use of whole allergen preparations is associated with frequent allergic adverse events during treatment. Many novel approaches are being designed to reduce the allergenicity of immunotherapy preparations whilst maintaining immunogenicity. One approach is the use of short synthetic peptides which representing dominant T cell epitopes of the allergen. Short peptides exhibit markedly reduced capacity to cross link IgE and activate mast cells and basophils, due to lack of tertiary structure. Murine pre-clinical studies have established the feasibility of this approach and clinical studies are currently in progress in both allergic and autoimmune diseases.

  7. The future of specific immunotherapy: strategies and challenges for the next generation of allergy vaccines.

    Science.gov (United States)

    Sørensen, P

    2011-07-01

    : The use of specific immunotherapy (SIT) for allergic disorders has recently been extended by introduction of a convenient, tablet-based, disease-modifying vaccine against grass pollen allergy. Allergy immunotherapy tablet (AIT) programmes targeting house dust mite and other allergies are currently in late-phase development. Next-generation allergy vaccines can have optimised potency and onset of action without compromising safety or convenience. Key to achieving these objectives is a combination of evidence-based mode-of-action studies and biomarker-centric translational research approaches. This will rely on using biobank and bioinformatics resources for multi-omic characterisations of the 'immunome' of allergic disease. Other important areas are ongoing paediatric trials and long-term studies in adults for further defining the potential role of SIT in allergic disease and primary prevention of asthma. Finally, combining cellular- and serological-based assays, and developments in targeted delivery platforms and component-resolved diagnostics will lead to increased ability to stratify patients, with more personalised diagnosis and treatment.

  8. Non-specific immunity of BCG vaccine: A perspective of BCG immunotherapy

    Directory of Open Access Journals (Sweden)

    Najeeha Talat Iqbal

    2014-01-01

    Full Text Available BCG is a widely used vaccine worldwide for neonates including Pakistan. BCG has more than 90% coverage through the EPI program which was introduced in 1965 in Pakistan. BCG has limited efficacy against the transmissible form of pulmonary tuberculosis in high TB endemic countries. However, BCG vaccination continues in these countries because BCG confers protection against the disseminated form of TB in children. BCG has also shown some protection against leprosy and certain forms of cancers. One reason for such nonspecific protection may be that BCG activates APCs via PAMPS that interacts with TLRs (2, 4 & 8, which initiate the inflammatory cascade thereby recruiting inflammatory cells to the site of infection and providing maturation signals for neutrophils, macrophages and dendritic cells. Such activation may be crucial for restricting the infection at the initial site. Furthermore, activation of the pro-inflammatory cascade also results in expression of adhesion molecules, co-stimulatory molecules as well as MHC class II molecule. MHC class II molecules engage CD4+ cells via the TCR receptor while the adhesion and costimulatory molecules bind to their respective receptors on CD4+ T cells for additional high affinity binding for T cell activation. Although activation of the innate arm may not provide subsequent memory, activation of T cells may introduce a certain level of memory response and therefore, may form a rational basis for BCG immunotherapy. This review, therefore, focuses on the immune activation related to both the innate and adaptive arm of the immune response that has been reported and further explores the utility of BCG immunotherapy related to non TB conditions.

  9. Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF(V600E) melanoma.

    Science.gov (United States)

    Hu-Lieskovan, Siwen; Mok, Stephen; Homet Moreno, Blanca; Tsoi, Jennifer; Robert, Lidia; Goedert, Lucas; Pinheiro, Elaine M; Koya, Richard C; Graeber, Thomas G; Comin-Anduix, Begoña; Ribas, Antoni

    2015-03-18

    Combining immunotherapy and BRAF targeted therapy may result in improved antitumor activity with the high response rates of targeted therapy and the durability of responses with immunotherapy. However, the first clinical trial testing the combination of the BRAF inhibitor vemurafenib and the CTLA4 antibody ipilimumab was terminated early because of substantial liver toxicities. MEK [MAPK (mitogen-activated protein kinase) kinase] inhibitors can potentiate the MAPK inhibition in BRAF mutant cells while potentially alleviating the unwanted paradoxical MAPK activation in BRAF wild-type cells that lead to side effects when using BRAF inhibitors alone. However, there is the concern of MEK inhibitors being detrimental to T cell functionality. Using a mouse model of syngeneic BRAF(V600E)-driven melanoma, SM1, we tested whether addition of the MEK inhibitor trametinib would enhance the antitumor activity of combined immunotherapy with the BRAF inhibitor dabrafenib. Combination of dabrafenib and trametinib with pmel-1 adoptive cell transfer (ACT) showed complete tumor regression, increased T cell infiltration into tumors, and improved in vivo cytotoxicity. Single-agent dabrafenib increased tumor-associated macrophages and T regulatory cells (Tregs) in tumors, which decreased with the addition of trametinib. The triple combination therapy resulted in increased melanosomal antigen and major histocompatibility complex (MHC) expression and global immune-related gene up-regulation. Given the up-regulation of PD-L1 seen with dabrafenib and/or trametinib combined with antigen-specific ACT, we tested the combination of dabrafenib, trametinib, and anti-PD1 therapy in SM1 tumors, and observed superior antitumor effect. Our findings support the testing of triple combination therapy of BRAF and MEK inhibitors with immunotherapy in patients with BRAF(V600E) mutant metastatic melanoma.

  10. Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma

    DEFF Research Database (Denmark)

    Jacobsen, L; Niggemann, B; Dreborg, S;

    2007-01-01

    evaluated the long-term clinical effect and the preventive effect of developing asthma 7-years after termination of SIT. METHODS: One hundred and forty-seven subjects, aged 16-25 years with grass and/or birch pollen allergy was investigated 10 years after initiation of a 3-year course of SIT......BACKGROUND: 3-year subcutaneous specific immunotherapy (SIT) in children with seasonal allergic rhinoconjunctivitis reduced the risk of developing asthma during treatment and 2 years after discontinuation of SIT (5-year follow-up) indicating long-term preventive effect of SIT. OBJECTIVE: We...... with standardized allergen extracts of grass and/or birch or no SIT respectively. Conjunctival provocations were performed outside the season and methacholine bronchial provocations were performed during the season and winter. Asthma was assessed by clinical evaluation. RESULTS: The significant improvements...

  11. [Placebo effect in clinical trials with allergen-specific immunotherapy with inhalant allergens].

    Science.gov (United States)

    Wedi, B; Wieczorek, D; Kapp, A

    2017-04-01

    Placebo effects play an important role in the treatment of allergic diseases. Therefore, in this study, we analysed the described effects of placebo in all double-blind placebo-controlled clinical trials of allergen-specific immunotherapy (ASIT) with inhalant allergens (birch, grass, house dust mites) listed in the tables (updated July 2016) attached to the German S2k guideline on allergen-specific immunotherapy in IgE-mediated allergic diseases. The most common placebo consisted of verum without allergen, but when the subcutaneous route was used, histamine was sometimes added. From the 33 studies analysed no conclusions could be drawn regarding the pure placebo effect. The symptom medication score (SMS) from an adequate baseline period was described in one single study. An untreated population was not included in any study. Indirect evidence points to substantial placebo effects in up to 77% of the subjects with respect to retrospective, subjective parameters. Well-known factors influencing the placebo effect such as age, gender, application route/composition of the placebo, individual and cultural differences, severity of symptoms at the beginning and the probability of receiving verum have not been addressed regarding ASIT and could not be estimated from available data. Taken together regarding ASIT the placebo effect has been investigated inadequately. In spite of significant expenditure of time and costs future ASIT studies should include assessment of the SMS in an adequate baseline period and preferably include an untreated trial arm. A better understanding of placebo effects in ASIT trials will improve the design of clinical trials and the assessment of therapeutic effects.

  12. Clinical practice recommendations for allergen-specific immunotherapy in children: the Italian consensus report.

    Science.gov (United States)

    Pajno, Giovanni Battista; Bernardini, Roberto; Peroni, Diego; Arasi, Stefania; Martelli, Alberto; Landi, Massimo; Passalacqua, Giovanni; Muraro, Antonella; La Grutta, Stefania; Fiocchi, Alessandro; Indinnimeo, Luciana; Caffarelli, Carlo; Calamelli, Elisabetta; Comberiati, Pasquale; Duse, Marzia

    2017-01-23

    Allergen-specific immunotherapy (AIT) is currently recognized as a clinically effective treatment for allergic diseases, with a unique disease-modifying effect. AIT was introduced in clinical practice one century ago, and performed in the early years with allergenic extracts of poor quality and definition. After the mechanism of allergic reaction were recognized, the practice of AIT was refined, leading to remarkable improvement in the efficacy and safety profile of the treatment. Currently AIT is accepted and routinely prescribed worldwide for respiratory allergies and hymenoptera venom allergy. Both the subcutaneous (SCIT) and sublingual (SLIT) routes of administration are used in the pediatric population.AIT is recommended in allergic rhinitis/conjunctivitis with/without allergic asthma, with an evidence of specific IgE-sensitization towards clinically relevant inhalant allergens. Long-term studies provided evidence that AIT can also prevent the onset of asthma and of new sensitizations. The favorable response to AIT is strictly linked to adherence to treatment, that lasts 3-5 years. Therefore, several factors should be carefully evaluated before starting this intervention, including the severity of symptoms, pharmacotherapy requirements and children and caregivers' preference and compliance.In recent years, there have been increasing interest in the role of AIT for the treatment of IgE-associated food allergy and extrinsic atopic dermatitis. A growing body of evidence shows that oral immunotherapy represents a promising treatment option for IgE-associated food allergy. On the contrary, there are still controversies on the effectiveness of AIT for patients with atopic dermatitis.This consensus document was promoted by the Italian Society of Pediatric Allergy and Immunology (SIAIP) to provide evidence-based recommendations on AIT in order to implement and optimize current prescription practices of this treatment for allergic children.

  13. Association of subcutaneous allergen-specific immunotherapy with incidence of autoimmune disease, ischemic heart disease, and mortality

    DEFF Research Database (Denmark)

    Linneberg, Allan; Jacobsen, Rikke Kart; Jespersen, Lasse;

    2012-01-01

    Subcutaneous allergen-specific immunotherapy (SCIT) is a well-documented treatment of IgE-mediated allergic disease. Little is known about potential effects of SCIT on the risk of other chronic immune-related diseases. Over the years, a few casuistic reports have caused concern that SCIT might ac...... as a trigger of autoimmune disease....

  14. European Academy of Allergy and Clinical Immunology task force report on 'dose-response relationship in allergen-specific immunotherapy'

    DEFF Research Database (Denmark)

    Calderón, M A; Larenas, D; Kleine-Tebbe, J;

    2011-01-01

    For a century, allergen-specific immunotherapy (SIT) has proven to be an effective treatment for allergic rhinitis, asthma, and insect sting allergy. However, as allergen doses are frequently adapted to the individual patient, there are few data on dose-response relationship in SIT. Allergen prod...

  15. The effect of specific immunotherapy on NK cell activity and the expression of basophil in children with asthma%特异性免疫治疗哮喘患儿NK细胞活性和嗜碱性细胞表达变化的影响

    Institute of Scientific and Technical Information of China (English)

    张慧娟; 董一慧; 袁显文

    2016-01-01

    目的 探讨特异性免疫治疗哮喘患儿自然杀伤细胞(natural killer cell,NK)活性和嗜碱性细胞表达变化的影响.方法 回顾性分析本院2012年12月至2014年12月收治的97例哮喘息儿的临床资料,按照治疗方法分为对照组(47例)和观察组(50例),分别给予常规治疗和特异性免疫治疗.观察两组的NK细胞活性和嗜碱性细胞表达变化,并进行比较.结果 治疗前,两组患者的NK细胞活性与嗜碱性细胞表达水平经比较差异无统计学意义(P<0.05);经过不同的治疗之后,观察组和对照组的NK细胞活性分别为(12.12±1.51)%、(10.10±2.10)%,较之本组治疗前均得到显著的提高(P<0.05);治疗后两组比较差异有统计学意义(P<0.05).观察组和对照组的嗜碱性细胞表达水平分别为(0.41±0.11)%、(0.51±0.15)%,较之本组治疗前均得到显著的下降(P<0.05);治疗后两组比较差异有统计学意义(P<0.05).结论 特异性免疫治疗哮喘患儿可以显著增强其NK细胞活性,并降低嗜碱性细胞的表达水平.%Objective To investigate the effect of specific immunotherapy on natural killer cell (NK cell) activity and the expression of basophil in asthmatic children.Methods A retrospective analysis was performed on clinical data of 97 children with asthma in our hospital from December 2013 to December 2014,and they were divided into control group (47 cases) and observation group (50 cases) according to treatment methods,and were given conventional therapy and specific immunotherapy respectively.The changes of NK cell activity and the expression of basophil in two groups were observed and compared.Results Before treatment,there were no statistically significant differences in NK cell activity and the expression of basophil between two groups (P>0.05);after treatment,NK cell activity in observation group and control group were (12.12±1.51)% and (10.10±2.10)% respectively,improved significantly compared

  16. Activation of matrix metalloproteinases following anti-Aβ immunotherapy; implications for microhemorrhage occurrence

    Directory of Open Access Journals (Sweden)

    Ridnour Lisa A

    2011-09-01

    Full Text Available Abstract Background Anti-Aβ immunotherapy is a promising approach to the prevention and treatment of Alzheimer's disease (AD currently in clinical trials. There is extensive evidence, both in mice and humans that a significant adverse event is the occurrence of microhemorrhages. Also, vasogenic edema was reported in phase 2 of a passive immunization clinical trial. In order to overcome these vascular adverse effects it is critical that we understand the mechanism(s by which they occur. Methods We have examined the matrix metalloproteinase (MMP protein degradation system in two previously published anti-Aβ immunotherapy studies. The first was a passive immunization study in which we examined 22 month old APPSw mice that had received anti-Aβ antibodies for 1, 2 or 3 months. The second is an active vaccination study in which we examined 16 month old APPSw/NOS2-/- mice treated with Aβ vaccination for 4 months. Results There is a significant activation of the MMP2 and MMP9 proteinase degradation systems by anti-Aβ immunotherapy, regardless of whether this is delivered through active vaccination or passive immunization. We have characterized this activation by gene expression, protein expression and zymography assessment of MMP activity. Conclusions Since the MMP2 and MMP9 systems are heavily implicated in the pathophysiology of intracerbral hemorrhage, these data may provide a potential mechanism of microhemorrhage due to immunotherapy. Increased activity of the MMP system, therefore, is likely to be a major factor in increased microhemorrhage occurrence.

  17. Debates in allergy medicine: specific immunotherapy efficiency in children with atopic dermatitis

    Directory of Open Access Journals (Sweden)

    Tatiana A. Slavyanakaya

    2016-04-01

    Full Text Available Abstract Allergen specific immunotherapy (AIT has been the only pathogenetically relevant treatment of IgE-mediated allergic diseases (ADs for many years. The use of AIT for atopic dermatitis (AD treatment is dubious and has both followers and opponents. The improvement of subcutaneous AIT (SCIT and introduction of Sublingual immunotherapy (SLIT gives prospects of their application both for adults and children suffering from AD. This review presents results of scientific research, system and meta-analyses that confirm the clinical efficacy of AIT for children with AD who has the sensitization to allergens of house dust mite, grass and plant pollen suffering from co-occurring respiratory ADs and with moderate and severe course of allergic AD. There have been analyzed the most advanced achievements in AIT studies as well as there have been specified the unmet needs in AD. The preliminary diagnostics of IgE-mediated AD and pathophysiological disorders, including immune ones, will allow a doctor to develop appropriate comprehensive treatment algorithm for children’s AD aimed at its correction. The including of AIT to the children’s comprehensive therapy program is reasonable only if AD has the allergic form. It is necessary better to design the randomized research studies and to acquire extended clinical practice in children with AD. Use of the successes of molecular-based allergy diagnostics will help to optimize and personalize the process of selecting the necessary allergens to determine the most appropriate vaccines for children considering the results of the allergen component diagnostics. The strategy of treatment of children with AD in future will be based on individual target therapy.

  18. Mechanisms of Allergen-Specific Immunotherapy and Novel Ways for Vaccine Development

    Directory of Open Access Journals (Sweden)

    Marek Jutel

    2013-01-01

    Full Text Available Allergen-specific immunotherapy (SIT is the only available curative treatment of allergic diseases. Recent evidence provided a plausible explanation to its multiple mechanisms inducing both rapid desensitization and long-term allergen-specific immune tolerance, and suppression of allergic inflammation in the affected tissues. During SIT, peripheral tolerance is induced by the generation of allergen-specific regulatory T cells, which suppress proliferative and cytokine responses against the allergen of interest. Regulatory T cells are characterized by IL-10 and TGF-beta secretion and expression of important cell surface suppressive molecules such as cytotoxic T lymphocyte antigen-4 and programmed death-1 that directly or indirectly influence effector cells of allergic inflammation, such as mast cells, basophils and eosinophils. Regulatory T cells and particularly IL-10 also have an influence on B cells, suppressing IgE production and inducing the production of blocking type IgG4 antibodies. In addition, development of allergen-specific B regulatory cells that produce IL-10 and develop into IgG4 producing plasma cells represent essential players in peripheral tolerance. These findings together with the new biotechnological approaches create a platform for development of the advanced vaccines. Moreover, reliable biomarkers could be selected and validated with the intention to select the patients who will benefit most from this immune-modifying treatment. Thus, allergen-SIT could provide a complete cure for a larger number of allergic patients and novel preventive approaches need to be elaborated.

  19. Inmunoterapia activa en el tratamiento de neoplasias hematológicas Active immunotherapy in the treatment of haematological neoplasias

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    S. Inogés

    2004-04-01

    Full Text Available La continua búsqueda de abordajes terapéuticos que mejoren los tratamientos convencionales de las enfermedades neoplásicas junto con el mejor conocimiento del sistema inmunitario ha llevado en los últimos años al desarrollo de la inmunoterapia. Básicamente se pueden distinguir dos formas de inmunoterapia: la inmunoterapia pasiva, que consiste en la transferencia de anticuerpos o células previamente generados in vitro que se dirigen contra el tumor, y la inmunoterapia activa, que pretende activar in vivo el sistema inmunitario e inducirlo a elaborar una respuesta específica contra los antígenos tumorales. Las neoplasias hematológicas, concretamente algunos linfomas B, expresan en su membrana una inmunoglobulina que se considera un verdadero antígeno específico de tumor; por eso estas enfermedades se han convertido en la diana ideal de los tratamientos de inmunoterapia. Las alternativas son muchas, desde las vacunas proteicas que ya han demostrado beneficios clínicos, hasta las de segunda generación, que aprovechan las nuevas técnicas de biología molecular para aumentar la eficacia de las vacunas y conseguir su producción de forma más rápida y menos costosa, pero con las que todavía no hay resultados clínicos definitivos.The continuous search for therapeutic approaches that improve the conventional treatments of neoplasms, together with an improved understanding of the immune system, has led in recent years to the development of Immunotherapy. Basically, a distinction can be made between two forms of immunotherapy: passive immunotherapy, which consists in the transfer of antibodies or cells previously generated in vitro that are directed against the tumour, and active immunotherapy, which attempts to activate in vivo the immune system and induce it to elaborate a specific response against the tumor antibodies. Hematological neoplasms, specifically some B lymphomas, express in their membrane an immunoglobulin that is considered

  20. Safety of allergen-specific immunotherapy. Relation between dosage regimen, allergen extract, disease and systemic side-effects during induction treatment

    DEFF Research Database (Denmark)

    Mellerup, M T; Hahn, G W; Poulsen, Lars K.;

    2000-01-01

    Allergen-specific immunotherapy is a well-documented treatment for allergic rhinitis, asthma, and allergy to Hymenoptera venoms. The drawbacks of injection immunotherapy are related to the risk of inducing systemic side-effects (especially during the induction phase), the time used to reach...

  1. MAGE-A Antigens and Cancer Immunotherapy

    Science.gov (United States)

    Zajac, Paul; Schultz-Thater, Elke; Tornillo, Luigi; Sadowski, Charlotte; Trella, Emanuele; Mengus, Chantal; Iezzi, Giandomenica; Spagnoli, Giulio C.

    2017-01-01

    MAGE-A antigens are expressed in a variety of cancers of diverse histological origin and germinal cells. Due to their relatively high tumor specificity, they represent attractive targets for active specific and adoptive cancer immunotherapies. Here, we (i) review past and ongoing clinical studies targeting these antigens, (ii) analyze advantages and disadvantages of different therapeutic approaches, and (iii) discuss possible improvements in MAGE-A-specific immunotherapies. PMID:28337438

  2. Human Leukocyte Antigen-G and Regulatory T Cells during Specific Immunotherapy for Pollen Allergy

    DEFF Research Database (Denmark)

    Sørensen, Anja Elaine; Johnsen, Claus R; Dalgaard, Louise Torp;

    2013-01-01

    with pollen extract in vitro and immune factors were evaluated. Results: During SIT, the main changes in the peripheral blood were an increase in CXCR3+CD4+CD25+CD127low/- Tregs and a decrease in CCR4+CD4+CD25+CD127low/- Tregs, an increase in allergen-specific IgG4, and a decrease in sHLA-G during the first......Background: TH2-biased immune responses are important in allergy pathogenesis. Mechanisms of allergen-specific immunotherapy (SIT) might include the induction of regulatory T cells (Tregs) and immunoglobulin (Ig) G4 blocking antibodies, a reduction in the number of effector cells, and skewing...... of the cytokine profile towards a TH1-polarized immune response. We investigated the effects of SIT on T cells, on immunomodulation of human leukocyte antigen (HLA)-G, which has been associated with allergy, on regulatory cytokine expression, and on serum allergen-specific antibody subclasses (IgE and IgG4...

  3. Specific immunotherapy in combination with Clostridium butyricum inhibits allergic inflammation in the mouse intestine.

    Science.gov (United States)

    Shi, Yanhong; Xu, Ling-Zhi; Peng, Kangsheng; Wu, Wei; Wu, Ruijin; Liu, Zhi-Qiang; Yang, Gui; Geng, Xiao-Rui; Liu, Jun; Liu, Zhi-Gang; Liu, Zhanju; Yang, Ping-Chang

    2015-12-02

    The current therapy on allergic inflammation is unsatisfactory. Probiotics improve the immunity in the body. This study aims to test a hypothesis that administration with Clostridium butyricum (C. butyricum) enforces the effect of specific immunotherapy (SIT) on intestinal allergic inflammation. In this study, an ovalbumin (OVA) specific allergic inflammation mouse model was created. The mice were treated with SIT or/and C. butyricum. The results showed that the intestinal allergic inflammation was only moderately alleviated by SIT, which was significantly enforced by a combination with C. butyricum; treating with C. butyricum alone did not show much inhibitory efficacy. The increase in the frequency of the interleukin (IL)-10-producing OVA-specific B cell (OVAsBC) was observed in mice in parallel to the inhibitory effect on the intestinal allergic inflammation. The in vitro treatment of the OVAsBCs with OVA increased the histone deacetylase-1 (HDAC1) phosphorylation, modulated the transcription of the Bcl6 gene, and triggered the OVAsBCs to differentiate to the IgE-producing plasma cells. Exposure to both OVA and butyrate sodium in the culture increased the expression of IL-10 in OVAsBCs. In conclusion, administration with C. butyricum enforces the inhibitory effect of SIT on allergic inflammation in the mouse intestine.

  4. Influenza virus-specific TCR-transduced T cells as a model for adoptive immunotherapy.

    Science.gov (United States)

    Berdien, Belinda; Reinhard, Henrike; Meyer, Sabrina; Spöck, Stefanie; Kröger, Nicolaus; Atanackovic, Djordje; Fehse, Boris

    2013-06-01

    Adoptive transfer of T lymphocytes equipped with tumor-antigen specific T-cell receptors (TCRs) represents a promising strategy in cancer immunotherapy, but the approach remains technically demanding. Using influenza virus (Flu)-specific T-cell responses as a model system we compared different methods for the generation of T-cell clones and isolation of antigen-specific TCRs. Altogether, we generated 12 CD8(+) T-cell clones reacting to the Flu matrix protein (Flu-M) and 6 CD4(+) T-cell clones reacting to the Flu nucleoprotein (Flu-NP) from 4 healthy donors. IFN-γ-secretion-based enrichment of antigen-specific cells, optionally combined with tetramer staining, was the most efficient way for generating T-cell clones. In contrast, the commonly used limiting dilution approach was least efficient. TCR genes were isolated from T-cell clones and cloned into both a previously used gammaretroviral LTR-vector, MP91 and the novel lentiviral self-inactivating vector LeGO-MP that contains MP91-derived promotor and regulatory elements. To directly compare their functional efficiencies, we in parallel transduced T-cell lines and primary T cells with the two vectors encoding identical TCRs. Transduction efficiencies were approximately twice higher with the gammaretroviral vector. Secretion of high amounts of IFN-γ, IL-2 and TNF-α by transduced cells after exposure to the respective influenza target epitope proved efficient specificity transfer of the isolated TCRs to primary T-cells for both vectors, at the same time indicating superior functionality of MP91-transduced cells. In conclusion, we have developed optimized strategies to obtain and transfer antigen-specific TCRs as well as designed a novel lentiviral vector for TCR-gene transfer. Our data may help to improve adoptive T-cell therapies.

  5. Allergen-specific immunotherapy: towards combination vaccines for allergic and infectious diseases.

    Science.gov (United States)

    Edlmayr, Johanna; Niespodziana, Katarzyna; Focke-Tejkl, Margarete; Linhart, Birgit; Valenta, Rudolf

    2011-01-01

    IgE-mediated allergies affect more than 25% of the population. Allergen-specific immunotherapy (SIT) is an antigen-specific and disease-modifying form of treatment. It is based on the therapeutic administration of the disease-causing allergens to allergic patients. However, the fact that only allergen extracts of insufficient quality are currently available and the possible occurrence of side effects during treatment limit the broad use of SIT and prophylactic vaccination is has not yet been performed. In the last 20 years the DNA sequences of the most common allergens have been isolated and the corresponding allergens have been produced as recombinant allergens. Based on the progress made in the field of allergen characterization it is possible to improve the quality and safety of allergy vaccines and to develop new, more effective strategies for a broad application of SIT and even for prophylactic treatment. Here we discuss the development of combination vaccines for allergy and infectious diseases. This approach is based on the selection of allergen-derived peptides with reduced IgE- and T cell reactivity in order to minimize IgE- and T cell-mediated side effects as well as the potential of the vaccine to induce allergic sensitization. These peptides are fused by recombinant technology onto a viral carrier protein to obtain a combination vaccine which induces protective immunity against allergy and viral infections. The application of such combination vaccines for therapy and prophylaxis of allergy and infectious diseases is discussed.

  6. Vitamin D3 inhibits micro RNA-17-92 to promote specific immunotherapy in allergic rhinitis.

    Science.gov (United States)

    Yu, Zhi-Jian; Zeng, Lu; Luo, Xiang-Qian; Geng, Xiao-Rui; Xu, Rui; Chen, Kun; Yang, Gui; Luo, Xi; Liu, Zhi-Qiang; Liu, Zhi-Gang; Liu, Da-Bo; Yang, Ping-Chang; Li, Hua-Bin

    2017-04-03

    It is recognized that T helper 2 (Th2) polarization plays a critical role in a large number of immune disorders. Yet, the remedies for reconciling the established Th2 polarization are still limited currently. Published data indicate that micro RNA-17-92 cluster is associated with the skewed immune response; 25 vitamin D3 (VD3) can regulate multiple bioactivities in the body. This study tests a hypothesis that VD3 facilitates the effect of specific immunotherapy (SIT) on Th2 response. We observed that treatment with either SIT or VD3 alleviated AR symptoms as well as reduced serum levels of specific IgE and T helper (Th) 2 cytokines, suppressed miR-19a (one of the members of the miR-17-92 cluster) and increased IL-10 in peripheral B cells, which was further improved in those AR patients treated with both SIT and VD3. The expression of miR-19a and IL-10 was significantly negatively correlated with each other in peripheral B cells of AR patients. Metabolites of VD3 formed a complex with retinoid acid receptor to repress the expression of miR-19a in B cells. We conclude that administration with VD3 promotes the effect of SIT on suppression of AR via repressing the expression of miR-19a in peripheral B cells.

  7. Oral glucocorticoids diminish the efficacy of allergen-specific immunotherapy in experimental feline asthma.

    Science.gov (United States)

    Chang, Chee-hoon; Cohn, Leah A; Declue, Amy E; Liu, Hong; Reinero, Carol R

    2013-08-01

    Allergen-specific rush immunotherapy (RIT) shows promise in treating asthma; however, pet cats will likely require at least initial concurrent glucocorticoids (GCs) to control serious clinical signs. How the immunosuppressive effects of GCs would impact RIT in cats is unknown. The hypothesis of this study was that oral, but not inhaled GCs will diminish the efficacy of RIT in experimental feline asthma. Cats (n=6/group) were sensitized using Bermuda grass allergen (BGA) and randomized to receive BGA-specific RIT for 9 months with an oral GC (prednisolone 10mg daily), inhaled GC (fluticasone 220 μg twice daily), or placebo administered for the first 6 months. Bronchoalveolar lavage fluid (BALF) percent eosinophils and other immunological assays were performed. Eosinophilic airway inflammation was suppressed in all groups at month 6 of RIT (group mean ± SD, 5 ± 2%, 13 ± 4%, and 7 ± 2% for oral GC, inhaled GC, and placebo, respectively; P=0.291). BALF percent eosinophils significantly increased over time only in oral GC/RIT cats between months 6 and 9 (P=0.031). Placebo/RIT cats had significant decreases over time in BGA-specific serum IgE (P=0.031). Concentration of interleukin (IL)-5 in BALF significantly increased over time in inhaled GC/RIT cats (P=0.031). No significant differences were found between groups at month 6 or over time in each group for BGA-specific lymphocyte blastogenesis, percent blood T regulatory cells, or number of IL-10-producing cells. Given the significant increase of airway eosinophilia over time in RIT cats initially treated with an oral GC, inhaled GCs might be better for dampening eosinophilic inflammation until RIT normalizes the dysregulated immune system.

  8. FoxP3 Tregs Response to Sublingual Allergen Specific Immunotherapy in Children Depends on the Manifestation of Allergy

    Directory of Open Access Journals (Sweden)

    Anna Stelmaszczyk-Emmel

    2015-01-01

    Full Text Available Over the last decades allergic diseases has become a major health problem worldwide. The only specific treatment to date is allergen specific immunotherapy (ASIT. Although it was shown that ASIT generates allergen-tolerant T cells, detailed mechanism underlying its activity is still unclear and there is no reliable method to monitor its effectiveness. The aim of our study was to evaluate ASIT influence on the frequency of forkhead box P3 (FoxP3 Tregs in allergic children with various clinical manifestations. The relative number of FoxP3 Tregs in 32 blood samples from allergic children at baseline and/or after 1 year of ASIT was assessed by flow cytometry. In the entire studied group, the percentage of FoxP3 Tregs did not increase 1 year after ASIT. Nevertheless, the percentage of FoxP3 Tregs after ASIT significantly increased in children with respiratory allergy (conjunctivitis, asthma, and rhinitis coexisting with nonrespiratory manifestations (food allergy and/or atopic dermatitis, whereas, in patients with respiratory allergy only, the percentage of FoxP3 Tregs decreased. To the best of our knowledge, this is the first report showing various differential FoxP3 Tregs response to ASIT in allergic children. FoxP3 Tregs number could be useful in treatment monitoring. Further studies are warranted to confirm these observations.

  9. Specific immunotherapy for common grass pollen allergies: pertinence of a five grass pollen vaccine.

    Science.gov (United States)

    Moingeon, Philippe; Hrabina, Maud; Bergmann, Karl-Christian; Jaeger, Siegfried; Frati, Franco; Bordas, Véronique; Peltre, Gabriel

    2008-01-01

    Patients throughout Europe are concomitantly exposed to multiple pollens from distinct Pooideae species. Given the overlap in pollination calendars and similar grain morphology, it is not possible to identify which grass species are present in the environment from pollen counts. Furthermore, neither serum IgE reactivity nor skin prick testing allow the identification of which grass species are involved in patient sensitisation. Due to their high level of amino acid sequence homology (e.g., >90% for group 1, 55-80% for group 5), significant cross-immunogenicity is observed between allergens from Pooideae pollens. Nevertheless, pollen allergens also contain species-specific T or B cell epitopes, and substantial quantitative differences exist in allergen (e.g., groups 1 and 5) composition between pollens from distinct grass species. In this context, a mixture of pollens from common and well-characterised Pooideae such as Anthoxanthum odoratum, Dactylis glomerata, Lolium perenne, Phleum pratense and Poa pratensis is suitable for immunotherapy purposes because (1) it has been validated, both in terms of safety and efficacy, by established clinical practice; (2) it reflects natural exposure and sensitisation conditions; (3) it ensures a consistent and well-balanced composition of critical allergens, thus extending the repertoire of T and B cell epitopes present in the vaccine.

  10. Basophil sensitivity through CD63 or CD203c is a functional measure for specific immunotherapy

    Directory of Open Access Journals (Sweden)

    Dahl Ronald

    2010-02-01

    Full Text Available Abstract Background Subcutaneous Immunotherapy (SCIT modifies the allergic response and relieves allergic symptoms. SCIT is the only and a very effective treatment for insect venom allergy. We hypothesized that basophil sensitivity, measured through the basophil activation test, would decrease during SCIT up dosing. Expression of CD203c was compared to CD63 as marker for basophil activation, using a Bland Altman plot and ROC curves. Methods Patients (n = 18 starting subcutaneous SCIT for wasp allergy with an up dosing scheme of 7 to 11 weeks were enrolled. Heparinised blood samples were drawn at weeks 1-4, 7 and at the first maintenance visit. Basophils were stimulated at 7 log dilutions of V. vespula allergen for 15 min, and were stained with CD203c and CD63. Basophils were identified as CD203c+ leukocytes, and the proportion of CD63+ and CD203c+ cells were plotted against allergen concentration. A sigmoid curve was fitted to the points, and the allergen concentration at which half of the maximal activation was achieved, LC50, was calculated. In another series of experiments, LC50 calculated in whole blood (AP was subtracted from LC50 calculated with basophils suspended in plasma from a nonatopic donor (HS to determine the protective effect of soluble factors in blood of patients treated with SCIT. Results Heparin blood basophil activation was similar through CD63 and CD203c. Basophils were significantly more sensitized three weeks after initiation of SCIT compared to baseline (p Conclusion Basophil activation is a versatile and sensitive tool that measures changes in the humoral immune response to allergen during SCIT.

  11. T Cell Epitope Immunotherapy Induces a CD4+ T Cell Population with Regulatory Activity

    Directory of Open Access Journals (Sweden)

    Verhoef Adrienne

    2005-01-01

    Full Text Available Background Synthetic peptides, representing CD4+ T cell epitopes, derived from the primary sequence of allergen molecules have been used to down-regulate allergic inflammation in sensitised individuals. Treatment of allergic diseases with peptides may offer substantial advantages over treatment with native allergen molecules because of the reduced potential for cross-linking IgE bound to the surface of mast cells and basophils. Methods and Findings In this study we address the mechanism of action of peptide immunotherapy (PIT in cat-allergic, asthmatic patients. Cell-division-tracking dyes, cell-mixing experiments, surface phenotyping, and cytokine measurements were used to investigate immunomodulation in peripheral blood mononuclear cells (PBMCs after therapy. Proliferative responses of PBMCs to allergen extract were significantly reduced after PIT. This was associated with modified cytokine profiles generally characterised by an increase in interleukin-10 and a decrease in interleukin-5 production. CD4+ cells isolated after PIT were able to actively suppress allergen-specific proliferative responses of pretreatment CD4neg PBMCs in co-culture experiments. PIT was associated with a significant increase in surface expression of CD5 on both CD4+ and CD8+ PBMCs. Conclusion This study provides evidence for the induction of a population of CD4+ T cells with suppressor/regulatory activity following PIT. Furthermore, up-regulation of cell surface levels of CD5 may contribute to reduced reactivity to allergen.

  12. Rush allergen specific immunotherapy protocol in feline atopic dermatitis: a pilot study of four cats.

    Science.gov (United States)

    Trimmer, Ann M; Griffin, Craig E; Boord, Mona J; Rosenkrantz, Wayne S

    2005-10-01

    Rush immunotherapy has been shown to be as safe as conventional immunotherapy in canine atopic patients. Rush immunotherapy has not been reported in the feline atopic patient. The purpose of this pilot study was to determine a safe protocol for rush immunotherapy in feline atopic patients. Four atopic cats diagnosed by history, physical examination and exclusion of appropriate differential diagnoses were included in the study. Allergens were identified via liquid phase immunoenzymatic testing (VARL: Veterinary Allergy Reference Labs, Pasadena, CA). Cats were premedicated with 1.5 mg triamcinolone orally 24 and 2 h prior to first injection and 10 mg hydroxyzine PO 24, 12 and 2 h prior to first injection. An intravenous catheter was placed prior to first injection. Allergen extracts (Greer Laboratories, Lenoir, North Carolina) were all administered subcutaneously at increasing protein nitrogen units (pnu) every 30 minutes for 5 h to maintenance dose of 15,000 pnus ml-1. Vital signs were assessed every 15 minutes. Two cats developed mild pruritus and the subsequent injection was delayed 30 minutes. No changes in either cat's vital signs were noted, nor was there any further pruritus. All four cats successfully completed rush immunotherapy. Two cats developed a dermal swelling on the dorsal neck one week later. In these four cats, this protocol appeared to be a safe regimen to reach maintenance therapy. A larger sample of feline patients is needed to determine the incidence of adverse reactions and to follow the success of ASIT based upon this method of induction.

  13. Effectiveness of Specific Sublingual Immunotherapy in Korean Patients with Atopic Dermatitis

    Science.gov (United States)

    You, Hyang-Suk; Yang, Min-Young; Kim, Gun-Wook; Cho, Hyun-Ho; Kim, Won-Jeong; Mun, Je-Ho; Song, Margaret; Kim, Hoon-Soo; Ko, Hyun-Chang; Kim, Moon-Bum

    2017-01-01

    Background Sublingual immunotherapy (SLIT) with house dust mites (HDM) preparation has recently been proven to be beneficial for treating allergic rhinitis and asthma. However, there has been no report regarding the efficacy and safety of SLIT in Korean patients with atopic dermatitis (AD). Objective We intended to investigate the efficacy and safety of SLIT in Korean patients with AD. Methods A total of 34 patients with AD and immunoglobulin E (IgE)-proven HDM sensitization (Class ≥3) were recruited. Eczema area and severity index (EASI) score, total serum IgE level, specific IgE assays to Dermatophagoides pteronyssinus, D. farinae, and adverse effects were recorded during follow-up. "Responder" was defined as a patient with ≥30% improvement in EASI score after SLIT. Results Twenty-three patients continued SLIT for 12 months or more, whereas 3 patients (8.8%) dropped out because of exacerbation of dermatitis, and 8 patients (23.5%) were lost to follow-up. The average duration of SLIT treatment was 22.4 months (range, 12~32 months). EASI scores reduced significantly after 6 months of treatment (p<0.05) compared with those at baseline. A total of 18 patients were determined to be responders to SLIT after 6 months. Total and specific IgE serum levels did not significantly reduce after SLIT. No patients experienced serious adverse events, with the exception of two patients who developed transient lip and tongue swelling. Conclusion Our study demonstrated that SLIT with HDM extracts is effective and tolerable in Korean patients with AD. Further controlled long-term trials are required to reinforce the current results. PMID:28223739

  14. Tau passive immunotherapy in mutant P301L mice: antibody affinity versus specificity.

    Directory of Open Access Journals (Sweden)

    Cristina d'Abramo

    Full Text Available The use of antibodies to treat neurodegenerative diseases has undergone rapid development in the past decade. To date, immunotherapeutic approaches to Alzheimer's disease have mostly targeted amyloid beta as it is a secreted protein that can be found in plasma and CSF and is consequently accessible to circulating antibodies. Few recent publications have suggested the utility of treatment of tau pathology with monoclonal antibodies to tau. Our laboratory has begun a systematic study of different classes of tau monoclonal antibodies using mutant P301L mice. Three or seven months old mutant tau mice were inoculated weekly with tau monoclonal antibodies at a dose of 10 mg/Kg, until seven or ten months of age were reached respectively. Our data strongly support the notion that in P301L animals treated with MC1, a conformational monoclonal antibody specific for PHF-tau, the rate of development of tau pathology is effectively reduced, while injecting DA31, a high affinity tau sequence antibody, does not exert such benefit. MC1 appears superior to DA31 in overall effects, suggesting that specificity is more important than affinity in therapeutic applications. Unfortunately the survival rate of the P301L treated mice was not improved when immunizing either with MC1 or PHF1, a high affinity phospho-tau antibody previously reported to be efficacious in reducing pathological tau. These data demonstrate that passive immunotherapy in mutant tau models may be efficacious in reducing the development of tau pathology, but a great deal of work remains to be done to carefully select the tau epitopes to target.

  15. Mutants of the major ryegrass pollen allergen, Lol p 5, with reduced IgE-binding capacity: candidates for grass pollen-specific immunotherapy.

    Science.gov (United States)

    Swoboda, Ines; De Weerd, Nicole; Bhalla, Prem L; Niederberger, Verena; Sperr, W R; Valent, Peter; Kahlert, Helga; Fiebig, Helmut; Verdino, Petra; Keller, Walter; Ebner, Christof; Spitzauer, Susanne; Valenta, Rudolf; Singh, Mohan B

    2002-01-01

    More than 400 million individuals are sensitized to grass pollen allergens. Group 5 allergens represent the most potent grass pollen allergens recognized by more than 80 % of grass pollen allergic patients. The aim of our study was to reduce the allergenic activity of group 5 allergens for specific immunotherapy of grass pollen allergy. Based on B- and T-cell epitope mapping studies and on sequence comparison of group 5 allergens from different grasses, point mutations were introduced by site-directed mutagenesis in highly conserved sequence domains of Lol p 5, the group 5 allergen from ryegrass. We obtained Lol p 5 mutants with low IgE-binding capacity and reduced allergenic activity as determined by basophil histamine release and by skin prick testing in allergic patients. Circular dichroism analysis showed that these mutants exhibited an overall structural fold similar to the recombinant Lol p 5 wild-type allergen. In addition, Lol p 5 mutants retained the ability to induce proliferation of group 5 allergen-specific T cell lines and clones. Our results demonstrate that a few point mutations in the Lol p 5 sequence yield mutants with reduced allergenic activity that represent potential vaccine candidates for immunotherapy of grass pollen allergy.

  16. Sarcoma Immunotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Gouw, Launce G., E-mail: launce.gouw@hsc.utah.edu [Departments of Oncology, Huntsman Cancer Institute at the University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112 (United States); Jones, Kevin B. [Departments of Orthopaedic Surgery, Huntsman Cancer Institute at the University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112 (United States); Sharma, Sunil [Departments of Oncology, Huntsman Cancer Institute at the University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112 (United States); Randall, R. Lor [Departments of Orthopaedic Surgery, Huntsman Cancer Institute at the University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112 (United States)

    2011-11-10

    Much of our knowledge regarding cancer immunotherapy has been derived from sarcoma models. However, translation of preclinical findings to bedside success has been limited in this disease, though several intriguing clinical studies hint at the potential efficacy of this treatment modality. The rarity and heterogeneity of tumors of mesenchymal origin continues to be a challenge from a therapeutic standpoint. Nonetheless, sarcomas remain attractive targets for immunotherapy, as they can be characterized by specific epitopes, either from their mesenchymal origins or specific alterations in gene products. To date, standard vaccine trials have proven disappointing, likely due to mechanisms by which tumors equilibrate with and ultimately escape immune surveillance. More sophisticated approaches will likely require multimodal techniques, both by enhancing immunity, but also geared towards overcoming innate mechanisms of immunosuppression that favor tumorigenesis.

  17. Pediatric investigation plans for specific immunotherapy: Questionable contributions to childhood health.

    Science.gov (United States)

    Rose, Klaus; Kopp, Matthias Volkmar

    2015-12-01

    Allergen-specific immunotherapy (SIT) is the only disease-modifying treatment for children, adolescents, and adults with allergic diseases. The EU has a combined system of national and EU-wide marketing authorization for all medicines. Germany introduced a new therapy allergen ordinance in 2008. Allergen products manufacturers had to apply for marketing authorization application for the major allergen groups (grass group, birch group, mites group, bee/wasp venom). Due to the EU pediatric regulation, in force since 2007, manufacturers had also to submit a pediatric investigation plan (PIP) for each allergen product. We investigated the allergic rhinoconjunctivitis (ARC) standard PIP, developed jointly by the European Medicines Agency (EMA) and the German Paul Ehrlich Institut (PEI). We analyzed the 118 EMA PIP decisions, looked for SIT trials in children in www.clinicaltrials.gov, and further analyzed EMA/EU justifications. The PIPs request a 1-year dose-finding study in adults, a 5-year placebo-controlled (PC) efficacy & safety (E&S) study in adults, and a 5-year PC E&S study in children. Fifty-eight PIP development programs will have to be performed until 2031. But children benefit even more from SIT for ARC than adults. There is no convincing medical/scientific justification for PC E&S studies in children in the relevant EMA documents. The PIP requirement to withhold effective treatment to thousands of children in the placebo group over a 5-year period raises profound concerns. The EMA justifications are formalistic and lack scientific foundation. A critical academic review of the ARC PIPs and the entire PIP system is urgently needed.

  18. Specific Genetic Immunotherapy Induced by Recombinant Vaccine Alpha-Fetoprotein-Heat Shock Protein 70 Complex

    Science.gov (United States)

    Wang, Xiaoping; Lin, Huanping; Wang, Qiaoxia

    Purposes: To construct a recombinant vaccine alpha-fetoprotein (AFP)-heat shock protein (HSP70) complex, and study its ability to induce specific CTL response and its protective effect against AFP-producing tumor. Material/Methods: A recombinant vaccine was constructed by conjugating mouse alpha-fetoprotein to heat shock protein 70. By way of intracutaneous injection, mice were primed and boosted with recombinant vaccine mAFP/HSP70, whereas single mAFP or HSP70 injection as controls. The ELISPOT and ELISA were used to measure the frequency of cells producing the cytokine IFN-γ in splenocytes and the level of anti-AFP antibody of serum from immunized mice respectively. In vivo tumor challenge were carried out to assess the immune effect of the recombinant vaccine. Results: By recombinant mAFP/HSP70 vaccine immunization, the results of ELISPOT and ELISA showed that the number of splenic cells producing IFN-γ and the level of anti-AFP antibody of serum were significantly higher in mAFP/HSP70 group than those in mAFP and HSP70 groups (108.50±11.70 IFN-γ spots/106 cells vs 41.60±10.40 IFN-γ spots/106 cells, 7.32±3.14 IFN-γ spots/106 cells, Precombinant mAFP/HSP70 vaccine could generate effective antitumor immunity on AFP-producing tumor. The recombined mAFP/HSP70 vaccine may be suitable for serving as an immunotherapy for hepatocellular carcinoma.

  19. Vaccine-specific local T cell reactivity in immunotherapy-associated vitiligo in melanoma patients.

    NARCIS (Netherlands)

    Jacobs, J.F.M.; Aarntzen, E.H.J.G.; Sibelt, L.A.G.; Blokx, W.A.M.; Boullart, A.C.I.; Gerritsen, M.J.P.; Hoogerbrugge, P.M.; Figdor, C.G.; Adema, G.J.; Punt, C.J.A.; Vries, I.J.M. de

    2009-01-01

    The occurrence of vitiligo in patients with melanoma is especially reported for patients undergoing immunotherapy. While vitiligo in these patients is thought to be related to an immune response directed against melanoma cells, solid evidence is lacking. Here we report local cytotoxic T cell reactiv

  20. Antigen-specific immunotherapy in ovarian cancer and p53 as tumor antigen

    NARCIS (Netherlands)

    Vermeij, Renee; Leffers, Ninke; Melief, Cornelis J.; Daemen, Toos; Nijman, Hans W.

    2012-01-01

    This review discusses the results of different immunization strategies, identifies possible drawbacks in study design and provides potential solutions for augmentation of clinical efficacy. A potential target for cancer immunotherapy is p53, as approximately 50% of ovarian cancer cells carry p53 mut

  1. Specific immunotherapy can greatly reduce the need for systemic steroids in allergic rhinitis

    DEFF Research Database (Denmark)

    Aasbjerg, Kristian; Torp-Pedersen, C; Backer, V

    2012-01-01

    Worldwide, more than 400 million individuals have allergic rhinitis, which has a significant impact on the individual's general health. Most patients self-medicate with over-the-counter drugs, but severe cases need treatment with topical corticosteroids and/or immunotherapy (SCIT). Although the A...

  2. Breast Cancer Immunotherapy

    Institute of Scientific and Technical Information of China (English)

    JuhuaZhou; YinZhong

    2004-01-01

    Breast cancer is a leading cause of cancer-related deaths in women worldwide. Although tumorectomy, radiotherapy, chemotherapy and hormone replacement therapy have been used for the treatment of breast cancer, there is no effective therapy for patients with invasive and metastatic breast cancer. Immunotherapy may be proved effective in treating patients with advanced breast cancer. Breast cancer immunotherapy includes antibody based immunotherapy, cancer vaccine immunotherapy, adoptive T cell transfer immunotherapy and T cell receptor gene transfer immunotherapy. Antibody based immunotherapy such as the monoclonal antibody against HER-2/neu (trastuzumab) is successfully used in the treatment of breast cancer patients with over-expressed HER-2/neu, however, HER-2/neu is over-expressed only in 25-30% of breast cancer patients. Cancer vaccine immunotherapy is a promising method to treat cancer patients. Cancer vaccines can be used to induce specific anti-tumor immunity in breast cancer patients, but cannot induce objective tumor regression. Adoptive T cell transfer immunotherapy is an effective method in the treatment of melanoma patients. Recent advances in anti-tumor T cell generation ex vivo and limited clinical trial data have made the feasibility of adoptive T cell transfer immunotherapy in the treatment of breast cancer patients. T cell receptor gene transfer can redirect the specificity of T cells. Chimeric receptor, scFv(anti-HER-2/neu)/zeta receptor, was successfully used to redirect cytotoxic T lymphocyte hybridoma cells to obtain anti-HER-2/neu positive tumor cells, suggesting the feasibility of treatment of breast cancer patients with T cell receptor gene transfer immunotherapy. Clinical trials will approve that immunotherapy is an effective method to cure breast cancer disease in the near future. Cellular & Molecular Immunology.

  3. Breast Cancer Immunotherapy

    Institute of Scientific and Technical Information of China (English)

    Juhua Zhou; Yin Zhong

    2004-01-01

    Breast cancer is a leading cause of cancer-related deaths in women worldwide. Although tumorectomy,radiotherapy, chemotherapy and hormone replacement therapy have been used for the treatment of breast cancer, there is no effective therapy for patients with invasive and metastatic breast cancer. Immunotherapy may be proved effective in treating patients with advanced breast cancer. Breast cancer immunotherapy includes antibody based immunotherapy, cancer vaccine immunotherapy, adoptive T cell transfer immunotherapy and T cell receptor gene transfer immunotherapy. Antibody based immunotherapy such as the monoclonal antibody against HER-2/neu (trastuzumab) is successfully used in the treatment of breast cancer patients with over-expressed HER-2/neu, however, HER-2/neu is over-expressed only in 25-30% of breast cancer patients. Cancer vaccine immunotherapy is a promising method to treat cancer patients. Cancer vaccines can be used to induce specific anti-tumor immunity in breast cancer patients, but cannot induce objective tumor regression. Adoptive T cell transfer immunotherapy is an effective method in the treatment of melanoma patients. Recent advances in anti-tumor T cell generation ex vivo and limited clinical trial data have made the feasibility of adoptive T cell transfer immunotherapy in the treatment of breast cancer patients. T cell receptor gene transfer can redirect the specificity of T cells. Chimeric receptor, scFv(anti-HER-2/neu)/zeta receptor, was successfully used to redirect cytotoxic T lymphocyte hybridoma cells to obtain anti-HER-2/neu positive tumor cells, suggesting the feasibility of treatment of breast cancer patients with T cell receptor gene transfer immunotherapy. Clinical trials will approve that immunotherapy is an effective method to cure breast cancer disease in the near future.

  4. Immunization of stromal cell targeting fibroblast activation protein providing immunotherapy to breast cancer mouse model.

    Science.gov (United States)

    Meng, Mingyao; Wang, Wenju; Yan, Jun; Tan, Jing; Liao, Liwei; Shi, Jianlin; Wei, Chuanyu; Xie, Yanhua; Jin, Xingfang; Yang, Li; Jin, Qing; Zhu, Huirong; Tan, Weiwei; Yang, Fang; Hou, Zongliu

    2016-08-01

    Unlike heterogeneous tumor cells, cancer-associated fibroblasts (CAF) are genetically more stable which serve as a reliable target for tumor immunotherapy. Fibroblast activation protein (FAP) which is restrictively expressed in tumor cells and CAF in vivo and plays a prominent role in tumor initiation, progression, and metastasis can function as a tumor rejection antigen. In the current study, we have constructed artificial FAP(+) stromal cells which mimicked the FAP(+) CAF in vivo. We immunized a breast cancer mouse model with FAP(+) stromal cells to perform immunotherapy against FAP(+) cells in the tumor microenvironment. By forced expression of FAP, we have obtained FAP(+) stromal cells whose phenotype was CD11b(+)/CD34(+)/Sca-1(+)/FSP-1(+)/MHC class I(+). Interestingly, proliferation capacity of the fibroblasts was significantly enhanced by FAP. In the breast cancer-bearing mouse model, vaccination with FAP(+) stromal cells has significantly inhibited the growth of allograft tumor and reduced lung metastasis indeed. Depletion of T cell assays has suggested that both CD4(+) and CD8(+) T cells were involved in the tumor cytotoxic immune response. Furthermore, tumor tissue from FAP-immunized mice revealed that targeting FAP(+) CAF has induced apoptosis and decreased collagen type I and CD31 expression in the tumor microenvironment. These results implicated that immunization with FAP(+) stromal cells led to the disruption of the tumor microenvironment. Our study may provide a novel strategy for immunotherapy of a broad range of cancer.

  5. Cancer immunotherapy targeting neoantigens.

    Science.gov (United States)

    Lu, Yong-Chen; Robbins, Paul F

    2016-02-01

    Neoantigens are antigens encoded by tumor-specific mutated genes. Studies in the past few years have suggested a key role for neoantigens in cancer immunotherapy. Here we review the discoveries of neoantigens in the past two decades and the current advances in neoantigen identification. We also discuss the potential benefits and obstacles to the development of effective cancer immunotherapies targeting neoantigens.

  6. Targets for active immunotherapy against pediatric solid tumors.

    NARCIS (Netherlands)

    Jacobs, J.F.M.; Coulie, P.G.; Figdor, C.G.; Adema, G.J.; Vries, I.J.M. de; Hoogerbrugge, P.M.

    2009-01-01

    The potential role of antibodies and T lymphocytes in the eradication of cancer has been demonstrated in numerous animal models and clinical trials. In the last decennia new strategies have been developed for the use of tumor-specific T cells and antibodies in cancer therapy. Effective anti-tumor im

  7. Quality assurance ofallergen-specific immunotherapy during a national outbreak of anaphylaxis: results of a continuous sentinel event surveillance system

    DEFF Research Database (Denmark)

    Madsen, F; Frølund, L; Christensen, M;

    2009-01-01

    BACKGROUND AND OBJECTIVE: Subcutaneous allergen-specific immunotherapy (SCIT) is an effective treatment for patients with allergic asthma and rhinitis. SCIT may be performed in many different ways and good safety profiles have been published. Other studies, however, have reported high frequencies...... of severe adverse events (SAEs) but without identifying the causes. After an increase in SCIT-related SAEs in Denmark between 2003 and 2004, strict performance regulations were imposed by the authorities. Because safety data from national databases were not available, we implemented a surveillance system...... was calculated at explore their causes...

  8. Both sublingual and supralingual routes of administration are effective in long-term allergen-specific immunotherapy.

    Science.gov (United States)

    Panzner, Petr; Petráš, Mark; Sýkora, Tomáš; Lesná, Ivana Králová; Liška, Martin

    2011-01-01

    The aim of this study was to confirm or refute the difference between efficacy of long-term specific immunotherapy (SIT) with standardized allergen vaccine consisting of six grass pollens (oat grass, orchard grass, fescue, rye grass, timothy grass, and rye) administered either by sublingual or by supralingual route. To investigate clinical and immunologic changes, 51 patients of a previous 1-year double-blind, placebo-controlled, randomized study were enrolled in an open randomized study that continued over the next 3 years. Sublingual or supralingual immunotherapy (SLIT) was performed in the same way, keeping the drops under or on the tongue, respectively, for 1-2 minutes before swallowing them. Data about symptoms scores and rescue medication intake during grass pollen seasons, as well as skin-prick test results, levels of specific IgG, and IgE antibodies were collected after each pollen season. It was clearly shown that both routes of administration were effective, leading to a significant decrease of clinical symptoms of grass pollen allergy after SIT lasting 3-4 years. No statistically significant difference between sublingually and supralingually treated patients was observed at the end of the study. Adverse effects were limited to a small number of generally mild local and/or systemic reactions with no significant difference between both administration ways of SIT. The significant therapeutic effect of both SLIT and supralingual immunotherapy lasting 3-4 years was clearly achieved. Despite no significant difference between efficacy of both administration ways of SIT, the onset of sublingual SIT effect seems to be slightly faster than that of supralingual SIT.

  9. Sipuleucel-T (Provenge): active cellular immunotherapy for advanced prostate cancer.

    Science.gov (United States)

    McKarney, I

    2007-09-01

    (1) Sipuleucel-T (Provenge) is an active cellular immunotherapy (therapeutic vaccine) that is designed to stimulate the patient's T-cells to recognize and attack prostate cancer cells that express prostatic acid phosphatase (PAP) antigen. (2) Sipuleucel-T demonstrated a survival benefit in men with advanced androgen-independent prostate cancer (AIPC), although this preliminary finding requires confirmation in larger trials. (3) Mild to moderate myalgia, chills, fever, and tremor are the most commonly reported adverse events for patients receiving sipuleucel-T. These events generally resolve quickly. (4) More studies are needed to evaluate sipuleucel-T in the earlier stages of prostate cancer and in combination with conventional therapies.

  10. A naturally occurring hypoallergenic variant of vespid Antigen 5 from Polybia scutellaris venom as a candidate for allergen-specific immunotherapy.

    Directory of Open Access Journals (Sweden)

    Sabrina E Vinzón

    Full Text Available Stings by insects from the Hymenoptera order are known to cause life-threatening allergic reactions and impair life quality. Despite the effectiveness of conventional vespid venom immunotherapy, more standardized and safer allergy vaccines are required and recombinant hypoallergenic variants are important clinical tools. Antigen 5 is a major allergen of vespid venoms and it was previously reported that Antigen 5 from Polybia scutellaris (Poly s 5 could be a hypoallergenic variant. In this work we assess the immunological behavior and allergenic activity of Poly s 5 in order to explore its suitability for specific immunotherapy. With this aim, recombinant Poly s 5 was expressed in Pichia pastoris and the presence of cross-reactive epitopes with Pol a 5, a known allergenic Antigen 5, was investigated both at the IgG and IgE levels, by ELISA assays and a basophil-mediator release assay respectively. A molecular model was also built to better understand the relationship between immunological and structural aspects. In mice, Poly s 5 induced IgG antibodies which cross-reacted with Pol a 5. However, Poly s 5 induced only minimal amounts of IgE and was a poor inducer of basophil-mediator release, even when the cells were sensitized with Pol a 5-specific IgE. Moreover, Poly s 5-specific serum showed a specific protective activity and was able to inhibit the Pol a 5-induced basophil degranulation. Structural analysis from the molecular model revealed that a few amino acid substitutions in the N-terminal region of Poly s 5 should lead to an alteration of the surface topography and electrostatic potential of the epitopes which could be responsible for its hypoallergenic behavior. These findings, taken as a whole, show that Poly s 5 is likely a naturally occurring hypoallergenic Antigen 5 variant.

  11. A naturally occurring hypoallergenic variant of vespid Antigen 5 from Polybia scutellaris venom as a candidate for allergen-specific immunotherapy.

    Science.gov (United States)

    Vinzón, Sabrina E; Marino-Buslje, Cristina; Rivera, Elena; Biscoglio de Jiménez Bonino, Mirtha

    2012-01-01

    Stings by insects from the Hymenoptera order are known to cause life-threatening allergic reactions and impair life quality. Despite the effectiveness of conventional vespid venom immunotherapy, more standardized and safer allergy vaccines are required and recombinant hypoallergenic variants are important clinical tools. Antigen 5 is a major allergen of vespid venoms and it was previously reported that Antigen 5 from Polybia scutellaris (Poly s 5) could be a hypoallergenic variant. In this work we assess the immunological behavior and allergenic activity of Poly s 5 in order to explore its suitability for specific immunotherapy. With this aim, recombinant Poly s 5 was expressed in Pichia pastoris and the presence of cross-reactive epitopes with Pol a 5, a known allergenic Antigen 5, was investigated both at the IgG and IgE levels, by ELISA assays and a basophil-mediator release assay respectively. A molecular model was also built to better understand the relationship between immunological and structural aspects. In mice, Poly s 5 induced IgG antibodies which cross-reacted with Pol a 5. However, Poly s 5 induced only minimal amounts of IgE and was a poor inducer of basophil-mediator release, even when the cells were sensitized with Pol a 5-specific IgE. Moreover, Poly s 5-specific serum showed a specific protective activity and was able to inhibit the Pol a 5-induced basophil degranulation. Structural analysis from the molecular model revealed that a few amino acid substitutions in the N-terminal region of Poly s 5 should lead to an alteration of the surface topography and electrostatic potential of the epitopes which could be responsible for its hypoallergenic behavior. These findings, taken as a whole, show that Poly s 5 is likely a naturally occurring hypoallergenic Antigen 5 variant.

  12. Spectrum of allergens for Japanese cedar pollinosis and impact of component-resolved diagnosis on allergen-specific immunotherapy.

    Science.gov (United States)

    Fujimura, Takashi; Kawamoto, Seiji

    2015-10-01

    The high prevalence of Japanese cedar pollinosis in Japan is associated with a negative impact on the quality of life of patients, as well as significant loss of productivity among the workforce in early spring, thus representing a serious social problem. Furthermore, the prevalence is increasing, and has risen by more than 10% in this decade. Cry j 1 and Cry j 2 were identified as the major allergens in Japanese cedar pollen (JCP), and in 2004, the existence of other major and minor allergens were revealed by a combination of two-dimensional electrophoresis and immunoblotting analysis. Allergenome analysis identified a chitinase, a lipid transfer protein, a serine protease, and an aspartic protease as novel IgE-reactive allergens in patients with JCP allergy. Thaumatin-like protein (Cry j 3) was shown to be homologous to Jun a 3, a major allergen from mountain cedar pollen. Isoflavone reductase-like protein was also characterized in a study of a JCP cDNA library. The characterization of component allergens is required to clarify the sensitizer or cross-reactive elicitor allergens for component-resolved diagnosis (CRD). Increasing evidence from numerous clinical trials indicates that CRD can be used to design effective allergen-specific immunotherapy. In this review, we summarize the eight characterized JCP allergens and discuss the impact of CRD and characterization of novel allergens on allergen-specific immunotherapy.

  13. 低致敏原应用于特异性免疫治疗的研究进展%The Study on Hypoallergenic Derivatives for Specific Immunotherapy

    Institute of Scientific and Technical Information of China (English)

    刘志刚; 易海涛; 夏立新

    2011-01-01

    Hypersensitivity disease is one of the three key prevention diseases in 21 century. Currently, it has no effective method for radical treatment. Specific immunotherapy is the only way to cure type I hypersensitivity dis ease thoroughgoingly. However, traditional specific immunotherapy has tremendous side-effects. Therefore, ex ploitation hypoallergenic derivatives vaccines will play an important role for safer specific immunotherapy.%过敏性疾病是21世纪重点防治的3大疾病之一,目前仍无有效方法对患者达到治愈的目的.特异性免疫治疗(SIT)是针对过敏性疾病唯一的对因治疗方法,传统的SIT具有很大的副作用,开发低致敏原疫苗将对SIT的安全性方面有着十分重要的意义.

  14. Cancer Immunotherapy

    Science.gov (United States)

    Immunotherapy is a cancer treatment that helps your immune system fight cancer. It is a type of biological therapy. Biological therapy uses substances ... t yet use immunotherapy as often as other cancer treatments, such as surgery, chemotherapy, and radiation therapy. ...

  15. The application of the fibroblast activation protein α-targeted immunotherapy strategy.

    Science.gov (United States)

    Jiang, Guan-Min; Xu, Wei; Du, Jun; Zhang, Kun-Shui; Zhang, Qiu-Gui; Wang, Xiao-Wei; Liu, Zhi-Gang; Liu, Shuang-Quan; Xie, Wan-Ying; Liu, Hui-Fang; Liu, Jing-Shi; Wu, Bai-Ping

    2016-05-31

    Cancer immunotherapy has primarily been focused on attacking tumor cells. However, given the close interaction between tumor cells and cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME), CAF-targeted strategies could also contribute to an integrated cancer immunotherapy. Fibroblast activation protein α (FAP α) is not detectible in normal tissues, but is overexpressed by CAFs and is the predominant component of the stroma in most types of cancer. FAP α has both dipeptidyl peptidase and endopeptidase activities, cleaving substrates at a post-proline bond. When all FAP α-expressing cells (stromal and cancerous) are destroyed, tumors rapidly die. Furthermore, a FAP α antibody, FAP α vaccine, and modified vaccine all inhibit tumor growth and prolong survival in mouse models, suggesting FAP α is an adaptive tumor-associated antigen. This review highlights the role of FAP α in tumor development, explores the relationship between FAP α and immune suppression in the TME, and discusses FAP α as a potential immunotherapeutic target.

  16. Research of Active Immunotherapy on Unexplained Recurrent Spontaneous Abortion(URSA)

    Institute of Scientific and Technical Information of China (English)

    Hong-chu BAO; Na LV; Cui-fang HAO

    2006-01-01

    Objective To investigate the effect of active immunotherapy on unexplained recurrent spontaneous abortion (URSA ) during the process of gestation and delivery period.Methods We collected the data of the women with URSA and their offsprings. The women were treated by immunization with paternal lymphocytes and then had a successful pregnancy. The fore mentioned group of women were compared with those who had a normal pregnancy and then delivered in the same period.Results The incidences of premature rupture of membranes, adherent placenta, and residual cauls in the group of URSA patients were statistically higher than those in the normal group.Correspondingly, gestational age at delivery and birth weight of the newborns of the group of URSA patients were lower,but there were no significant differences between the two groups.Conclusion These results indicate that paternal lymphocyte immunotherapy is effective on the maintenance of pregnancy in women with URSA, and has no deleterious effects on the fetus or newborns. However,in case of the higher incidence of premature rupture of membranes, adherent placenta, and residual cauls, more attention should be paid to the treated patients to avoid intrauterine growth retardation and postpartum hemorrhage.

  17. Evaluation of subcutaneous versus mucosal (intranasal) allergen-specific rush immunotherapy in experimental feline asthma.

    Science.gov (United States)

    Lee-Fowler, Tekla M; Cohn, Leah A; DeClue, Amy E; Spinka, Christine M; Reinero, Carol R

    2009-05-15

    Rush immunotherapy (RIT) is effective for the treatment of experimental feline allergic asthma. In humans, the safety profile of immunotherapy is improved by delivering allergen by a mucosal route. We hypothesized that mucosal (intranasal) RIT would have similar efficacy to subcutaneous RIT with improved safety. Twelve cats sensitized and challenged with Bermuda grass allergen (BGA) were randomized to receive subcutaneous (SC) or intranasal (IN) RIT. Increasing doses of BGA (20-200 microg) were administered over 24h followed by 200 microg BGA weekly as maintenance. Adverse reactions were recorded. Clinical respiratory scores after BGA aerosol challenge, bronchoalveolar lavage fluid (BALF) % eosinophils, and cytokine concentrations were measured before RIT (day 1) and at months 1, 3 and 6 (M1, M3, M6). More adverse events were recorded with SC RIT (n=12) compared with IN RIT (n=6). Respiratory scores were lower by M6 compared with D1 in both the groups. The % BALF eosinophils declined significantly after RIT for both groups (mean+/-SEM, SC RIT D1 62+/-12, M6 9+/-4; IN RIT D1 54+/-9, M6 14+/-6). The BALF IL-4:IFN-gamma ratio significantly decreased over time in the IN RIT group (mean+/-SEM, D1 2.4+/-0.2, M6 1.0+/-0.2). While both protocols decreased eosinophilic airway inflammation, the SC RIT protocol did not cause life-threatening adverse events and demonstrated more consistent resolution of clinical signs after allergen challenge. Either protocol could be considered for the treatment of feline allergic asthma.

  18. Ex vivo generation of human alloantigen-specific regulatory T cells from CD4(posCD25(high T cells for immunotherapy.

    Directory of Open Access Journals (Sweden)

    Jorieke H Peters

    Full Text Available BACKGROUND: Regulatory T cell (Treg based immunotherapy is a potential treatment for several immune disorders. By now, this approach proved successful in preclinical animal transplantation and auto-immunity models. In these models the success of Treg based immunotherapy crucially depends on the antigen-specificity of the infused Treg population. For the human setting, information is lacking on how to generate Treg with direct antigen-specificity ex vivo to be used for immunotherapy. METHODOLOGY/PRINCIPAL FINDINGS: Here, we demonstrate that in as little as two stimulation cycles with HLA mismatched allogeneic stimulator cells and T cell growth factors a very high degree of alloantigen-specificity was reached in magnetic bead isolated human CD4(posCD25(high Treg. Efficient increases in cell numbers were obtained. Primary allogeneic stimulation appeared a prerequisite in the generation of alloantigen-specific Treg, while secondary allogeneic or polyclonal stimulation with anti-CD3 plus anti-CD28 monoclonal antibodies enriched alloantigen-specificity and cell yield to a similar extent. CONCLUSIONS/SIGNIFICANCE: The ex vivo expansion protocol that we describe will very likely increase the success of clinical Treg-based immunotherapy, and will help to induce tolerance to selected antigens, while minimizing general immune suppression. This approach is of particular interest for recipients of HLA mismatched transplants.

  19. Engineering opportunities in cancer immunotherapy.

    Science.gov (United States)

    Jeanbart, Laura; Swartz, Melody A

    2015-11-24

    Immunotherapy has great potential to treat cancer and prevent future relapse by activating the immune system to recognize and kill cancer cells. A variety of strategies are continuing to evolve in the laboratory and in the clinic, including therapeutic noncellular (vector-based or subunit) cancer vaccines, dendritic cell vaccines, engineered T cells, and immune checkpoint blockade. Despite their promise, much more research is needed to understand how and why certain cancers fail to respond to immunotherapy and to predict which therapeutic strategies, or combinations thereof, are most appropriate for each patient. Underlying these challenges are technological needs, including methods to rapidly and thoroughly characterize the immune microenvironment of tumors, predictive tools to screen potential therapies in patient-specific ways, and sensitive, information-rich assays that allow patient monitoring of immune responses, tumor regression, and tumor dissemination during and after therapy. The newly emerging field of immunoengineering is addressing some of these challenges, and there is ample opportunity for engineers to contribute their approaches and tools to further facilitate the clinical translation of immunotherapy. Here we highlight recent technological advances in the diagnosis, therapy, and monitoring of cancer in the context of immunotherapy, as well as ongoing challenges.

  20. Immunotherapy with Allergen Peptides

    OpenAIRE

    Larché Mark

    2007-01-01

    Specific allergen immunotherapy (SIT) is disease-modifying and efficacious. However, the use of whole allergen preparations is associated with frequent allergic adverse events during treatment. Many novel approaches are being designed to reduce the allergenicity of immunotherapy preparations whilst maintaining immunogenicity. One approach is the use of short synthetic peptides which representing dominant T cell epitopes of the allergen. Short peptides exhibit markedly reduced capacity to cro...

  1. What Is Cancer Immunotherapy?

    Science.gov (United States)

    ... and Side Effects Treatment Types Immunotherapy What is cancer immunotherapy? Immunotherapy is treatment that uses certain parts of ... so that it will destroy them. Types of cancer immunotherapy The main types of immunotherapy now being used ...

  2. Phase I clinical trial of HER2-specific immunotherapy with concomitant HER2 kinase inhibtion

    Directory of Open Access Journals (Sweden)

    Hamilton Erika

    2012-02-01

    Full Text Available Abstract Background Patients with HER2-overexpressing metastatic breast cancer, despite initially benefiting from the monoclonal antibody trastuzumab and the EGFR/HER2 tyrosine kinase inhibitor lapatinib, will eventually have progressive disease. HER2-based vaccines induce polyclonal antibody responses against HER2 that demonstrate enhanced anti-tumor activity when combined with lapatinib in murine models. We wished to test the clinical safety, immunogenicity, and activity of a HER2-based cancer vaccine, when combined with lapatinib. Methods We immunized women (n = 12 with metastatic, trastuzumab-refractory, HER2-overexpressing breast cancer with dHER2, a recombinant protein consisting of extracellular domain (ECD and a portion of the intracellular domain (ICD of HER2 combined with the adjuvant AS15, containing MPL, QS21, CpG and liposome. Lapatinib (1250 mg/day was administered concurrently. Peripheral blood antibody and T cell responses were measured. Results This regimen was well tolerated, with no cardiotoxicity. Anti-HER2-specific antibody was induced in all patients whereas HER2-specific T cells were detected in one patient. Preliminary analyses of patient serum demonstrated downstream signaling inhibition in HER2 expressing tumor cells. The median time to progression was 55 days, with the majority of patients progressing prior to induction of peak anti-HER2 immune responses; however, 300-day overall survival was 92% (95% CI: 77-100%. Conclusions dHER2 combined with lapatinib was safe and immunogenic with promising long term survival in those with HER2-overexpressing breast cancers refractory to trastuzumab. Further studies to define the anticancer activity of the antibodies induced by HER2 vaccines along with lapatinib are underway. Trial registry ClinicalTrials.gov NCT00952692

  3. Immunotherapy of tumor by targeting angiogenesis

    Institute of Scientific and Technical Information of China (English)

    HOU Jianmei; TIAN Ling; WEI Yuquan

    2004-01-01

    Tumor growth and metastasis are angiogenesis-dependent. Anti-angiogenic therapy represents a new strategy for the development of anti-cancer therapies. In recent years, there has been made great progress in anti-angiogenic therapy. As far as the passive immunotherapy is concerned, a recombinant humanized antibody to vascular endothelial growth factor (VEGF)-Avastin has been approved by FDA as the first angiogenesis inhibitor to treat colorectal cancer. For active specific immunotherapy, various strategies for cancer vaccines, including whole endothelial cell vaccines, dendritic cell vaccines, DNA vaccines, and peptides or protein vaccines, have been developed to break immune tolerance against important molecules associated with tumor angiogenesis and induce angiogenesis-specific immune responses. This article reviews the angiogenesis-targeted immunotherapy of tumor from the above two aspects.

  4. Sublingual allergen immunotherapy

    DEFF Research Database (Denmark)

    Calderón, M A; Simons, F E R; Malling, Hans-Jørgen;

    2012-01-01

    To cite this article: Calderón MA, Simons FER, Malling H-J, Lockey RF, Moingeon P, Demoly P. Sublingual allergen immunotherapy: mode of action and its relationship with the safety profile. Allergy 2012; 67: 302-311. ABSTRACT: Allergen immunotherapy reorients inappropriate immune responses...... in allergic patients. Sublingual allergen immunotherapy (SLIT) has been approved, notably in the European Union, as an effective alternative to subcutaneous allergen immunotherapy (SCIT) for allergic rhinitis patients. Compared with SCIT, SLIT has a better safety profile. This is possibly because oral antigen...... cells and eosinophils (mostly located in submucosal areas) and, in comparison with subcutaneous tissue, are less likely to give rise to anaphylactic reactions. SLIT-associated immune responses include the induction of circulating, allergen-specific Th1 and regulatory CD4+ T cells, leading to clinical...

  5. A constant threat for HIV: Fc-engineering to enhance broadly neutralizing antibody activity for immunotherapy of the acquired immunodeficiency syndrome.

    Science.gov (United States)

    Nimmerjahn, Falk

    2015-08-01

    Passive immunotherapy with polyclonal or hyperimmune serum immunoglobulin G (IgG) preparations provides an efficient means of protecting immunocompromised patients from microbial infections. More recently, the use of passive immunotherapy to prevent or to treat established infections with the human immunodeficiency virus (HIV) has gained much attention, due to promising preclinical data obtained in monkey and humanized mouse in vivo model systems, demonstrating that the transfer of HIV-specific antibodies can not only prevent HIV infection, but also diminish virus load during chronic infection. Furthermore, an array of broadly neutralizing HIV-specific antibodies has become available and the importance of the IgG constant region as a critical modulator of broadly neutralizing activity has been demonstrated. The aim of this review is to summarize the most recent findings with regard to the molecular and cellular mechanisms responsible for antibody-mediated clearance of HIV infection, and to discuss how this may help to improve HIV therapy via optimizing Fcγ-receptor-dependent activities of HIV-specific antibodies.

  6. Absolute quantification of allergens from complex mixtures: a new sensitive tool for standardization of allergen extracts for specific immunotherapy.

    Science.gov (United States)

    Seppälä, Ulla; Dauly, Claire; Robinson, Sarah; Hornshaw, Martin; Larsen, Jørgen Nedergaard; Ipsen, Henrik

    2011-04-01

    Products for specific diagnosis and immunotherapy of IgE-mediated allergies are currently based on natural extracts. Quantification of major allergen content is an important aspect of standardization as important allergens particularly impact vaccine potency. The aim of the study was to develop a mass spectrometry (MS) based assay for absolute quantification of Timothy (Phleum pratense) pollen allergens Phl p 1 and Phl p 5 in P. pratense extract. High-resolution and accurate mass (HRAM) MS was selected for its ability to detect peptides with high selectivity and mass accuracy (extract. Robustness and linearity of the method was demonstrated with intra day precision ≤ 5% (n = 3). Phl p 1b was shown to be 5 times less abundant than its variant Phl p 1a and Phl p 5b was shown to be 9 times more abundant than the Phl p 5a. The present study shows that allergen, and/or isoallergen specific, surrogate signature peptides analyzed with HRAM MS is a sensitive and accurate tool for identification and quantification of allergens from complex allergen sources.

  7. Immunotherapy for Lung Cancers

    Directory of Open Access Journals (Sweden)

    Ming-Yi Ho

    2011-01-01

    Full Text Available Lung cancer is the leading cause of cancer-related deaths worldwide. Although treatment methods in surgery, irradiation, and chemotherapy have improved, prognosis remains unsatisfactory and developing new therapeutic strategies is still an urgent demand. Immunotherapy is a novel therapeutic approach wherein activated immune cells can specifically kill tumor cells by recognition of tumor-associated antigens without damage to normal cells. Several lung cancer vaccines have demonstrated prolonged survival time in phase II and phase III trials, and several clinical trials are under investigation. However, many clinical trials involving cancer vaccination with defined tumor antigens work in only a small number of patients. Cancer immunotherapy is not completely effective in eradicating tumor cells because tumor cells escape from host immune scrutiny. Understanding of the mechanism of immune evasion regulated by tumor cells is required for the development of more effective immunotherapeutic approaches against lung cancer. This paper discusses the identification of tumor antigens in lung cancer, tumor immune escape mechanisms, and clinical vaccine trials in lung cancer.

  8. Development of a questionnaire to assess patient satisfaction with allergen-specific immunotherapy in adults: item generation, item reduction, and preliminary validation

    Directory of Open Access Journals (Sweden)

    Justícia JL

    2011-05-01

    Full Text Available Jose Luis Justícia1, Eva Baró2, Victoria Cardona3, Pedro Guardia4, Pedro Ojeda5, José Maria Olaguíbel6, José Maria Vega7, Carmen Vidal81Medical Department, Stallergenes Ibérica, Barcelona, Spain; 2Health Outcomes Research Department, 3D Health Research, Barcelona, Spain; 3Hospital Vall d'Hebron, Barcelona, Spain; 4Hospital Virgen Macarena, Sevilla, Spain; 5Clínica de Asma y Alergia Dres. Ojeda, Madrid, Spain; 6Complejo Hospitalario de Navarra, Pamplona, Spain; 7Hospital Regional Universitario Carlos Haya Málaga, Spain; 8Complejo Hospitalario Universitario de Santiago, Santiago de Compostela, SpainBackground: Allergen-specific immunotherapy (SIT is a treatment capable of modifying the natural course of allergy, so ensuring good adherence to SIT is fundamental. Up until now there has not existed an instrument specifically developed to measure patient satisfaction with SIT, although its assessment could help us to comprehend better and improve treatment adherence and effectiveness. The aim of this study was to develop an instrument to measure adult patient satisfaction with SIT.Methods: Items were generated from a literature review, focus groups with allergic adult patients undergoing SIT, and a meeting with experts. Potential items were administered to allergic patients undergoing SIT in an observational, cross-sectional, multicenter study. Item reduction was based on quantitative and qualitative criteria. A preliminary assessment of feasibility, reliability, and validity of the retained items was performed.Results: An initial pool of 70 items was administered to 257 patients undergoing SIT. Fifty-four items were eliminated resulting in a provisional instrument with 16 items. Factor analysis yielded four factors that were identified as perceived efficacy, activities and environment, cost-benefit balance, and overall satisfaction, explaining 74.8% of variance. Ceiling and floor effects were negligible for overall score. Overall score was

  9. Safety and Efficacy of Tree Pollen Specific Immunotherapy on the Ultrarush Administration Schedule Method Using Purethal Trees

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    Andrzej Bozek

    2014-01-01

    Full Text Available Background. Specific immunotherapy (SIT with an ultrarush administration schedule with Purethal for tree pollen allergens has been evaluated to assess its efficacy and safety. Methods. The study group consisted of 22 patients with symptoms of allergic rhinitis and confirmed allergy to tree pollens. Patients were randomized and given an administration schedule of either ultrarush therapy or conventional preseasonal SIT. Treatment was performed during three consecutive years. Results. After three years of treatment, a similar reduction in nasal symptoms was observed; according to the visual analog scale, there was a decrease from 3.991 ± 0.804 points to 1.634 ± 0.540 in the ultrarush group and from 3.845 ± 0.265 to 1.501 ± 0.418 in the group desensitized using the conventional method (P>0.05. There was also a comparable reduction in the use of relief drugs during pollen season and an increase in the serum concentration of IgG4 to tree pollens. No significant differences in the safety profile were observed. Conclusion. An administration schedule of ultrarush SIT with Purethal Trees is a safe treatment in preliminary observations. This therapy is comparable with conventional administration of SIT in the field of efficacy and safety.

  10. Advances in personalized cancer immunotherapy.

    Science.gov (United States)

    Kakimi, Kazuhiro; Karasaki, Takahiro; Matsushita, Hirokazu; Sugie, Tomoharu

    2017-01-01

    There are currently three major approaches to T cell-based cancer immunotherapy, namely, active vaccination, adoptive cell transfer therapy and immune checkpoint blockade. Recently, this latter approach has demonstrated remarkable clinical benefits, putting cancer immunotherapy under the spotlight. Better understanding of the dynamics of anti-tumor immune responses (the "Cancer-Immunity Cycle") is crucial for the further development of this form of treatment. Tumors employ multiple strategies to escape from anti-tumor immunity, some of which result from the selection of cancer cells with immunosuppressive activity by the process of cancer immunoediting. Apart from this selective process, anti-tumor immune responses can also be inhibited in multiple different ways which vary from patient to patient. This implies that cancer immunotherapy must be personalized to (1) identify the rate-limiting steps in any given patient, (2) identify and combine strategies to overcome these hurdles, and (3) proceed with the next round of the "Cancer-Immunity Cycle". Cancer cells have genetic alterations which can provide the immune system with targets by which to recognize and eradicate the tumor. Mutated proteins expressed exclusively in cancer cells and recognizable by the immune system are known as neoantigens. The development of next-generation sequencing technology has made it possible to determine the genetic landscape of human cancer and facilitated the utilization of genomic information to identify such candidate neoantigens in individual cancers. Future immunotherapies will need to be personalized in terms of the identification of both patient-specific immunosuppressive mechanisms and target neoantigens.

  11. Development of Auto Antigen-specific Regulatory T Cells for Diabetes Immunotherapy

    Science.gov (United States)

    2016-01-01

    CD4+ regulatory T cells (Tregs) are essential for normal immune surveillance, and their dysfunction can lead to the development of autoimmune diseases, such as type-1 diabetes (T1D). T1D is a T cell-mediated autoimmune disease characterized by islet β cell destruction, hypoinsulinemia, and severely altered glucose homeostasis. Tregs play a critical role in the development of T1D and participate in peripheral tolerance. Pluripotent stem cells (PSCs) can be utilized to obtain a renewable source of healthy Tregs to treat T1D as they have the ability to produce almost all cell types in the body, including Tregs. However, the right conditions for the development of antigen (Ag)-specific Tregs from PSCs (i.e., PSC-Tregs) remain undefined, especially molecular mechanisms that direct differentiation of such Tregs. Auto Ag-specific PSC-Tregs can be programmed to be tissue-associated and infiltrate to local inflamed tissue (e.g., islets) to suppress autoimmune responses after adoptive transfer, thereby avoiding potential overall immunosuppression from non-specific Tregs. Developing auto Ag-specific PSC-Tregs can reduce overall immunosuppression after adoptive transfer by accumulating inflamed islets, which drives forward the use of therapeutic PSC-Tregs for cell-based therapies in T1D.

  12. Effect of allergen-specific immunotherapy with purified Alt a1 on AMP responsiveness, exhaled nitric oxide and exhaled breath condensate pH: a randomized double blind study

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    Prieto Luis

    2010-09-01

    Full Text Available Abstract Background Little information is available on the effect of allergen-specific immunotherapy on airway responsiveness and markers in exhaled air. The aims of this study were to assess the safety of immunotherapy with purified natural Alt a1 and its effect on airway responsiveness to direct and indirect bronchoconstrictor agents and markers in exhaled air. Methods This was a randomized double-blind trial. Subjects with allergic rhinitis with or without mild/moderate asthma sensitized to A alternata and who also had a positive skin prick test to Alt a1 were randomized to treatment with placebo (n = 18 or purified natural Alt a1 (n = 22 subcutaneously for 12 months. Bronchial responsiveness to adenosine 5'-monophosphate (AMP and methacholine, exhaled nitric oxide (ENO, exhaled breath condensate (EBC pH, and serum Alt a1-specific IgG4 antibodies were measured at baseline and after 6 and 12 months of treatment. Local and systemic adverse events were also registered. Results The mean (95% CI allergen-specific IgG4 value for the active treatment group increased from 0.07 μg/mL (0.03-0.11 at baseline to 1.21 μg/mL (0.69-1.73, P 4 value increased nonsignificantly from 0.09 μg/mL (0.06-0.12 at baseline to 0.13 μg/mL (0.07-0.18 at 6 months and to 0.11 μg/mL (0.07-0.15 at 12 months of treatment. Changes in the active treatment group were significantly higher than in the placebo group both at 6 months (P Conclusion Although allergen-specific immunotherapy with purified natural Alt a1 is well tolerated and induces an allergen-specific IgG4 response, treatment is not associated with changes in AMP or methacholine responsiveness or with significant improvements in markers of inflammation in exhaled air. These findings suggest dissociation between the immunotherapy-induced increase in IgG4 levels and its effect on airway responsiveness and inflammation.

  13. A computational approach to the description of individual immune responses. IgE and IgG-subclass allergen-specific antibodies formed during immunotherapy

    DEFF Research Database (Denmark)

    Søndergaard, I; Poulsen, L K; Osterballe, O;

    1991-01-01

    in the IgG4 antibody response, and for other antigens the opposite was true, indicating a regulatory mechanism between the IgE and the IgG4 synthesis. The IgE immune response to a number of antigens, including the major allergens before the start of immunotherapy, was quantitatively diminished during...... the period of immunotherapy when IgG1 was present early (week 12) in the period, and for other antigens there was a rise in IgE without an early IgG1 antibody response. This suggests that IgG1 can have a regulating influence on the IgE synthesis. Finally, we have found that IgE antibodies with specificities...

  14. [Current Approaches in Cancer Immunotherapy].

    Science.gov (United States)

    Otáhal, P; Trněný, M

    2015-01-01

    Methods of cancer immunotherapy have finally entered clinical medicine after years of preclinical research. Currently, there are several methods, which have proven to be very effective even in cases of incurable cancer. Antitumor monoclonal antibodies are among major therapeutic anti-cancer drugs and have been successfully used for many ears. Novel group of antibodies are immunomodulatory antibodies which can break tumor -specific immune tolerance and induce regression of tumors by nonspecific activation of immune system. Bispecific antibodies represent a novel class of anticancer agents which can induce expansion of T cells in vivo, blinatumomab is an example of such agents and is currently available for the treatment of acute B -cell leukemia. Cellular immunotherapy is also very effective, especially the use of Chimeric receptor modified T-cells for the therapy of B- cell lymphoproliferative diseases. Although it is a very complicated and expensive method, it is highly effective approach which can induce remission even in previously hopeless conditions. The goal of this article is to explain the basic principles of cancer immunotherapy and summarize the newest findings in this field.

  15. Immunotherapy in gastric cancer.

    Science.gov (United States)

    Matsueda, Satoko; Graham, David Y

    2014-02-21

    Gastric cancer is the second most common of cancer-related deaths worldwide. In the majority of cases gastric cancer is advanced at diagnosis and although medical and surgical treatments have improved, survival rates remain poor. Cancer immunotherapy has emerged as a powerful and promising clinical approach for treatment of cancer and has shown major success in breast cancer, prostate cancer and melanoma. Here, we provide an overview of concepts of modern cancer immunotherapy including the theory, current approaches, remaining hurdles to be overcome, and the future prospect of cancer immunotherapy in the treatment of gastric cancer. Adaptive cell therapies, cancer vaccines, gene therapies, monoclonal antibody therapies have all been used with some initial successes in gastric cancer. However, to date the results in gastric cancer have been disappointing as current approaches often do not stimulate immunity efficiently allowing tumors continue to grow despite the presence of a measurable immune response. Here, we discuss the identification of targets for immunotherapy and the role of biomarkers in prospectively identifying appropriate subjects or immunotherapy. We also discuss the molecular mechanisms by which tumor cells escape host immunosurveillance and produce an immunosuppressive tumor microenvironment. We show how advances have provided tools for overcoming the mechanisms of immunosuppression including the use of monoclonal antibodies to block negative regulators normally expressed on the surface of T cells which limit activation and proliferation of cytotoxic T cells. Immunotherapy has greatly improved and is becoming an important factor in such fields as medical care and welfare for human being. Progress has been rapid ensuring that the future of immunotherapy for gastric cancer is bright.

  16. Distinct modulation of allergic T cell responses by subcutaneous vs. sublingual allergen-specific immunotherapy

    DEFF Research Database (Denmark)

    Schulten, V; Tripple, V; Aasbjerg, Kristian

    2016-01-01

    injections or SLIT tablets or neither. PBMCs were tested for Timothy grass (TG)-specific cytokine production by ELISPOT after in vitro expansion with TG-peptide pools. Phenotypic characterization of cytokine-producing cells was performed by FACS. RESULTS: In the SCIT group, decreased IL-5 production...... was observed starting 10 months after treatment commenced. At 24 months, T cell responses showed IL-5 levels significantly below the before-treatment baseline. No significant reduction of IL-5 was observed in the SLIT or untreated group. However, a significant transient increase in IL-10 production after 10......: The most dominant immunological changes on a cellular level were a decrease in IL-5 in the SCIT group and a significant, transient increase of IL-10 observed after 10 months of treatment in both treated groups. The distinct routes of AIT administration may induce different immunomodulatory mechanisms...

  17. Specific immunotherapy in atopic dermatitis--Four-year treatment in different age and airborne allergy type subgroups.

    Science.gov (United States)

    Czarnecka-Operacz, Magdalena; Silny, Wojciech

    2006-01-01

    Atopic dermatitis (AD) is a common inflammatory disease involving the skin and frequently other organs and systems such as respiratory system. The recently recognized atopic nature of the skin inflammation in AD has raised a growing interest in the treatment with allergen-specific immunotherapy (SIT). In this study, the efficacy of SIT was evaluated in a group of 37 AD patients aged 5-44 years: 14 allergic to house dust mites (HDM), 17 to grass pollen allergens, and 6 allergic to grass and mugwort pollen allergens. IgE-mediated airborne allergy was well documented in all cases. SIT was performed with Novo Helisen Depot allergy vaccines of appropriate composition. Control group included 29 patients with AD and confirmed IgE-mediated airborne allergy to analogous allergens: HDM, 14 patients; grass pollen allergens, 11 patients; and grass and mugwort pollen allergens, 4 patients. Conventional methods of AD treatment were used in the control group. Clinical evaluation of patients was performed with W-AZS index after 12, 24, 36 and 48 months of therapy. SIT was found to be an efficacious and safe method of treatment for selected patients with AD and IgE-mediated airborne allergy. The efficacy of this therapeutic method was significantly higher than that recorded by conventional methods used in the control group in all 3 age subgroups and all 3 types of airborne allergy (HDM, grass pollen, and grass and mugwort pollen). It is concluded that SIT may be highly promising method of controlling skin inflammation in AD with the potential to prevent the development of AD into respiratory allergy.

  18. Effect of allergen-specific immunotherapy on recombinant human interleukin 3-mediated amplification of allergen-induced basophil histamine release.

    Science.gov (United States)

    Kowal, Krzysztof; Nolte, Hendrik; Skov, Per Stahl; DuBuske, Lawrence M

    2005-01-01

    Decreased allergen-induced histamine release from peripheral blood basophils in allergic rhinitis patients treated with specific immunotherapy (SIT) correlates with clinical outcomes of SIT. The aim of this study was to investigate if decreased histamine release is a permanent effect of SIT. Fifty-one patients (mean age, 35.3 years) with allergic rhinitis, diagnosed based on clinical history and positive skin-prick test results to common aeroallergens, were studied. Twenty-three patients had never received SIT (group A), and 28 patients had been treated with inhalant allergen extracts (group B). Eleven patients from group A participated in a prospective part of this study. Basophil histamine release in these patients was evaluated before (TO) and after-1 year (TI) of SIT. Histamine release from peripheral blood with and without interleukin (IL)-3 pretreatment was performed using the glass-fiber-based histamine release test. Brief pretreatment of whole blood basophils with one of the four concentrations (0.01, 0.1, 1, or 10 ng/mL) of recombinant human IL(rhIL)-3, rhIL-5, or rh-granulocyte-macrophage colony-stimulating factor resulted in a significant amplification of allergen-induced basophil histamine release. The amplification using cytokines at the optimal concentrations was the greatest with rhIL-3 and the lowest with rhIL-5; therefore, for further studies rhIL-3 was used. Prospective analysis showed no significant difference in allergen-induced basophil histamine release on rhIL-3 pretreatment after 1 year of SIT (192.7 +/- 75.3 ng and 176.1 +/- 76.4 ng for T0 and T1, respectively; p = 0.18). Short-term SIT does not decrease rhIL-3-mediated amplification of allergen-induced histamine release from peripheral blood basophils.

  19. Microarray gene expression analysis to evaluate cell type specific expression of targets relevant for immunotherapy of hematological malignancies

    NARCIS (Netherlands)

    M.J. Pont (Margot); M.W. Honders; A.N. Kremer; C. van Kooten (Cees); C. Out; P.S. Hiemstra (Pieter); H.C. De Boer; M.J. Jager (Martine); E. Schmelzer; R.G.J. Vries (Robert); A.S. Al Hinai; W.G. Kroes (W.); R. Monajemi (Ramin); J.J. Goeman (Jelle); S. Böhringer (Stefan); W.A.F. Marijt; J.H.F. Falkenburg (Frederik); M. Griffioen

    2016-01-01

    textabstractCellular immunotherapy has proven to be effective in the treatment of hematological cancers by donor lymphocyte infusion after allogeneic hematopoietic stem cell transplantation and more recently by targeted therapy with chimeric antigen or T-cell receptor-engineered T cells. However, de

  20. Microarray evidence of glutaminyl cyclase gene expression in melanoma: implications for tumor antigen specific immunotherapy

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    Gillis John

    2006-07-01

    Full Text Available Abstract Background In recent years encouraging progress has been made in developing vaccine treatments for cancer, particularly with melanoma. However, the overall rate of clinically significant results has remained low. The present research used microarray datasets from previous investigations to examine gene expression patterns in cancer cell lines with the goal of better understanding the tumor microenvironment. Methods Principal Components Analyses with Promax rotational transformations were carried out with 90 cancer cell lines from 3 microarray datasets, which had been made available on the internet as supplementary information from prior publications. Results In each of the analyses a well defined melanoma component was identified that contained a gene coding for the enzyme, glutaminyl cyclase, which was as highly expressed as genes from a variety of well established biomarkers for melanoma, such as MAGE-3 and MART-1, which have frequently been used in clinical trials of melanoma vaccines. Conclusion Since glutaminyl cyclase converts glutamine and glutamic acid into a pyroglutamic form, it may interfere with the tumor destructive process of vaccines using peptides having glutamine or glutamic acid at their N-terminals. Finding ways of inhibiting the activity of glutaminyl cyclase in the tumor microenvironment may help to increase the effectiveness of some melanoma vaccines.

  1. A review of clinical efficacy, safety, new developments and adherence to allergen-specific immunotherapy in patients with allergic rhinitis caused by allergy to ragweed pollen (Ambrosia artemisiifolia)

    Science.gov (United States)

    Turkalj, Mirjana; Banic, Ivana; Anzic, Srdjan Ante

    2017-01-01

    Allergic rhinitis is a common health problem in both children and adults. The number of patients allergic to ragweed (Ambrosia artemisiifolia) is on the rise throughout Europe, having a significant negative impact on the patients’ and their family’s quality of life. Allergen-specific immunotherapy (AIT) has disease-modifying effects and can induce immune tolerance to allergens. Both subcutaneous immunotherapy and sublingual immunotherapy with ragweed extracts/preparations have clear positive clinical efficacy, especially over pharmacological treatment, even years after the treatment has ended. AIT also has very good safety profiles with extremely rare side effects, and the extracts/preparations used in AIT are commonly well tolerated by patients. However, patient adherence to treatment with AIT seems to be quite low, mostly due to the fact that treatment with AIT is relatively time-demanding and, moreover, due to patients not receiving adequate information and education about the treatment before it starts. AIT is undergoing innovations and improvements in clinical efficacy, safety and patient adherence, especially with new approaches using new adjuvants, recombinant or modified allergens, synthetic peptides, novel routes of administration (epidermal or intralymphatic), and new protocols, which might make AIT more acceptable for a wider range of patients and novel indications. Patient education and support (eg, recall systems) is one of the most important goals for AIT in the future, to further enhance treatment success.

  2. Allergy immunotherapy across the life cycle to promote active and healthy ageing

    DEFF Research Database (Denmark)

    Calderon, M A; Demoly, P; Casale, T

    2016-01-01

    Allergic diseases often occur early in life and persist throughout life. This life-course perspective should be considered in allergen immunotherapy. In particular it is essential to understand whether this al treatment may be used in old age adults. The current paper was developed by a working g...

  3. Allergy immunotherapy across the life cycle to promote active and healthy ageing: From research to policies

    NARCIS (Netherlands)

    M. Calderon (Moises); P. Demoly; T.B. Casale (Thomas); C.A. Akdis; C. Bachert (Claus); Bewick, M.; Bilò, B.M.; B. Bohle (B.); S. Bonini (Sergio); A. Bush (Andrew); Caimmi, D.P.; G. Canonica (Gwalter); D. Cardona (Doris); A.M. Chiriac (A.); L. Cox (Linda); A. Custovic; F. de Blay; Devillier, P.; Didier, A.; Di Lorenzo, G.; G. Du Toit (George); S.R. Durham (Stephen); C. Eng (Charis); A. Fiocchi (Alessandro); Fox, A.T.; R.G. van Wijk (Roy Gerth); Gomez, R.M.; Haathela, T.; S. Halken (Susanne); P.W. Hellings (P.); L. Jacobsen; P.M. Just; Tanno, L.K.; J. Kleine-Tebbe (Jörg); L. Klimek (Ludger); E.F. Knol (Edward Frank); P. Kuna; D. Larenas-Linnemann (Désirée); A. Linneberg (Allan); Matricardi, M.; H.-J. Malling; Moesges, R.; Mullol, J.; Muraro, A.; N. Papadopoulos; G. Passalacqua (Giovanni); Pastorello, E.; O. Pfaar (Oliver); D. Price (David); P.R. Del Rio (P. Rodriguez); Ruëff, R.; Samolinski, B.; G.K. Scadding; Senti, G.; Shamji, M.H.; A. Sheikh (Aziz); J.C. Sisul (J.); D. Solé (D.); G.J. Sturm; Tabar, A.; R. Van Ree; Ventura, M.T.; C. Vidal (Carmen); E.M. Varga; M. Worm (M.); T. Zuberbier (Torsten); J. Bousquet (Jean)

    2016-01-01

    textabstractAllergic diseases often occur early in life and persist throughout life. This life-course perspective should be considered in allergen immunotherapy. In particular it is essential to understand whether this al treatment may be used in old age adults. The current paper was developed by a

  4. Low-Dose Cyclophosphamide Synergizes with Dendritic Cell-Based Immunotherapy in Antitumor Activity

    Directory of Open Access Journals (Sweden)

    Joris D. Veltman

    2010-01-01

    Full Text Available Clinical immunotherapy trials like dendritic cell-based vaccinations are hampered by the tumor's offensive repertoire that suppresses the incoming effector cells. Regulatory T cells are instrumental in suppressing the function of cytotoxic T cells. We studied the effect of low-dose cyclophosphamide on the suppressive function of regulatory T cells and investigated if the success rate of dendritic cell immunotherapy could be improved. For this, mesothelioma tumor-bearing mice were treated with dendritic cell-based immunotherapy alone or in combination with low-dose of cyclophosphamide. Proportions of regulatory T cells and the cytotoxic T cell functions at different stages of disease were analyzed. We found that low-dose cyclophosphamide induced beneficial immunomodulatory effects by preventing the induction of Tregs, and as a consequence, cytotoxic T cell function was no longer affected. Addition of cyclophosphamide improved immunotherapy leading to an increased median and overall survival. Future studies are needed to address the usefulness of this combination treatment for mesothelioma patients.

  5. Effects of dermatophagoides pteronyssinus allergen-specific immunotherapy on the serum interleukin-13 and pulmonary functions in asthmatic children

    Institute of Scientific and Technical Information of China (English)

    CHEN Zhuang-gui; LI Ming; CHEN Yan-feng; JI Jing-zhi; LI Ya-ting; CHEN Wei; CHEN Fen-hua; CHEN Hong

    2009-01-01

    Background Airway remodeling is the specific pathological characteristics of asthma, which is related to the clinical symptoms, pulmonary function, and airway hyperreactivity. This study aimed at exploring the effects of dermatophagoides pteronyssinus allergen-specific immunotherapy (SIT) on the serum interleukin (IL)-13 and pulmonary functions in asthmatic children.Methods Fifty-eight pediatric asthma patients allergic to dust mite participated in this study. Thirty-five children received SIT with a standardized dermatophagoides pteronyssinus extract for one year (SIT group), and the other 23 children treated with inhaled corticosteroids (ICS group) according to the Global Initiative for Asthma (GINA) for one year. Serum levels of IL-13, IL-4 and interferon (IFN)-y were examined and the pulmonary functions were checked before and after the treatment.Results After the treatment, the number of emergency visiting for asthma attack in SIT group was significantly less than that in ICS group. The serum levels of IL-4 and IL-13 were clearly reduced, IFN-γ and the ratio of IFN-γ/IL-4 were significantly increased, the pulmonary functions (forced vital capacity (FVC), forced expiratory volume in one second percentage (FEV1%) and peak expiratory flow percentage (PEF%) were significantly improved in the SIT group.Meanwhile, IFN-y and the ratio of IFN-γ/IL-4 were greatly increased, but serum levels of IL-4 and IL-13 had less changes,the pulmonary functions (FVC, FEV1% and PEF%) were poorly improved in ICS group. The basic pulmonary functions in both groups were at the same level, which had made more improvement in SIT group than in ICS group one year later.Conclusions One year of dermatophagoides pteronyssinus SIT can significantly reduce the frequencies of emergency visiting for asthma attack and improve the pulmonary functions of children with allergic asthma, and that is attributed to SIT, which can reduce the levels of IL-4 and IL-13 and regulate the imbalance of the

  6. Regulation of Gag- and Env-Specific CD8+ T Cell Responses in ART-Naive HIV-Infected Patients: Potential Implications for Individualized Immunotherapy.

    Directory of Open Access Journals (Sweden)

    Christian Prebensen

    Full Text Available Strategies to develop a functional cure for HIV infection will likely require boosting of effector T cell responses to eliminate reactivated, latently infected cells. We have recently explored an assay for assessing antigen-specific regulation of T cell proliferation, which was related to clinical progression in untreated patients and to vaccine efficacy in two trials of therapeutic Gag-based vaccines. We here expand the same assay to further investigate regulation mediated by various inhibitory pathways. Peripheral blood mononuclear cells from 26 asymptomatic HIV-infected, antiretroviral therapy-naïve patients were stimulated with Gag and Env overlapping peptide panels for 5 days. Monoclonal antibodies (mAbs blocking inhibitory mediators interleukin (IL 10, transforming growth factor (TGF β, programmed death ligand (PD-L 1 and herpes virus entry mediator (HVEM were added to parallel cultures. Functional T cell regulation (FTR was defined as the difference in proliferation between stimulated cultures with and without blocking mAbs. FTR was detected in 54% of patients. Blockade of IL-10/PD-L1 and IL10/TGF-β detected all cases with Gag- and Env-associated FTR, respectively. In accordance with previous findings, isolated Env FTR was associated with higher plasma HIV RNA and lower CD4 counts, while patients with both Gag and Env FTR also had higher Gag- and Env-specific proliferative CD8+ T cell responses. There was no association between FTR and frequencies of activated regulatory T cells. In conclusion, we observed substantial heterogeneity in FTR between patients, inhibitory pathways and HIV antigens. FTR may help to individualize immunomodulation and warrants further assessment in clinical immunotherapy trials.

  7. Regulation of Gag- and Env-Specific CD8+ T Cell Responses in ART-Naïve HIV-Infected Patients: Potential Implications for Individualized Immunotherapy.

    Science.gov (United States)

    Prebensen, Christian; Lind, Andreas; Dyrhol-Riise, Anne-Ma; Kvale, Dag

    2016-01-01

    Strategies to develop a functional cure for HIV infection will likely require boosting of effector T cell responses to eliminate reactivated, latently infected cells. We have recently explored an assay for assessing antigen-specific regulation of T cell proliferation, which was related to clinical progression in untreated patients and to vaccine efficacy in two trials of therapeutic Gag-based vaccines. We here expand the same assay to further investigate regulation mediated by various inhibitory pathways. Peripheral blood mononuclear cells from 26 asymptomatic HIV-infected, antiretroviral therapy-naïve patients were stimulated with Gag and Env overlapping peptide panels for 5 days. Monoclonal antibodies (mAbs) blocking inhibitory mediators interleukin (IL) 10, transforming growth factor (TGF) β, programmed death ligand (PD-L) 1 and herpes virus entry mediator (HVEM) were added to parallel cultures. Functional T cell regulation (FTR) was defined as the difference in proliferation between stimulated cultures with and without blocking mAbs. FTR was detected in 54% of patients. Blockade of IL-10/PD-L1 and IL10/TGF-β detected all cases with Gag- and Env-associated FTR, respectively. In accordance with previous findings, isolated Env FTR was associated with higher plasma HIV RNA and lower CD4 counts, while patients with both Gag and Env FTR also had higher Gag- and Env-specific proliferative CD8+ T cell responses. There was no association between FTR and frequencies of activated regulatory T cells. In conclusion, we observed substantial heterogeneity in FTR between patients, inhibitory pathways and HIV antigens. FTR may help to individualize immunomodulation and warrants further assessment in clinical immunotherapy trials.

  8. Measurement of serum antibodies against NY-ESO-1 by ELISA: A guide for the treatment of specific immunotherapy for patients with advanced colorectal cancer.

    Science.gov (United States)

    Long, Yan-Yan; Wang, Yu; Huang, Qian-Rong; Zheng, Guang-Shun; Jiao, Shun-Chang

    2014-10-01

    NY-ESO-1 has been identified as one of the most immunogenic antigens; thus, is a highly attractive target for cancer immunotherapy. The present study analyzed the expression of serum antibodies (Abs) against NY-ESO-1 in patients with advanced colorectal cancer (CRC), with the aim of guiding the treatment of NY-ESO-1-based specific-immunotherapy for these patients. Furthermore, the present study was the first to evaluate the kinetic expression of anti-NY-ESO-1 Abs and investigate the possible influencing factors. A total of 239 serum samples from 155 pathologically confirmed patients with advanced CRC (stages III and IV) were collected. The presence of spontaneous Abs against NY-ESO-1 was analyzed using an enzyme-linked immunosorbent assay (ELISA). The results demonstrated that 24.5% (38/155) of the investigated patients were positive for NY-ESO-1-specific Abs. No statistically significant correlations were identified between the expression of anti-NY-ESO-1 Abs and clinicopathological parameters, including age and gender, location, grading, local infiltration, lymph node status, metastatic status and K-ras mutation status (P>0.05). In 59 patients, the kinetic expression of anti-NY-ESO-1 Abs was analyzed, of which 14 patients were initially positive and 45 patients were initially negative. Notably, 16/59 (27.1%) patients changed their expression status during the study period, and the initially positive patients were more likely to change compared with the initially negative patients (85.7 vs. 8.8%; PESO-1 by ELISA is an easy and feasible method. The high expression rate of NY-ESO-1-specific Abs in CRC patients indicates that measuring the levels of serum Abs against NY-ESO-1 may guide the treatment of NY-ESO-1-based specific immunotherapy for patients with advanced CRC.

  9. Carbon anhydrase IX specific immune responses in patients with metastatic renal cell carcinoma potentially cured by interleukin-2 based immunotherapy

    DEFF Research Database (Denmark)

    Rasmussen, Susanne; Donskov, Frede; Pedersen, Johannes W

    2013-01-01

    Abstract The majority of clear-cell renal cell carcinomas (ccRCC) show high and homogeneous expression levels of the tumor associated antigen (TAA) carbonic anhydrase IX (CAIX), and treatment with interleukin-2 (IL-2) based immunotherapy can lead to cure in patients with metastatic renal cell...... of disease (NED) following treatment with IL-2 based immunotherapy, and thus potentially cured. Immune reactivity in these patients was compared with samples from patients with dramatic tumor response obtained immediately at the cessation of therapy, samples from patients that experienced progressive disease...... interest in future cancer vaccines, but more studies are needed to elucidate the immunological mechanisms of action in potentially cured patients treated with an immunotherapeutic agent....

  10. Microarray Gene Expression Analysis to Evaluate Cell Type Specific Expression of Targets Relevant for Immunotherapy of Hematological Malignancies.

    Directory of Open Access Journals (Sweden)

    M J Pont

    Full Text Available Cellular immunotherapy has proven to be effective in the treatment of hematological cancers by donor lymphocyte infusion after allogeneic hematopoietic stem cell transplantation and more recently by targeted therapy with chimeric antigen or T-cell receptor-engineered T cells. However, dependent on the tissue distribution of the antigens that are targeted, anti-tumor responses can be accompanied by undesired side effects. Therefore, detailed tissue distribution analysis is essential to estimate potential efficacy and toxicity of candidate targets for immunotherapy of hematological malignancies. We performed microarray gene expression analysis of hematological malignancies of different origins, healthy hematopoietic cells and various non-hematopoietic cell types from organs that are often targeted in detrimental immune responses after allogeneic stem cell transplantation leading to graft-versus-host disease. Non-hematopoietic cells were also cultured in the presence of IFN-γ to analyze gene expression under inflammatory circumstances. Gene expression was investigated by Illumina HT12.0 microarrays and quality control analysis was performed to confirm the cell-type origin and exclude contamination of non-hematopoietic cell samples with peripheral blood cells. Microarray data were validated by quantitative RT-PCR showing strong correlations between both platforms. Detailed gene expression profiles were generated for various minor histocompatibility antigens and B-cell surface antigens to illustrate the value of the microarray dataset to estimate efficacy and toxicity of candidate targets for immunotherapy. In conclusion, our microarray database provides a relevant platform to analyze and select candidate antigens with hematopoietic (lineage-restricted expression as potential targets for immunotherapy of hematological cancers.

  11. Microarray Gene Expression Analysis to Evaluate Cell Type Specific Expression of Targets Relevant for Immunotherapy of Hematological Malignancies

    OpenAIRE

    Pont, M. J.; Honders, M.W.; Kremer, A. N.; van Kooten, C.; C Out; Hiemstra, P. S.; de Boer, H. C.; Jager, M J; Schmelzer, E; Vries, R.G.; A S Al Hinai; Kroes, W. G.; Monajemi, R.; Goeman, J.J.; Böhringer, S

    2016-01-01

    Cellular immunotherapy has proven to be effective in the treatment of hematological cancers by donor lymphocyte infusion after allogeneic hematopoietic stem cell transplantation and more recently by targeted therapy with chimeric antigen or T-cell receptor-engineered T cells. However, dependent on the tissue distribution of the antigens that are targeted, anti-tumor responses can be accompanied by undesired side effects. Therefore, detailed tissue distribution analysis is essential to estimat...

  12. Microarray Gene Expression Analysis to Evaluate Cell Type Specific Expression of Targets Relevant for Immunotherapy of Hematological Malignancies.

    Science.gov (United States)

    Pont, M J; Honders, M W; Kremer, A N; van Kooten, C; Out, C; Hiemstra, P S; de Boer, H C; Jager, M J; Schmelzer, E; Vries, R G; Al Hinai, A S; Kroes, W G; Monajemi, R; Goeman, J J; Böhringer, S; Marijt, W A F; Falkenburg, J H F; Griffioen, M

    2016-01-01

    Cellular immunotherapy has proven to be effective in the treatment of hematological cancers by donor lymphocyte infusion after allogeneic hematopoietic stem cell transplantation and more recently by targeted therapy with chimeric antigen or T-cell receptor-engineered T cells. However, dependent on the tissue distribution of the antigens that are targeted, anti-tumor responses can be accompanied by undesired side effects. Therefore, detailed tissue distribution analysis is essential to estimate potential efficacy and toxicity of candidate targets for immunotherapy of hematological malignancies. We performed microarray gene expression analysis of hematological malignancies of different origins, healthy hematopoietic cells and various non-hematopoietic cell types from organs that are often targeted in detrimental immune responses after allogeneic stem cell transplantation leading to graft-versus-host disease. Non-hematopoietic cells were also cultured in the presence of IFN-γ to analyze gene expression under inflammatory circumstances. Gene expression was investigated by Illumina HT12.0 microarrays and quality control analysis was performed to confirm the cell-type origin and exclude contamination of non-hematopoietic cell samples with peripheral blood cells. Microarray data were validated by quantitative RT-PCR showing strong correlations between both platforms. Detailed gene expression profiles were generated for various minor histocompatibility antigens and B-cell surface antigens to illustrate the value of the microarray dataset to estimate efficacy and toxicity of candidate targets for immunotherapy. In conclusion, our microarray database provides a relevant platform to analyze and select candidate antigens with hematopoietic (lineage)-restricted expression as potential targets for immunotherapy of hematological cancers.

  13. Progress in mechanism of specific immunotherapy%特异性免疫治疗机制的研究进展

    Institute of Scientific and Technical Information of China (English)

    胡亚琼

    2011-01-01

    特异性免疫治疗是治疗过敏性疾病的最有效方法,至今已有90多年的历史.其机制尚未明确,早期的研究重点集中于循环抗体和效应细胞,目前主要集中于免疫治疗对T细胞的作用及由此引起的一系列细胞因子的变化、CD4+调节性T细胞亚群、修饰抗原递呈细胞诱导免疫耐受、免疫效应细胞募集机制、单克隆技术支持下的重组变应原、变应原DNA疫苗、变应原耦联佐剂.%Specific immunotherapy(SIT)is the most effective therapy for allergies.Although specific immunotherapy has existed for more than 90 years and has made a great progress,its mechanism is not well defined.Early studies focused on the circulating antibodies and effector cells.At present.the research of the mechanism mainly concentrates on the immune therapy on T cells role and a series of cytokines arising from the change,CD4+ regulatory T cells subsets,modified APC induction of immune tolerance,aggregation mechanism of immune effector cells,restructuring allergens under the support of monoclonal antibody technique,allergens DNA vaccines,allergens coupling adjuvants.This essay is a review of progress in mechanism of specific immunotherapy.

  14. Basics of cancer immunotherapy.

    Science.gov (United States)

    Fujioka, Yuki; Nishikawa, Hiroyoshi

    The immune system is the body's defense against infectious organisms and other invaders including cancer cells. Cancer immunotherapy, which employs our own immune systems to attack cancer cells, is now emerging as a promising modality of cancer treatment based upon the clinical successes of immune checkpoint blockade and adoptive T cell transfer. In hematologic malignancies, clinical application of anti-PD-1 mAb and CAR (chimeric antigen receptor) T therapy is now being extensively tested in Hodgkin's disease, multiple myeloma, and CD19(+) acute lymphocytic leukemia. In sharp contrast to conventional anti-cancer reagents which directly kill cancer cells, cancer immunotherapy activates various types of immune effector cells to attack cancer cells. However, more than half of the treated patients showed no activation of anti-tumor CD8(+) killer T cells and CD4(+) helper T cells and failed to respond to immune therapies such as immune checkpoint blockade, even when administered in combination regimens. Thus, development of novel immunotherapies to achieve more effective activation of anti-cancer immunity and immuno-monitoring of biomarkers, allowing proper evaluation of immune responses in cancer patients in order to detect responders, are urgent issues. Additionally, we must pay attention to characteristic immunological side effects not observed following treatment with conventional anti-cancer reagents. Herein, we present a summary outline and discuss the future direction of cancer immunotherapy.

  15. Systemic Reactions Induced by Allergen Specific Immunotherapy%变应原免疫治疗致全身反应

    Institute of Scientific and Technical Information of China (English)

    关凯; 文昭明

    2011-01-01

    目的 对变应原免疫治疗过程中发生的全身反应进行临床观察,以期找到其发生规律,便于及时发现、处理和预防.方法 回顾近15年接受变应原免疫治疗(AIT)过程中出现全身反应的29例患者,依据反应发生时间与程度按欧洲变态反应和临床免疫学会(EAACI)分类标准分为4级.结果 29例患者均为吸入变应原致呼吸道过敏性疾病,在AIT过程中共出现59例次全身反应.29例患者中男女比例17:12,开始接受AIT的平均年龄为27.3岁(6~59岁).吸入变应原致敏情况:夏秋花粉24例(蒿属花粉22例、葎草花粉1例、混合夏秋花粉1例),蚕丝4例,交链孢霉1例.皮下注射后症状出现时间:≤20 min占67.8% (40/59),≤30 min占84.7% (50/59).59例次全身反应中,荨麻疹占55.9% (33/59),哮喘占50.9% (30/59),上呼吸道过敏症状占23.7%(14/59),喉水肿占5.1% (3/59),低血容量休克占1.7%(1/59).全身反应中,较轻的Ⅰ类和Ⅱ类占76.3% (45/59),较重的Ⅲ类和Ⅳ类均发生于皮下注射后15 min内.结论 全身反应严重程度与皮试反应强度无关.AIT注射后应留院密切观察,特别是前15 min应予充分重视.%Objective Systemic reactions induced by allergen specific immunotherapy (SIT) injections can be observed in clinical practice, which are rarely life-threaten but the most dangerous reactions. Summary of the clinical features will benefit to early recognition, adequate management and prevention of systemic reactions. Methods Systemic reactions were collected and reviewed from patients who were prescribed SIT by using aqueous allergen extracts during the past fifteen years from Department of Allergy, Peking Union Medical College Hospital. All systemic reactions were graded into level I to IV based on the grading system of EAACI Immunotherapy Position Paper, according to the onset and severity of clinical symptoms. Results 59 systemic reactions were collected from 29 respiratory allergic

  16. Current progress in immunotherapy for pancreatic cancer.

    Science.gov (United States)

    Foley, Kelly; Kim, Victoria; Jaffee, Elizabeth; Zheng, Lei

    2016-10-10

    Pancreatic cancer remains one of the most lethal cancers with few treatment options. Immune-based strategies to treat pancreatic cancer, such as immune checkpoint inhibitors, therapeutic vaccines, and combination immunotherapies, are showing promise where other approaches have failed. Immune checkpoint inhibitors, including anti-CTLA4, anti-PD-1, and anti-PD-L1 antibodies, are effective as single agents in immune sensitive cancers like melanoma, but lack efficacy in immune insensitive cancers including pancreatic cancer. However, these inhibitors are showing clinical activity, even in traditionally non-immunogenic cancers, when combined with other interventions, including chemotherapy, radiation therapy, and therapeutic vaccines. Therapeutic vaccines given together with immune modulating agents are of particular interest because vaccines are the most efficient way to induce effective anti-tumor T cell responses, which is required for immunotherapies to be effective. In pancreatic cancer, early studies suggest that vaccines can induce T cells that have the potential to recognize and kill pancreatic cancer cells, but the tumor microenvironment inhibits effective T cell trafficking and function. While progress has been made in the development of immunotherapies for pancreatic cancer over the last several years, additional trials are needed to better understand the signals within the tumor microenvironment that are formidable barriers to T cell infiltration and function. Additionally, as more pancreatic specific antigens are identified, immunotherapies will continue to be refined to provide the most significant clinical benefit.

  17. Immunotherapy of non-Hodgkin's lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells.

    Science.gov (United States)

    Turtle, Cameron J; Hanafi, Laïla-Aïcha; Berger, Carolina; Hudecek, Michael; Pender, Barbara; Robinson, Emily; Hawkins, Reed; Chaney, Colette; Cherian, Sindhu; Chen, Xueyan; Soma, Lorinda; Wood, Brent; Li, Daniel; Heimfeld, Shelly; Riddell, Stanley R; Maloney, David G

    2016-09-07

    CD19-specific chimeric antigen receptor (CAR)-modified T cells have antitumor activity in B cell malignancies, but factors that affect toxicity and efficacy have been difficult to define because of differences in lymphodepletion and heterogeneity of CAR-T cells administered to individual patients. We conducted a clinical trial in which CD19 CAR-T cells were manufactured from defined T cell subsets and administered in a 1:1 CD4(+)/CD8(+) ratio of CAR-T cells to 32 adults with relapsed and/or refractory B cell non-Hodgkin's lymphoma after cyclophosphamide (Cy)-based lymphodepletion chemotherapy with or without fludarabine (Flu). Patients who received Cy/Flu lymphodepletion had increased CAR-T cell expansion and persistence, and higher response rates [50% complete remission (CR), 72% overall response rate (ORR)] than patients who received Cy-based lymphodepletion without Flu (8% CR, 50% ORR). The CR rate in patients treated with Cy/Flu at the maximally tolerated dose was 64% (82% ORR; n = 11). Cy/Flu minimized the effects of an immune response to the murine single-chain variable fragment component of the CAR, which limited CAR-T cell expansion and clinical efficacy in patients who received Cy-based lymphodepletion without Flu. Severe cytokine release syndrome (sCRS) and grade ≥3 neurotoxicity were observed in 13 and 28% of all patients, respectively. Serum biomarkers, one day after CAR-T cell infusion, correlated with subsequent sCRS and neurotoxicity. Immunotherapy with CD19 CAR-T cells in a defined CD4(+)/CD8(+) ratio allowed identification of correlative factors for CAR-T cell expansion, persistence, and toxicity, and facilitated optimization of lymphodepletion that improved disease response and overall and progression-free survival.

  18. Immunotherapy for gastric premalignant lesions and cancer.

    Science.gov (United States)

    Zorzetto, Valerio; Maddalo, Gemma; Basso, Daniela; Farinati, Fabio

    2012-06-01

    Chronic atrophic gastritis, a precancerous change for gastric cancer, shows a loss of appropriate glands, Helicobacter pylori infection and autoimmune gastritis being the two main etiologic factors. While H. pylori eradication is the mandatory treatment for the former, no etiologic treatment is available for the latter, in which a Th1-type response, modulated by Tregs and Th17 cells, is involved. H. pylori-related atrophic gastritis is a risk factor for gastric adenocarcinoma, while autoimmune atrophic gastritis is also linked to a substantial risk of gastric type I carcinoid, related to the chronic stimulus exerted by hypergastrinemia on enterochromaffin-like cells. Several studies have been published on gastric cancer treatment through an active specific immunotherapy, aimed at improving the immunoregulatory response and increasing the circulating tumor-specific T cells. No study on immunotherapy of carcinoids is available but, in our experience, the administration of an antigastrin 17 vaccine induced carcinoid regression in two out of three patients treated.

  19. Melanoma immunotherapy.

    Science.gov (United States)

    Sivendran, Shanthi; Glodny, Bradley; Pan, Michael; Merad, Miriam; Saenger, Yvonne

    2010-01-01

    Melanoma immunotherapy has been an area of intense research for decades, and this work is now yielding more tangible results for patients. Work has focused on 4 main areas: cytokine therapy, administration of immune-modulating antibodies, adoptive T-cell therapy, and vaccines. Cytokine therapy is an established treatment for advanced melanoma, and immune-modulating antibodies have recently emerged as an exciting new area of drug development with efficacy now established in a phase III trial. Adoptive T-cell therapy provides the proof of principle that T cells can attack and eliminate tumors. It has been challenging, however, to adapt this treatment for widespread use. Vaccines have generally yielded poor results, but intratumor pathogen-based strategies have shown encouraging results in recent trials, perhaps due to stronger immune stimulation. A review of the field of melanoma immunotherapy is provided here, with emphasis on those agents that have reached clinical testing. Novel strategies to induce the immune system to attack melanomas are reviewed. In the future, it is envisioned that immunotherapy will have further application in combination with cytotoxic and targeted therapies.

  20. Application of nanostructured drug delivery systems in immunotherapy of cancer: a review.

    Science.gov (United States)

    Asadi, Nahideh; Davaran, Soodabeh; Panahi, Yunes; Hasanzadeh, Arash; Malakootikhah, Javad; Fallah Moafi, Hadi; Akbarzadeh, Abolfazl

    2017-02-01

    The cancer immunotherapy method uses the specificity of the immune system to provide a more effective than more conventional treatments, such as chemotherapy and radiotherapy. Immunotherapy has two main strategies (passive or active) to organize the immune system. Passive strategies use advantage of tumor-hyperpermeable cells, which have enhanced permeability and retention effects. Nanoparticles due to their better accumulation within tissues and cells of the immune system are well suitable for delivery of immune therapies such as vaccines or adjuvants. In this review, we explained application of nanotechnology in immunotherapy of cancer.

  1. Genomic determinants of cancer immunotherapy.

    Science.gov (United States)

    Miao, Diana; Van Allen, Eliezer M

    2016-08-01

    Cancer immunotherapies - including therapeutic vaccines, adoptive cell transfer, oncolytic viruses, and immune checkpoint blockade - yield durable responses in many cancer types, but understanding of predictors of response is incomplete. Genomic characterization of human cancers has already contributed to the success of targeted therapies; in cancer immunotherapy, identification of tumor-specific antigens through whole-exome sequencing may be key to designing individualized, highly immunogenic therapeutic vaccines. Additionally, pre-treatment tumor mutational and gene expression signatures can predict which patients are most likely to benefit from cancer immunotherapy. Continued work in harnessing genomic, transcriptomic, and immunological data from clinical cohorts of immunotherapy-treated patients will bring the promises of precision medicine to immuno-oncology.

  2. Cancer Immunotherapy of Targeting Angiogenesis

    Institute of Scientific and Technical Information of China (English)

    JianmeiHou; LingTian; YuquanWei

    2004-01-01

    Tumor growth and metastasis are angiogenesis-dependent. Anti-angiogenic therapy may be a useful approach to cancer therapy. This review discussed tumor angiogenesis and immunotherapy of targeting tumor angiogenesis from two main aspects: (1) active vaccination to induce effective anti-angiogenesis immunity; (2) passive immunotherapy with anti-pro-angiogenic molecules relevant antibody. Evidence from the recent years suggested that anti-angiogenic therapy should be one of the most promising approaches to cancer therapy.

  3. The New Era of Cancer Immunotherapy: Manipulating T-Cell Activity to Overcome Malignancy.

    Science.gov (United States)

    Khalil, Danny N; Budhu, Sadna; Gasmi, Billel; Zappasodi, Roberta; Hirschhorn-Cymerman, Daniel; Plitt, Tamar; De Henau, Olivier; Zamarin, Dmitriy; Holmgaard, Rikke B; Murphy, Judith T; Wolchok, Jedd D; Merghoub, Taha

    2015-01-01

    Using the immune system to control cancer has been investigated for over a century. Yet it is only over the last several years that therapeutic agents acting directly on the immune system have demonstrated improved overall survival for cancer patients in phase III clinical trials. Furthermore, it appears that some patients treated with such agents have been cured of metastatic cancer. This has led to increased interest and acceleration in the rate of progress in cancer immunotherapy. Most of the current immunotherapeutic success in cancer treatment is based on the use of immune-modulating antibodies targeting critical checkpoints (CTLA-4 and PD-1/PD-L1). Several other immune-modulating molecules targeting inhibitory or stimulatory pathways are being developed. The combined use of these medicines is the subject of intense investigation and holds important promise. Combination regimens include those that incorporate targeted therapies that act on growth signaling pathways, as well as standard chemotherapy and radiation therapy. In fact, these standard therapies have intrinsic immune-modulating properties that can support antitumor immunity. In the years ahead, adoptive T-cell therapy will also be an important part of treatment for some cancer patients. Other areas which are regaining interest are the use of oncolytic viruses that immunize patients against their own tumors and the use of vaccines against tumor antigens. Immunotherapy has demonstrated unprecedented durability in controlling multiple types of cancer and we expect its use to continue expanding rapidly.

  4. 特异性免疫治疗的进展及展望%Progress and prospect of allergen-specific immunotherapy

    Institute of Scientific and Technical Information of China (English)

    王良录

    2012-01-01

    Allergen-specific immunotherapy is the only treatment that may affect the natural course of allergic diseases besides allergen avoidance. Many research works had been finished to try to resolve the problem of SIT, especially of SCIT. The progress and prospect in the filed of novel routes of administration, new indication, allergen extracts, combination with Anti-IgE therapy and cDNA Immunotherapy were summarized in this short review.%特异性免疫治疗(SIT)是变态反应疾病特有的病因治疗方法,是除避免接触变应原外能够影响变态反应疾病自然进程的惟一治疗手段.针对目前SIT特别是皮下注射免疫治疗(SCIT)存在的问题,国内外变态反应学者进行了大量研究,文章对SIT新的给药途径、新的适应证、变应原提取液制剂的改进、合并应用Anti-IgE治疗及cDNA免疫治疗等方面的研究进展进行了简要综述并对其临床应用前景进行了展望.

  5. DC-based immunotherapy for hematological malignancies.

    Science.gov (United States)

    Kitawaki, Toshio

    2014-02-01

    Great advances have been made in the treatment of hematological malignancies, but achieving a definitive cure remains an elusive goal for the majority of patients. Antigen-specific tumor immunotherapy has the potential to improve clinical outcome in patients with such diseases by eradicating chemotherapy-resistant tumor cell clones without damaging normal tissues. Dendritic cells (DCs) serve as an essential link between the innate and the adaptive immune systems, acting as key controllers of antigen-specific T cell responses. Molecular identification of tumor-specific antigens recognized by T lymphocytes and technical advances in ex vivo generation of human DCs has enabled us to develop DC-based tumor immunotherapies (also called "DC vaccines"). To date, a large number of clinical trials of DC vaccines have been conducted for a variety of tumors, including hematological malignancies. Overall, these trials have demonstrated that DC vaccines have excellent safety profiles, moderate immunological activity, and mild clinical efficacy. To establish a role for DC vaccines in the treatment of hematological malignancies, we need both to define patient populations that can obtain clinical benefit from DC vaccines and to develop combination therapies that augment clinical efficacy of DC vaccines. In this review, I will describe current status of DC-based immunotherapy for hematological malignancies, and discuss future perspectives in this field.

  6. Immunotherapy of distant metastatic disease

    DEFF Research Database (Denmark)

    Schadendorf, D; Algarra, S M; Bastholt, L

    2009-01-01

    Immunotherapy of metastatic melanoma consists of various approaches leading to specific or non-specific immunomodulation. The use of FDA-approved interleukin (IL)-2 alone, in combination with interferon alpha, and/or with various chemotherapeutic agents (biochemotherapy) is associated with signif......Immunotherapy of metastatic melanoma consists of various approaches leading to specific or non-specific immunomodulation. The use of FDA-approved interleukin (IL)-2 alone, in combination with interferon alpha, and/or with various chemotherapeutic agents (biochemotherapy) is associated...... antibodies targeting cytotoxic T lymphocyte-associated antigen 4 (anti-CTLA-4) or CD137 are discussed. Recent advances of intratumour gene transfer technologies and adoptive immunotherapy, which represents a promising although technically challenging direction, are also discussed....

  7. Polymeric particulate systems for immunotherapy of cancer

    NARCIS (Netherlands)

    Rahimian, S.

    2015-01-01

    Immunotherapy has been established as a groundbreaking approach to treat cancer. It involves modulation of the host’s immune response to fight cancer. This is achieved by either enhancing tumor-specific T cell responses or inhibition of the tumor-induced immune suppression. Immunotherapy, however fa

  8. Hypoallergenic molecules for subcutaneous immunotherapy.

    Science.gov (United States)

    Jongejan, Laurian; van Ree, Ronald; Poulsen, Lars K

    2016-01-01

    Although a large part of the population suffers from allergies, a cure is not yet available. Allergen-specific immunotherapy (AIT) offers promise for these patients. AIT has proven successful in insect and venom allergies; however, for food allergy this is still unclear. In this editorial we focus on the recent advances in a proof of concept study in food allergy, FAST (Food allergy specific immunotherapy), which may increase interest within the biomolecular and pharmaceutical industry to embark on similar projects of immunology driven precision medicine within the allergy field.

  9. Building and optimizing a virus-specific T cell receptor library for targeted immunotherapy in viral infections.

    Science.gov (United States)

    Banu, Nasirah; Chia, Adeline; Ho, Zi Zong; Garcia, Alfonso Tan; Paravasivam, Komathi; Grotenbreg, Gijsbert M; Bertoletti, Antonio; Gehring, Adam J

    2014-02-25

    Restoration of antigen-specific T cell immunity has the potential to clear persistent viral infection. T cell receptor (TCR) gene therapy can reconstitute CD8 T cell immunity in chronic patients. We cloned 10 virus-specific TCRs targeting 5 different viruses, causing chronic and acute infection. All 10 TCR genetic constructs were optimized for expression using a P2A sequence, codon optimization and the addition of a non-native disulfide bond. However, maximum TCR expression was only achieved after establishing the optimal orientation of the alpha and beta chains in the expression cassette; 9/10 TCRs favored the beta-P2A-alpha orientation over alpha-P2A-beta. Optimal TCR expression was associated with a significant increase in the frequency of IFN-gamma+ T cells. In addition, activating cells for transduction in the presence of Toll-like receptor ligands further enhanced IFN-gamma production. Thus, we have built a virus-specific TCR library that has potential for therapeutic intervention in chronic viral infection or virus-related cancers.

  10. Tumor and Host Factors Controlling Antitumor Immunity and Efficacy of Cancer Immunotherapy.

    Science.gov (United States)

    Spranger, Stefani; Sivan, Ayelet; Corrales, Leticia; Gajewski, Thomas F

    2016-01-01

    Despite recent clinical advances in immunotherapy, a fraction of cancer patients fails to respond to these interventions. Evidence from preclinical mouse models as well as clinical samples has provided evidence that the extent of activated T cell infiltration within the tumor microenvironment is associated with clinical response to immunotherapies including checkpoint blockade. Therefore, understanding the molecular mechanisms mediating the lack of T cell infiltration into the tumor microenvironment will be instrumental for the development of new therapeutic strategies to render those patients immunotherapy responsive. Recent data have suggested that major sources of intersubject heterogeneity include differences in somatic mutations in specific oncogene pathways between cancers of individual subjects and also environmental factors including commensal microbial composition. Successful identification of such causal factors should lead to new therapeutic approaches that may facilitate T cell entry into noninflamed tumors and expand the fraction of patients capable of responding to novel immunotherapies.

  11. Expansion and activation of natural killer cells from PBMC for immunotherapy of hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Bao-Gang Peng; Li-Jian Liang; Qiang He; Jie-Fu Huang; Ming-De Lu

    2004-01-01

    AIM: To induce efficient expansion of natural killer (NK) cells from peripheral blood mononuclear cells (PBMCs) using a culture of anchorage-dependent Wilms tumor cell lines, and to provide a reliable supply for adoptive immunotherapy of hepatocellular carcinoma.METHODS: Culture expansion of NK cells was achieved using PBMCs cultured with Wilms tumor cells. Cytotoxicity was measured using a standard 51Cr release assay and crystal violet staining technique. The proportions of CD3+, CD4+, CD8+,CD16+, and CD56+ cells were determined by flow cytometry.RESULTS: After PBMCs from healthy donors and hepatocellular carcinoma (HCC) were cultured with irradiated HFWT cells for 10-21 d, CD56+ CD16+ cells shared more than 50% of the cell population, and more than 80% of fresh HFWT cells were killed at an effector/target ratio of 2 over 24 h. NK-enriched lymphocyte population from HCC patients killed HCC-1 and 2 cells with sensitivities comparable to fresh TKB-17RGB cells. HCC cells proliferated 196-fold with the irradiated HFWT cells at 18 d. Stimulation by HFWT cells required intimate cell-cell interaction with PBMC. However, neither the soluble factors released from HFWT cells nor the fixed HFWT cells were effective for NK expansion. The lymphocytes expanded with IL-2 killed fresh HFWT target cells more effectively than the lymphocytes expanded with the 4-cytokine cocktail (IL-1 β, IL-2, IL-4 and IL-6). IL-2 was the sole cytokine required for NK expansion.CONCLUSION: Wilms tumor is sensitive to human NK cells and is highly efficient for selective expansion of NK cells from PBMCs.

  12. Regulatory activity of azabisphosphonate-capped dendrimers on human CD4+ T cell proliferation enhances ex-vivo expansion of NK cells from PBMCs for immunotherapy

    Directory of Open Access Journals (Sweden)

    Caminade Anne-Marie

    2009-09-01

    specificity of the interaction of dendrimers with CD4+ T cell, we hypothesize that regulatory activity may signal through a specific receptor that remains to be indentified. Therefore phosphonate-capped dendrimers constitute not only tools for the ex-vivo expansion of NK cells in immunotherapy of cancers but their mode of action could also lead to further medical applications where T cell activation and proliferation need to be dampened.

  13. Identification of prostate-specific G-protein coupled receptor as a tumor antigen recognized by CD8(+ T cells for cancer immunotherapy.

    Directory of Open Access Journals (Sweden)

    Satoko Matsueda

    Full Text Available BACKGROUND: Prostate cancer is the most common cancer among elderly men in the US, and immunotherapy has been shown to be a promising strategy to treat patients with metastatic castration-resistant prostate cancer. Efforts to identify novel prostate specific tumor antigens will facilitate the development of effective cancer vaccines against prostate cancer. Prostate-specific G-protein coupled receptor (PSGR is a novel antigen that has been shown to be specifically over-expressed in human prostate cancer tissues. In this study, we describe the identification of PSGR-derived peptide epitopes recognized by CD8(+ T cells in an HLA-A2 dependent manner. METHODOLOGY/PRINCIPAL FINDINGS: Twenty-one PSGR-derived peptides were predicted by an immuno-informatics approach based on the HLA-A2 binding motif. These peptides were examined for their ability to induce peptide-specific T cell responses in peripheral blood mononuclear cells (PBMCs obtained from either HLA-A2(+ healthy donors or HLA-A2(+ prostate cancer patients. The recognition of HLA-A2 positive and PSGR expressing LNCaP cells was also tested. Among the 21 PSGR-derived peptides, three peptides, PSGR3, PSGR4 and PSGR14 frequently induced peptide-specific T cell responses in PBMCs from both healthy donors and prostate cancer patients. Importantly, these peptide-specific T cells recognized and killed LNCaP prostate cancer cells in an HLA class I-restricted manner. CONCLUSIONS/SIGNIFICANCE: We have identified three novel HLA-A2-restricted PSGR-derived peptides recognized by CD8(+ T cells, which, in turn, recognize HLA-A2(+ and PSGR(+ tumor cells. The PSGR-derived peptides identified may be used as diagnostic markers as well as immune targets for development of anticancer vaccines.

  14. Hypoallergenic molecules for subcutaneous immunotherapy

    DEFF Research Database (Denmark)

    Jongejan, Laurian; van Ree, Ronald; Poulsen, Lars K

    2016-01-01

    Although a large part of the population suffers from allergies, a cure is not yet available. Allergen-specific immunotherapy (AIT) offers promise for these patients. AIT has proven successful in insect and venom allergies; however, for food allergy this is still unclear. In this editorial we focu...

  15. Concentrated protein body product derived from rice endosperm as an oral tolerogen for allergen-specific immunotherapy--a new mucosal vaccine formulation against Japanese cedar pollen allergy.

    Directory of Open Access Journals (Sweden)

    Yuhya Wakasa

    Full Text Available The endoplasmic reticulum-derived type-I protein body (PB-I from rice endosperm cells is an ideal candidate formulation for the oral delivery of bioencapsulated peptides as tolerogens for allergen-specific immunotherapy. In the present study, PBs containing the deconstructed Japanese cedar pollen allergens Cryptomeria japonica 1 (Cry j 1 and Cry j 2 were concentrated by treatment with thermostable α-amylase at 90°C to remove the starch from milled rice powder, which resulted in a 12.5-fold reduction of dry weight compared to the starting material. The modified Cry j 1 and Cry j 2 antigens in this concentrated PB product were more resistant to enzymatic digestion than those in the milled seed powder despite the absence of intact cell wall and starch, and remained stable for at least 10 months at room temperature without detectable loss or degradation. The high resistance of these allergens could be attributed to changes in protein physicochemical properties induced by the high temperature concentration process, as suggested by the decreased solubility of the antigens and seed proteins in PBs in step-wise-extraction experiments. Confocal microscopy showed that the morphology of antigen-containing PB-Is was preserved in the concentrated PB product. The concentrated PB product induced specific immune tolerance against Cry j 1 and Cry j 2 in mice when orally administered, supporting its potential use as a novel oral tolerogen formulation.

  16. Efficacy and toxicity management of CAR-T-cell immunotherapy: a matter of responsiveness control or tumour-specificity?

    Science.gov (United States)

    Alonso-Camino, Vanesa; Harwood, Seandean Lykke; Álvarez-Méndez, Ana; Alvarez-Vallina, Luis

    2016-04-15

    Chimaeric antigen receptor (CAR)-expressing T-cells have demonstrated potent clinical efficacy in patients with haematological malignancies. However, the use of CAR-T-cells targeting solid tumour-associated antigens (TAAs) has been limited by organ toxicities related to activation of T-cell effector functions through the CAR. Most existing CARs recognize TAAs, which are also found in normal tissues. CAR-T-cell-mediated destruction of normal tissues constitutes a major roadblock to CAR-T-cell therapy, and must be avoided or mitigated. There is a broad range of strategies for modulating antigen responsiveness of CAR-T-cells, with varying degrees of complexity. Some of them might ameliorate the acute and chronic toxicities associated with current CAR constructs. However, further embellishments to CAR therapy may complicate clinical implementation and possibly create new immunogenicity issues. In contrast, the development of CARs targeting truly tumour-specific antigens might circumvent on-target/off-tumour toxicities without adding additional complexity to CAR-T-cell therapies, but these antigens have been elusive and may require novel selection strategies for their discovery.

  17. Immunotherapy of Genitourinary Malignancies

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    Teruo Inamoto

    2012-01-01

    Full Text Available Most cancer patients are treated with some combination of surgery, radiation, and chemotherapy. Despite recent advances in local therapy with curative intent, chemotherapeutic treatments for metastatic disease often remain unsatisfying due to severe side effects and incomplete long-term remission. Therefore, the evaluation of novel therapeutic options is of great interest. Conventional, along with newer treatment strategies target the immune system that suppresses genitourinary (GU malignancies. Metastatic renal cell carcinoma and non-muscle-invasive bladder caner represent the most immune-responsive types of all human cancer. This review examines the rationale and emerging evidence supporting the anticancer activity of immunotherapy, against GU malignancies.

  18. Lactobacillus buchneri S-layer as carrier for an Ara h 2-derived peptide for peanut allergen-specific immunotherapy.

    Science.gov (United States)

    Anzengruber, Julia; Bublin, Merima; Bönisch, Eva; Janesch, Bettina; Tscheppe, Angelika; Braun, Matthias L; Varga, Eva-Maria; Hafner, Christine; Breiteneder, Heimo; Schäffer, Christina

    2017-05-01

    Peanut allergy is an IgE-mediated severe hypersensitivity disorder. The lack of a treatment of this potentially fatal allergy has led to intensive research on vaccine development. Here, we describe the design and initial characterization of a carrier-bound peptide derived from the most potent peanut allergen, Ara h 2, as a candidate vaccine. Based on the adjuvant capability of bacterial surface (S-) layers, a fusion protein of the S-layer protein SlpB from Lactobacillus buchneri CD034 and the Ara h 2-derived peptide AH3a42 was produced. This peptide comprised immunodominant B-cell epitopes as well as one T cell epitope. The fusion protein SlpB-AH3a42 was expressed in E. coli, purified, and tested for its IgE binding capacity as well as for its ability to activate sensitized rat basophil leukemia (RBL) cells. The capacity of Ara h 2-specific IgG rabbit-antibodies raised against SlpB-AH3a42 or Ara h 2 to inhibit IgE-binding was determined by ELISA inhibition assays using sera of peanut allergic patients sensitized to Ara h 2. IgE specific to the SlpB-AH3a42 fusion protein was detected in 69% (25 of 36) of the sera. Despite the recognition by IgE, the SlpB-AH3a42 fusion protein was unable to induce β-hexosaminidase release from sensitized RBL cells at concentrations up to 100ng per ml. The inhibition of IgE-binding to the natural allergen observed after pre-incubation of the 20 sera with rabbit anti-SlpB-AH3a42 IgG was more than 30% for four sera, more than 20% for eight sera, and below 10% for eight sera. In comparison, anti-Ara h 2 rabbit IgG antibodies inhibited binding to Ara h 2 by 48% ±13.5%. Our data provide evidence for the feasibility of this novel approach towards the development of a peanut allergen peptide-based carrier-bound vaccine. Our experiments further indicate that more than one allergen-peptide will be needed to induce a broader protection of patients allergic to Ara h 2.

  19. Targeted cancer immunotherapy with oncolytic adenovirus coding for a fully human monoclonal antibody specific for CTLA-4.

    Science.gov (United States)

    Dias, J D; Hemminki, O; Diaconu, I; Hirvinen, M; Bonetti, A; Guse, K; Escutenaire, S; Kanerva, A; Pesonen, S; Löskog, A; Cerullo, V; Hemminki, A

    2012-10-01

    Promising clinical results have been achieved with monoclonal antibodies (mAbs) such as ipilimumab and tremelimumab that block cytotoxic T lymphocyte-associated antigen-4 (CTLA-4, CD152). However, systemic administration of these agents also has the potential for severe immune-related adverse events. Thus, local production might allow higher concentrations at the target while reducing systemic side effects. We generated a transductionally and transcriptionally targeted oncolytic adenovirus Ad5/3-Δ24aCTLA4 expressing complete human mAb specific for CTLA-4 and tested it in vitro, in vivo and in peripheral blood mononuclear cells (PBMCs) of normal donors and patients with advanced solid tumors. mAb expression was confirmed by western blotting and immunohistochemistry. Biological functionality was determined in a T-cell line and in PBMCs from cancer patients. T cells of patients, but not those of healthy donors, were activated by an anti-CTLA4mAb produced by Ad5/3-Δ24aCTLA4. In addition to immunological effects, a direct anti-CTLA-4-mediated pro-apoptotic effect was observed in vitro and in vivo. Local production resulted in 43-fold higher (P<0.05) tumor versus plasma anti-CTLA4mAb concentration. Plasma levels in mice remained below what has been reported safe in humans. Replication-competent Ad5/3-Δ24aCTLA4 resulted in 81-fold higher (P<0.05) tumor mAb levels as compared with a replication-deficient control. This is the first report of an oncolytic adenovirus producing a full-length human mAb. High mAb concentrations were seen at tumors with lower systemic levels. Stimulation of T cells of cancer patients by Ad5/3-Δ24aCTLA4 suggests feasibility of testing the approach in clinical trials.

  20. Beneficial cross-protection of allergen-specific immunotherapy on airway eosinophilia using unrelated or a partial repertoire of allergen(s) implicated in experimental feline asthma.

    Science.gov (United States)

    Reinero, Carol; Lee-Fowler, Tekla; Chang, Chee-Hoon; Cohn, Leah; Declue, Amy

    2012-06-01

    The study hypothesis was that in experimentally asthmatic cats rush immunotherapy (RIT) using allergens not completely matched with sensitizing allergen(s) would at least partially attenuate the asthmatic phenotype and modulate the aberrant immune response. In phase I, cats sensitized to Bermuda grass allergen (BGA), house dust mite allergen (HDMA) or placebo received BGA RIT. In phase II, cats dually sensitized to BGA and HDMA received RIT using BGA, HDMA or placebo. Efficacy of RIT was assessed using percentage bronchoalveolar lavage fluid (BALF) eosinophils. Additionally, a variety of immunologic assays were performed. Eosinophilic airway inflammation significantly decreased over time in asthmatic cats given RIT using sensitizing allergen or unrelated allergen (P<0.001). In dually sensitized cats, single allergen RIT but not placebo reduced airway eosinophilia (P=0.038). Differences in allergen-specific lymphocyte proliferation, in the number of IL-10 producing cells and in the percentage T regulatory cells were detected between asthmatic cats getting RIT and controls. Cross-protection manifested by reduced airway eosinophilia was noted in cats treated with RIT allergens which did not completely match allergen used in asthma induction. However, the mechanism of immunologic tolerance may differ when improperly matched allergens to the sensitizing allergens are used in RIT.

  1. [Effectiveness of specific immunotherapy in the treatment of children and youngsters suffering from atopic dermatitis. Part III. Serum concentrations of selected immunologic parameters].

    Science.gov (United States)

    Silny, Wojciech; Czarnecka-Operacz, Magdalena; Silny, Pawel

    2005-01-01

    Etiology and pathomechanism of atopic dermatitis still remains partially unclear and therefore contemporary methods of treatment are not always satisfactory from the clinical standpoint. The aim of this study was to evaluate selected immunological parameters (tIgE, ECP, sIL-2R, IFN-gamma, IL-4,IL-5) in sera of atopic dermatitis patients in the course of specific immunotherapy performed for the time period of 3 years. Novo-Helisen Depot allergy vaccines of appropriate composition were used for the treatment of 36 children and youngsters with atopic dermatitis, allergic to house dust mites (24 patients) and grass pollen allergens (12 patients). The control group consisted of 20 patients with atopic dermatitis and analogous IgE-mediated airborne allergy who were treated with conventional methods. There was a clear difference between two investigated groups of patients in terms of immunological parameters. In the group treated with allergy vaccines serum concentrations of total IgE and ECP tended to decrease (p < 0.001) as well as sIL-2R (p < 0.01). On the contrary in the control group serum tIgE increased and IL-4 as well as IL-5 concentrations tended to increase significantly (p < 0.01; p < 0.05 respectively).

  2. Vaccine development for allergen-specific immunotherapy based on recombinant allergens and synthetic allergen peptides: Lessons from the past and novel mechanisms of action for the future.

    Science.gov (United States)

    Valenta, Rudolf; Campana, Raffaela; Focke-Tejkl, Margit; Niederberger, Verena

    2016-02-01

    In the past, the development of more effective, safe, convenient, broadly applicable, and easy to manufacture vaccines for allergen-specific immunotherapy (AIT) has been limited by the poor quality of natural allergen extracts. Progress made in the field of molecular allergen characterization has now made it possible to produce defined vaccines for AIT and eventually for preventive allergy vaccination based on recombinant DNA technology and synthetic peptide chemistry. Here we review the characteristics of recombinant and synthetic allergy vaccines that have reached clinical evaluation and discuss how molecular vaccine approaches can make AIT more safe and effective and thus more convenient. Furthermore, we discuss how new technologies can facilitate the reproducible manufacturing of vaccines of pharmaceutical grade for inhalant, food, and venom allergens. Allergy vaccines in clinical trials based on recombinant allergens, recombinant allergen derivatives, and synthetic peptides allow us to target selectively different immune mechanisms, and certain of those show features that might make them applicable not only for therapeutic but also for prophylactic vaccination.

  3. A Full GMP Process to Select and Amplify Epitope-Specific T Lymphocytes for Adoptive Immunotherapy of Metastatic Melanoma

    Directory of Open Access Journals (Sweden)

    N. Labarriere

    2013-01-01

    Full Text Available A number of trials of adoptive transfer of tumor-specific T lymphocytes have been performed in the last 20 years in metastatic melanoma, with increasingly encouraging results as the relevant melanoma antigens were identified and the purity/specificity of injected T cells improved. We have previously described a sorting method of epitope-specific T lymphocytes that uses magnetic beads coated with HLA/peptide complexes and we suggested that this method could be applied to a clinical setting. In the present work, we provide a detailed description of the whole GMP process of sorting and amplification of clinical grade T cells specific for the melanoma antigens Melan-A and MELOE-1. All the reagents used in this process including the sorting reagent were produced in GMP conditions and we document the optimization of the different steps of the process such as peptide stimulation, sorting, and amplification. The optimized procedure, validated in 3 blank runs in a clinical setting, allowed the production of at least 108 pure (>90% Melan-A- and MELOE-1-specific T cells within 28 days starting with 100 mL of blood from metastatic melanoma patients. This GMP process is thus ready to be used in an upcoming phase I/II clinical trial on metastatic melanoma patients.

  4. Activation of endothelium by immunotherapy with interleukin-2 in patients with malignant disorders.

    Science.gov (United States)

    Locker, G J; Kapiotis, S; Veitl, M; Mader, R M; Stoiser, B; Kofler, J; Sieder, A E; Rainer, H; Steger, G G; Mannhalter, C; Wagner, O F

    1999-06-01

    Treatment with intravenous recombinant human interleukin-2 (rh IL-2) is frequently accompanied by the capillary leak syndrome and disturbances of the coagulation system. Although the exact mechanisms are still not fully understood, the involvement of the endothelium is proven. This investigation aimed to elucidate more precisely the role of the endothelium in the generation of IL-2-based side-effects. In nine tumour patients receiving intravenous rh IL-2, parameters characterizing endothelial cell activation as well as activation of the coagulation system were evaluated. A significant increase of the circulating endothelial leucocyte adhesion molecule-1 (cELAM-1) and the vasoconstrictor peptide endothelin-1 (ET-1) was observed (P<0.05), indicating activation of endothelial cells. The simultaneous increase of tissue-plasminogen activator and plasminogen activator inhibitor type-1 during therapy (P<0.05) corroborated this observation. A decrease in platelet count parallelled by an increase of fibrin degradation products, the prolongation of partial thromboplastin time, and the decrease of fibrinogen (P<0.05) suggested the development of disseminated intravascular coagulation (DIC), induced by activated endothelium and intensified by transient hepatic failure. We concluded that activation of the endothelium mediated by IL-2 was accompanied by a loss of endothelial integrity and capillary leak. The activated endothelium can trigger DIC via activation of the coagulation cascade. The increased ET-1 might act as an endogenous counter-regulator of the disadvantageous haemodynamic side-effects induced by IL-2.

  5. Big Data Offers Novel Insights for Oncolytic Virus Immunotherapy

    Science.gov (United States)

    Swift, Stephanie L.; Stojdl, David F.

    2016-01-01

    Large-scale assays, such as microarrays, next-generation sequencing and various “omics” technologies, have explored multiple aspects of the immune response following virus infection, often from a public health perspective. Yet a lack of similar data exists for monitoring immune engagement during oncolytic virus immunotherapy (OVIT) in the cancer setting. Tracking immune signatures at the tumour site can create a snapshot or longitudinally analyse immune cell activation, infiltration and functionality within global populations or individual cells. Mapping immune changes over the course of oncolytic biotherapy—from initial infection to tumour stabilisation/regression through to long-term cure or escape/relapse—has the potential to generate important therapeutic insights around virus-host interactions. Further, correlating such immune signatures with specific tumour outcomes has significant value for guiding the development of novel oncolytic virus immunotherapy strategies. Here, we provide insights for OVIT from large-scale analyses of immune populations in the infection, vaccination and immunotherapy setting. We analyse several approaches to manipulating immune engagement during OVIT. We further explore immunocentric changes in the tumour tissue following immunotherapy, and compile several immune signatures of therapeutic success. Ultimately, we highlight clinically relevant large-scale approaches with the potential to strengthen future oncolytic strategies to optimally engage the immune system. PMID:26861383

  6. Immunotherapy of Head and Neck Cancer: Current and Future Considerations

    Directory of Open Access Journals (Sweden)

    Alexander D. Rapidis

    2009-01-01

    Full Text Available Patients with head and neck squamous cell carcinoma (HNSCC are at considerable risk for death, with 5-year relative survival rates of approximately 60%. The profound multifaceted deficiencies in cell-mediated immunity that persist in most patients after treatment may be related to the high rates of treatment failure and second primary malignancies. Radiotherapy and chemoradiotherapy commonly have severe acute and long-term side effects on immune responses. The development of immunotherapies reflects growing awareness that certain immune system deficiencies specific to HNSCC and some other cancers may contribute to the poor long-term outcomes. Systemic cell-mediated immunotherapy is intended to activate the entire immune system and mount a systemic and/or locoregional antitumor response. The delivery of cytokines, either by single cytokines, for example, interleukin-2, interleukin-12, interferon-, interferon-, or by a biologic mix of multiple cytokines, such as IRX-2, may result in tumor rejection and durable immune responses. Targeted immunotherapy makes use of monoclonal antibodies or vaccines. All immunotherapies for HNSCC except cetuximab remain investigational, but a number of agents whose efficacy and tolerability are promising have entered phase 2 or phase 3 development.

  7. Dendritic-tumor fusion cells in cancer immunotherapy.

    Science.gov (United States)

    Takakura, Kazuki; Kajihara, Mikio; Ito, Zensho; Ohkusa, Toshifumi; Gong, Jianlin; Koido, Shigeo

    2015-03-01

    A promising area of clinical investigation is the use of cancer immunotherapy to treat cancer patients. Dendritic cells (DCs) operate as professional antigen-presenting cells (APCs) and play a critical role in the induction of antitumor immune responses. Thus, DC-based cancer immunotherapy represents a powerful strategy. One DC-based cancer immunotherapy strategy that has been investigated is the administration of fusion cells generated with DCs and whole tumor cells (DC-tumor fusion cells). The DC-tumor fusion cells can process a broad array of tumor-associated antigens (TAAs), including unidentified molecules, and present them through major histocompatibility complex (MHC) class I and II pathways in the context of co-stimulatory signals. Improving the therapeutic efficacy of DC-tumor fusion cell-based cancer immunotherapy requires increased immunogenicity of DCs and whole tumor cells. We discuss the potential ability of DC-tumor fusion cells to activate antigen-specific T cells and strategies to improve the immunogenicity of DC-tumor fusion cells as anticancer vaccines.

  8. Immunotherapy for Prostate Cancer with Gc Protein-Derived Macrophage-Activating Factor, GcMAF.

    Science.gov (United States)

    Yamamoto, Nobuto; Suyama, Hirofumi; Yamamoto, Nobuyuki

    2008-07-01

    Serum Gc protein (known as vitamin D(3)-binding protein) is the precursor for the principal macrophage-activating factor (MAF). The MAF precursor activity of serum Gc protein of prostate cancer patients was lost or reduced because Gc protein was deglycosylated by serum alpha-N-acetylgalactosaminidase (Nagalase) secreted from cancerous cells. Therefore, macrophages of prostate cancer patients having deglycosylated Gc protein cannot be activated, leading to immunosuppression. Stepwise treatment of purified Gc protein with immobilized beta-galactosidase and sialidase generated the most potent MAF (termed GcMAF) ever discovered, which produces no adverse effect in humans. Macrophages activated by GcMAF develop a considerable variation of receptors that recognize the abnormality in malignant cell surface and are highly tumoricidal. Sixteen nonanemic prostate cancer patients received weekly administration of 100 ng of GcMAF. As the MAF precursor activity increased, their serum Nagalase activity decreased. Because serum Nagalase activity is proportional to tumor burden, the entire time course analysis for GcMAF therapy was monitored by measuring the serum Nagalase activity. After 14 to 25 weekly administrations of GcMAF (100 ng/week), all 16 patients had very low serum Nagalase levels equivalent to those of healthy control values, indicating that these patients are tumor-free. No recurrence occurred for 7 years.

  9. In vivo and in vitro studies of Th17 response to specific immunotherapy in house dust mite-induced allergic rhinitis patients.

    Directory of Open Access Journals (Sweden)

    Chun Wei Li

    Full Text Available T helper (Th17 cells have been implicated in the development of allergic rhinitis (AR, but their response to specific immunotherapy (SIT remains unclear. We investigated the impact of SIT on Th17 response and Th1/Th2 changes in AR patients. Blood samples from AR patients (n = 20 who were monosensitized to house dust mite (HDM were collected before the initiation of SIT (SIT-untreated and after the end of 2-year SIT (SIT-treated treatment. Twenty healthy volunteers were recruited as controls. In vitro HDM stimulation in peripheral blood mononuclear cells (PBMCs was also performed. Expression levels of Th17 associated genes were determined in both PBMCs and plasma by PCR and ELISA, while Th17/Th1/Th2/IL10 producing cell proportions were evaluated in PBMCs by flow cytometry. The SIT effect was evaluated by assessing clinical symptoms. mRNA levels of Th17 specific genes (IL17 and RORC were increased in SIT-untreated AR versus controls, and decreased following SIT treatment. SIT can change the production of Th17 associated genes (reduction of IL17, IL6, and IL23, but increase of IL27 in plasma from AR patients. Th2/Th1 ratio and proportions of Th17 cells were suppressed while IL10 producing CD4+ T cells were elevated after SIT. In vitro HDM challenge presents concordant patterns with in vivo findings: 1 increase of Th2 and Th17 response in AR patients; 2 suppression of IL10 producing CD4+ T cells in SIT-untreated AR but elevation in SIT-treated AR patients. Most importantly, a positive correlation between IL17 mRNA/protein levels and clinical symptom scores was observed. SIT significantly inhibits Th17 mediated inflammation in AR and IL17 may be a useful biomarker for both AR severity and SIT therapeutic effect.Australian New Zealand Clinical Trials Registry (ANZCTR ACTRN12613000445774.

  10. Cytotoxic immunotherapy strategies for cancer: mechanisms and clinical development.

    Science.gov (United States)

    Aguilar, Laura K; Guzik, Brian W; Aguilar-Cordova, Estuardo

    2011-08-01

    Traditional therapies for cancer include surgery, chemotherapy, and radiation. Chemotherapy has widespread systemic cytotoxic effects against tumor cells but also affects normal cells. Radiation has more targeted local cytotoxicity but is limited to killing cells in the radiation field. Immunotherapy has the potential for systemic, specific killing of tumor cells. However, if the immune response is specific to a single antigen, tumor evasion can occur by down-regulation of that antigen. An immunotherapy approach that induces polyvalent immunity to autologous tumor antigens can provide a personalized vaccine with less potential for immunologic escape. A cytotoxic immunotherapy strategy creates such a tumor vaccine in situ. Immunogenic tumor cell death provides tumor antigen targets for the adaptive immune response and stimulates innate immunity. Attraction and activation of antigen presenting cells such as dendritic cells is important to process and present tumor antigens to T cells. These include cytotoxic T cells that kill tumor cells and T cells which positively and negatively regulate immunity. Tipping the balance in favor of anti-tumor immunity is an important aspect of an effective strategy. Clinically, immunotherapies may be most effective when combined with standard therapies in a complimentary way. An example is gene-mediated cytotoxic immunotherapy (GMCI) which uses an adenoviral vector, AdV-tk, to deliver a cytotoxic and immunostimulatory gene to tumor cells in vivo in combination with standard therapies creating an immunostimulatory milieu. This approach, studied extensively in animal models and early stage clinical trials, is now entering a definitive Phase 3 trial for prostate cancer.

  11. Novel Approaches to Pediatric Cancer: Immunotherapy

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    Payal A. Shah

    2015-06-01

    Full Text Available From the early 20th century, immunotherapy has been studied as a treatment modality for cancers, including in children. Since then, developments in monoclonal antibodies and vaccine therapies have helped to usher in a new era of cancer immunotherapeutics. However, efficacy of these types of therapies has been limited, mostly in part due to low tumor immunogenicity, cancer escape pathways, and toxicities. As researchers investigate the cellular and molecular components of immunotherapies, mechanisms to improve tumor specificity and overcome immune escape have been identified. The goal of immunotherapy now has been to modulate tumor escape pathways while amplifying the immune response by combining innate and adaptive arms of the immune system. Although several limiting factors have been identified, these recent advances in immunotherapy remain at the forefront of pediatric oncologic therapeutic trials. Immunotherapy is now coming to the forefront of precision treatment for a variety of cancers, with evidence that agents targeting immunosuppressive mechanisms for cancer progression can be effective therapy [1-3]. In this review, we review various types of immunotherapy, including the cellular biology, limitations, recent novel therapeutics, and the application of immunotherapy to pediatric oncology.

  12. PROSTVAC® targeted immunotherapy candidate for prostate cancer.

    Science.gov (United States)

    Shore, Neal D

    2014-01-01

    Targeted immunotherapies represent a valid strategy for the treatment of metastatic castrate-resistant prostate cancer. A randomized, double-blind, Phase II clinical trial of PROSTVAC® demonstrated a statistically significant improvement in overall survival and a large, global, Phase III trial with overall survival as the primary end point is ongoing. PROSTVAC immunotherapy contains the transgenes for prostate-specific antigen and three costimulatory molecules (designated TRICOM). Research suggests that PROSTVAC not only targets prostate-specific antigen, but also other tumor antigens via antigen cascade. PROSTVAC is well tolerated and has been safely combined with other cancer therapies, including hormonal therapy, radiotherapy, another immunotherapy and chemotherapy. Even greater benefits of PROSTVAC may be recognized in earlier-stage disease and low-disease burden settings where immunotherapy can trigger a long-lasting immune response.

  13. Development of Augmented Leukemia/Lymphoma-Specific T-Cell Immunotherapy for Deployment with Haploidentical Hematopoietic Progenitor-Cell Transplant

    Science.gov (United States)

    2009-05-01

    555441), anti-human CD28 PerCP Cy5.5 (cat # 337181), anti-human CD62L APC (cat # 559772), anti-human CCR7 PE (cat # FAB197P, R&D systems, Minneapolis...and CCR7 . These data have implications for improved in vivo efficacy as antigen-specific TCM cell subsets are associated with long-term

  14. Human cerebrospinal fluid contains CD4+ memory T cells expressing gut- or skin-specific trafficking determinants: relevance for immunotherapy

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    Campbell James J

    2006-07-01

    Full Text Available Abstract Background Circulating memory T cells can be divided into tissue-specific subsets, which traffic through distinct tissue compartments during physiologic immune surveillance, based on their expression of adhesion molecules and chemokine receptors. We reasoned that a bias (either enrichment or depletion of CSF T cell expression of known organ-specific trafficking determinants might suggest that homing of T cells to the subarachnoid space could be governed by a CNS-specific adhesion molecule or chemokine receptor. Results The expression of cutaneous leukocyte antigen (CLA and CC-chemokine receptor 4 (CCR4; associated with skin-homing as well as the expression of integrin α4β7 and CCR9 (associated with gut-homing was analyzed on CD4+ memory T cells in CSF from individuals with non-inflammatory neurological diseases using flow cytometry. CSF contained similar proportions of CD4+ memory T cells expressing CLA, CCR4, integrin α4β7 and CCR9 as paired blood samples. Conclusion The results extend our previous findings that antigen-experienced CD4+ memory T cells traffic through the CSF in proportion to their abundance in the peripheral circulation. Furthermore, the ready access of skin- and gut-homing CD4+ memory T cells to the CNS compartment via CSF has implications for the mechanisms of action of immunotherapeutic strategies, such as oral tolerance or therapeutic immunization, where immunogens are administered using an oral or subcutaneous route.

  15. Immunotherapy for lung cancer.

    Science.gov (United States)

    Steven, Antonius; Fisher, Scott A; Robinson, Bruce W

    2016-07-01

    Treatment of lung cancer remains a challenge, and lung cancer is still the leading cause of cancer-related mortality. Immunotherapy has previously failed in lung cancer but has recently emerged as a very effective new therapy, and there is now growing worldwide enthusiasm in cancer immunotherapy. We summarize why immune checkpoint blockade therapies have generated efficacious and durable responses in clinical trials and why this has reignited interest in this field. Cancer vaccines have also been explored in the past with marginal success. Identification of optimal candidate neoantigens may improve cancer vaccine efficacy and may pave the way to personalized immunotherapy, alone or in combination with other immunotherapy such as immune checkpoint blockade. Understanding the steps in immune recognition and eradication of cancer cells is vital to understanding why previous immunotherapies failed and how current therapies can be used optimally. We hold an optimistic view for the future prospect in lung cancer immunotherapy.

  16. Inmunoterapia local Local immunotherapy

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    E. Lasa

    2003-01-01

    Full Text Available La inmunoterapia específica, junto con la evitación del alergeno y el tratamiento sintomático, forma parte del tratamiento de la patología alérgica. La modalidad más antigua, más conocida y mejor estudiada es la inmunoterapia subcutánea (ITSC, cuya eficacia tanto a corto como a largo plazo, ha sido ampliamente demostrada en numerosos estudios. Sin embargo, a pesar de haberse demostrado segura, no está exenta de efectos adversos y precisa ser administrada bajo supervisión de personal médico. Esto ha animado a buscar nuevas vías de administración de eficacia similar, con un buen perfil de seguridad, y de buena cumplimentación por parte del paciente. De las distintas alternativas estudiadas la más relevante es la inmunoterapia sublingual (ITSL. En ésta, se administra el antígeno en forma de gotas debajo de la lengua. Existen diferentes pautas de administración en función del alergeno implicado. La dosis óptima de tratamiento está aún sin determinar, hallándose en este momento en un rango amplio de dosis respecto a la inmunoterapia subcutánea. Su mecanismo de acción es poco conocido aunque en diversos estudios se han observado cambios inmunológicos. La ITSL ha mostrado un buen perfil de seguridad con escasos efectos secundarios, habitualmente de carácter local. Asimismo se han realizado distintos ensayos clínicos en los que se ha demostrado su eficacia en el tratamiento de la alergia respiratoria tanto en niños como en adultos. Por ello, aunque aún existen datos sin resolver respecto a esta vía de administración de inmunoterapia, ha sido propuesta por la OMS como una alternativa válida a la ITSC.Specific immunotherapy, together with avoidance of the allergen and symptomatic treatment, forms part of the treatment of allergic pathology. The oldest, best known and most studied form is subcutaneous immunotherapy (SCIT, whose efficacy, both in the short and the long term, has been widely demonstrated in numerous studies

  17. Immunotherapy for tuberculosis: future prospects

    Directory of Open Access Journals (Sweden)

    Abate G

    2016-04-01

    Full Text Available Getahun Abate,1 Daniel F Hoft1,2 1Department of Internal Medicine, Division of Infectious Diseases, Allergy and Immunology, 2Department of Molecular Microbiology and Immunology, Saint Louis University, St. Louis, MO, USA Abstract: Tuberculosis (TB is still a major global health problem. A third of the world's population is infected with Mycobacterium tuberculosis. Only ~10% of infected individuals develop TB but there are 9 million TB cases with 1.5 million deaths annually. The standard prophylactic treatment regimens for latent TB infection take 3–9 months, and new cases of TB require at least 6 months of treatment with multiple drugs. The management of latent TB infection and TB has become more challenging because of the spread of multidrug-resistant and extremely drug-resistant TB. Intensified efforts to find new TB drugs and immunotherapies are needed. Immunotherapies could modulate the immune system in patients with latent TB infection or active disease, enabling better control of M. tuberculosis replication. This review describes several types of potential immunotherapies with a focus on those which have been tested in humans. Keywords: tuberculosis, HDT, immunotherapy, treatment

  18. Efficacy and toxicity management of CAR-T cell immunotherapy: A matter of responsiveness control or tumor-specificity?

    DEFF Research Database (Denmark)

    Alonso-Camino, Vanesa; Harwood, Seandean Lykke; Alvarez-Méndez, Ana M;

    2016-01-01

    Chimeric antigen receptor (CAR)-expressing T cells have demonstrated potent clinical efficacy in patients with hematological malignancies. However, the use of CAR-T cells targeting solid tumor-associated antigens (TAAs) has been limited by organ toxicities related to activation of T cell effector...... functions through the CAR. Most existing CARs recognize TAAs, which are also found in normal tissues. CAR-T cell-mediated destruction of normal tissues constitutes a major roadblock to CAR-T cell therapy, and must be avoided or mitigated. There is a broad range of strategies for modulating antigen...... responsiveness of CAR-T cells, with varying degrees of complexity. Some of them might ameliorate the acute and chronic toxicities associated with current CAR constructs. However, further embellishments to CAR therapy may complicate clinical implementation and possibly create new immunogenicity issues...

  19. Overview of Cellular Immunotherapy for Patients with Glioblastoma

    Directory of Open Access Journals (Sweden)

    Elodie Vauleon

    2010-01-01

    Full Text Available High grade gliomas (HGG including glioblastomas (GBM are the most common and devastating primary brain tumours. Despite important progresses in GBM treatment that currently includes surgery combined to radio- and chemotherapy, GBM patients' prognosis remains very poor. Immunotherapy is one of the new promising therapeutic approaches that can specifically target tumour cells. Such an approach could also maintain long term antitumour responses without inducing neurologic defects. Since the past 25 years, adoptive and active immunotherapies using lymphokine-activated killer cells, cytotoxic T cells, tumour-infiltrating lymphocytes, autologous tumour cells, and dendritic cells have been tested in phase I/II clinical trials with HGG patients. This paper inventories these cellular immunotherapeutic strategies and discusses their efficacy, limits, and future perspectives for optimizing the treatment to achieve clinical benefits for GBM patients.

  20. New types of immunotherapy in children.

    Science.gov (United States)

    Rodríguez-Pérez, Noel; Penagos, Martin; Portnoy, Jay M

    2008-11-01

    Injection immunotherapy has been shown to be particularly beneficial in treating allergic rhinitis, mild to moderate asthma, and anaphylaxis caused by bee and wasp venom. It also produces a long-term, antigen-specific, protective immune effect and is the only treatment that offers the possibility of reducing the risk of asthma development in children with allergic rhinitis. Nonetheless, the potentially severe side effects associated with this form of immunotherapy limit its widespread use. Diverse preparations are being developed to increase its safety and improve its efficacy. These include alternative routes of administration, particularly the sublingual route; use of novel adjuvants, such as CpG oligonucleotides and mycobacterial vaccines; and other approaches, such as peptide immunotherapy, recombinant allergens, DNA vaccination, and combined therapy. Some of these immunotherapy forms have been evaluated in children.

  1. New Concepts in Tumor Antigens: Their Significance in Future Immunotherapies for Tumors

    Institute of Scientific and Technical Information of China (English)

    Fan Yang; Xiao-Feng Yang

    2005-01-01

    The identification and molecular characterization of self-antigens expressed by human malignancies that are capable of elicitation of anti-tumor immune responses in patients have been an active field in tumor immunology.More than 2,000 tumor antigens have been identified, and most of these antigens are self-antigens. These significant progresses have led to the renaissance of tumor immunology and studies on anti-tumor immunotherapy.However, despite of the progress in the identification of self-tumor antigens, current antigen-specific immunotherapies for tumors are far less satisfied than expected, which reflects the urgent need to improve our understanding on self-tumor antigens. In order to develop more effective antigen specific anti-tumor immunotherapies and to monitor the responses to these immunotherapies in patients with tumors, many important fundamental questions need to be addressed. We propose for the first time that the studies in addressing the characteristics of self-tumor antigens and autoantigens are grouped as a new subject termed "antigenology". In this brief review, we would outline the progress in the identification of tumor antigens in solid tumors and hematologic malignancies, and overview the new concepts and principles of antigenology and their significance for future immunotherapies to these malignancies. Cellular & Molecular Immunology.

  2. 上海粉尘螨变应原及特异性免疫治疗%Dermatophagoides farinae Mite Allergen and Specific Immunotherapy in Shanghai

    Institute of Scientific and Technical Information of China (English)

    温廷桓

    2009-01-01

    Studies on mite allergy had been launched by the Shanghai First Medical College since 1970's in this country.The preparations of SMU-Df from the local specimens of Dermatophagoides farinae(Df)in Shanghai have been shown the highest allergenic potency in comparison with that of the foreign ones,including the Df preparations from USFDA,VUS and ALK.Similar patterns of the protein curves were yielded by gel filtration,indicating almost similar allergenicities with both Df pure mite body and its spent culture medium.Around 80% of the allergic cases were sensitive to mite allergen and can be diagnosed by skin prick test,nasal provocation test and serum IgE level assay.Seasonal classic immunotherapy for allergic patients by Injectio Dermatophagoidei farinae,the first commercial allergen licensed by the Chinese government,achieved significant effect in relieving symptoms of allergic disorders in majority of cases,and long lasting effect of mite specific immunotherapy was also documented with minimal adverse reactions.Modifications of the Df crude extract and various modes of treatment have been studied.Studies on sublingual mite vaccine for mite allergic disorders developed synchronously with foreign trend since 1992.Sublingual drops were well acceptable by child cases almost without age restriction with higher efficacy.Rush schedule of mite immunotherapy led to a quick relief of allergic symptoms and long lasting curative effects.The Df allergen induced immunological regulation of human beings was established not only among the atopic patients,but also in healthy persons.%我国螨性变态反应的研究开始于1970年代上海第一医学院(现为复旦大学上海医学院).上海当地的粉尘螨螨种制备的变应原SMU-Df,其过敏活性与国外同种比较,超过许多倍属于最高的,包括美国食品药品管理局参考品、弗吉尼亚大学标准品、丹麦哥本哈根变态反应研究所标准质量品等.SMU-Df经凝胶层析所显示的蛋白

  3. Tracking in vivo migration and distribution of antigen-specific cytotoxic T lymphocytes by 5,6-carboxyfluorescein diacetate succinimidyl ester staining during cancer immunotherapy

    Institute of Scientific and Technical Information of China (English)

    XU Wei-li; LI Suo-lin; WEN Ming; WEN Jun-ye; HAN Jie; ZHANG Hong-zhen; GAO Fei

    2013-01-01

    Background Killing of targeted tumors during adoptive cell transfer therapy is associated with cytotoxic T lymphocyte (CTL) numbers,immunophenotype,tumor-specificity,and in vivo residence time,migration,and distribution.Therefore,tracing in vivo persistence,migration,and distribution of CTLs is important for cancer immunotherapy.Methods Optimal staining concentration for CTL proliferation was determined by cell counting kit-8 (CCK-8) assay and killing efficiencies of CTLs or carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled melanoma antigen-specific cytotoxic T lymphocytes (CFSE-CTLs) for malignant melanoma cells in vitro were compared.Additionally,CFSE-CTLs were intravenously transfused to mice receiving B16 melanoma,and their residence time,migration,and distribution in vivo were observed by measuring fluorescence intensities of CFSE-CTLs per gram of tissue (%FI/g) in various tissues and analyzing tumor/non-tumor (T/NT) values.Anti-tumor effects of transferred CTLs and correlation between %FI/g and D-value of tumor size were analyzed.Results Five-micromolar CFSE was optimal for labeling CTLs with minimal cytotoxicity.No significant difference occurred between CTLs and CFSE-CTLs for tumor cell killing (P=0.849) or interleukin-2 (P=0.318) and interferon-y (P=0.201)levels.Distribution of CTLs in vivo varied with time.A negative correlation between %FI/g in tumors and D-value of tumor sizes by Spearman correlation analysis was observed.CTLs were recruited to and killed tumors from 6 hours to 3 days after cell infusion.CTLs were observed up to three weeks later in the tumor,liver,kidneys,and spleen; this was related to the abundant blood supply or the nature of immune organs.Conclusions CCK-8 assay is a novel method to select optimal CFSE staining concentrations.Fluorescence intensity of transferred CTLs reflects their killing efficiency of tumors.CFSE fluorescent markers can trace in vivo CTL persistence,migration,and distribution because of its

  4. Awareness and understanding of cancer immunotherapy in Europe.

    Science.gov (United States)

    Mellstedt, Håkan; Gaudernack, Gustav; Gerritsen, Winald R; Huber, Christoph; Melero, Ignacio; Parmiani, Giorgio; Scholl, Suzy; Thatcher, Nicholas; Wagstaff, John; Zielinski, Christoph

    2014-01-01

    The use of immunotherapy in the management of cancer is growing, and a range of new immunotherapeutic strategies is becoming available. It is important that people involved in the care of cancer understand how cancer immunotherapies differ from conventional chemotherapy and apply this knowledge to their clinical practice. Therefore, from August-September 2011 we undertook a survey of awareness, attitudes, and perceptions of cancer immunotherapy among 426 healthcare professionals (HCPs) in Europe with the aim of identifying and prioritizing educational needs. Nearly all (98%) HCPs were aware of cancer immunotherapy. While 68% of HCPs indicated a high level of interest in cancer immunotherapies, only 24% of the HCPs had direct experience with them. Overall perceptions of cancer immunotherapy among HCPs were largely positive (60%) and rarely negative (3%). The key advantages of cancer immunotherapy were perceived to be good safety and tolerability (75%), a targeted mechanism of action (61%) and good efficacy (48%). The leading barriers to use of immunotherapies were costs of treatment (58%), past clinical trial failures (45%), and access/formulary restrictions (44%). The results indicate that, among the respondents, awareness of cancer immunotherapy was high but that knowledge levels varied and direct experience with their use was limited. There appears to be a need for educational activities on cancer immunotherapy, as well as generation and communication of clinical data on long-term efficacy and safety.

  5. Mathematical Model Creation for Cancer Chemo-Immunotherapy

    Directory of Open Access Journals (Sweden)

    Lisette de Pillis

    2009-01-01

    Full Text Available One of the most challenging tasks in constructing a mathematical model of cancer treatment is the calculation of biological parameters from empirical data. This task becomes increasingly difficult if a model involves several cell populations and treatment modalities. A sophisticated model constructed by de Pillis et al., Mixed immunotherapy and chemotherapy of tumours: Modelling, applications and biological interpretations, J. Theor. Biol. 238 (2006, pp. 841–862; involves tumour cells, specific and non-specific immune cells (natural killer (NK cells, CD8+T cells and other lymphocytes and employs chemotherapy and two types of immunotherapy (IL-2 supplementation and CD8+T-cell infusion as treatment modalities. Despite the overall success of the aforementioned model, the problem of illustrating the effects of IL-2 on a growing tumour remains open. In this paper, we update the model of de Pillis et al. and then carefully identify appropriate values for the parameters of the new model according to recent empirical data. We determine new NK and tumour antigen-activated CD8+T-cell count equilibrium values; we complete IL-2 dynamics; and we modify the model in de Pillis et al. to allow for endogenous IL-2 production, IL-2-stimulated NK cell proliferation and IL-2-dependent CD8+T-cell self-regulations. Finally, we show that the potential patient-specific efficacy of immunotherapy may be dependent on experimentally determinable parameters.

  6. Heat shock proteins and immunotherapy

    Institute of Scientific and Technical Information of China (English)

    XinZHAO; XueMeiXU; GuoxingSONG

    2005-01-01

    Being one of the most abundant intracellular proteins,heat shock proteins(HSPs) have many housekeeping functions which are crucial for the survival of organisms.In addition,some HSPs are new immunoactive molecules which play important roles in both adaptive and innate immunity.They could activate CD8+ and CD4+ lymphocytes,induce innate immune response including natural killer(NK) cell activation and cytokine secretion,and induce maturation of dendritic cells(DCs).These characteristics have been used for immunotherapy of various types of cancers and infectious disenses.This review focuses on the main HSP families——HSP70 and 90 families.The mechanism of HSPs’ function in eliciting immune response are elucidated and various forms of HSPs used in immunotherapy are discussed in details.At the end of this review,authors summarize clinical trials related to HSPs and evaluate their clinical efficacy.

  7. The application of natural killer (NK cell immunotherapy for the treatment of cancer

    Directory of Open Access Journals (Sweden)

    Rayne H Rouce

    2015-11-01

    Full Text Available Natural killer (NK cells are essential components of the innate immune system and play a critical role in host immunity against cancer. Recent progress in our understanding of NK cell immunobiology has paved the way for novel NK cell-based therapeutic strategies for the treatment of cancer. In this review, we will focus on recent advances in the field of NK cell immunotherapy, including augmentation of antibody-dependent cellular cytotoxicity, manipulation of receptor-mediated activation, and adoptive immunotherapy with ex vivo expanded, chimeric antigen receptor (CAR engineered or engager-modified NK cells. In contrast to T lymphocytes, donor NK cells do not attack non-hematopoietic tissues, suggesting that an NK-mediated anti-tumor effect can be achieved in the absence of graft-versus-host disease. Despite reports of clinical efficacy, a number of factors limit the application of NK cell immunotherapy for the treatment of cancer such as the failure of infused NK cells to expand and persist in vivo. Therefore efforts to enhance the therapeutic benefit of NK cell-based immunotherapy by developing strategies to manipulate the NK cell product, host factors and tumor targets are the subject of intense research. In the preclinical setting, genetic engineering of NK cells to express CARs to redirect their antitumor specificity has shown significant promise. Given the short lifespan and potent cytolytic function of mature NK cells, they are attractive candidate effector cells to express CARs for adoptive immunotherapies. Another innovative approach to redirect NK cytotoxicity towards tumor cells is to create either bispecific or trispecific antibodies, thus augmenting cytotoxicity against tumor-associated antigens. These are exciting times for the study of NK cells; with recent advances in the field of NK cell biology and translational research, it is likely that NK cell immunotherapy will move to the forefront of cancer immunotherapy over the next

  8. IL-13 receptor-directed cancer vaccines and immunotherapy.

    Science.gov (United States)

    Nakashima, Hideyuki; Husain, Syed R; Puri, Raj K

    2012-04-01

    Many immunotherapy approaches including therapeutic cancer vaccines targeting specific tumor-associated antigens are at various stages of development. Although the significance of overexpression of (IL-13Rα2) in cancer is being actively investigated, we have reported that IL-13Rα2 is a novel tumor-associated antigen. The IL-13Rα2-directed cancer vaccine is one of the most promising approaches to tumor immunotherapy, because of the selective expression of IL-13Rα2 in various solid tumor types but not in normal tissues. In this article, we will summarize its present status and potential strategies to improve IL-13Rα2-directed cancer vaccines for an optimal therapy of cancer.

  9. Defining the critical hurdles in cancer immunotherapy

    Directory of Open Access Journals (Sweden)

    Fox Bernard A

    2011-12-01

    Full Text Available Abstract Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC, convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators; others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet if overcome, have the potential to improve outcomes of patients with cancer.

  10. The efficacy and safety of specific immunotherapy for bronchial asthma through two different administration routes%不同给药途径的特异性免疫治疗的疗效及安全性

    Institute of Scientific and Technical Information of China (English)

    方萍; 孙秀珍; 冯向莉; 刘昀; 鱼宝萍; 魏萍

    2011-01-01

    Objective To evaluate the clinical efficacy and safety of specific immunotherapy for mite allergic bronchial asthma through two different administration routes.Methods Totally 40 patients with relieved mite allergic asthma were divided randomly into two groups.The two groups were treated with sublingual immunotherapy (SLIT) and subcutaneous immunotherapy (SCIT), respectively, for one year.Then wc recorded the clinical efficacy and safety indexes of the two groups.Results There were significant differences before and after immunotherapy in the percentage of controlled patients, dosage of inhaled corticosteroids, ACQ and AQLQ scores, and skin prick test in the two groups (P<0.05).The indexes above were all improved to different extents after immunotherapy,but there was no difference in the improved level between the two groups (P>0.05).Lung function, percentage of eosinophils and sIgE did no change significantly in the two groups after therapy (P> 0.05).Common adverse reactions such as tongue swelling, prick, gastrointestinal discomfort and throat discomfort were observed in SLIT group, while asthma attack, rash and fatigue were found in SCIT group.Conclusion Sublingual immunotherapy and subcutaneous therapy have equivalent therapeutic effects in specific immunotherapy for mite allergen, and the former has a greater advantage in compliance and safety.%目的 比较两种不同给药方式进行尘螨变应原特异性免疫治疗对缓解期哮喘患者的临床疗效和安全性.方法 筛选40例缓解期尘螨过敏的哮喘患者,随机分为两组,分别给予尘螨变应原舌下含服(SLIT)和皮下注射(SCIT)脱敏治疗,总疗程为1年,观察两组的临床疗效和安全性.结果 两组患者治疗前后吸入糖皮质激素日剂量、哮喘控制问卷(ACQ)、哮喘生命质量调查问卷(AQLQ)评分、尘螨皮肤试验反应度均得到改善(P<0.05),但改善程度组间比较无显著性差异(P>0.05).两组患者哮喘得以控制的

  11. Recombinant allergens for pollen immunotherapy.

    Science.gov (United States)

    Wallner, Michael; Pichler, Ulrike; Ferreira, Fatima

    2013-12-01

    Specific immunotherapy (IT) represents the only potentially curative therapeutic intervention of allergic diseases capable of suppressing allergy-associated symptoms not only during treatment, but also after its cessation. Presently, IT is performed with allergen extracts, which represent a heterogeneous mixture of allergenic, as well as nonallergenic, compounds of a given allergen source. To overcome many of the problems associated with extract-based IT, strategies based on the use of recombinant allergens or derivatives thereof have been developed. This review focuses on recombinant technologies to produce allergy therapeuticals, especially for allergies caused by tree, grass and weed pollen, as they are among the most prevalent allergic disorders affecting the population of industrialized societies. The reduction of IgE-binding of recombinant allergen derivatives appears to be mandatory to increase the safety profile of vaccine candidates. Moreover, increased immunogenicity is expected to reduce the dosage regimes of the presently cumbersome treatment. In this regard, it has been convincingly demonstrated in animal models that hypoallergenic molecules can be engineered to harbor inherent antiallergenic immunologic properties. Thus, strategies to modulate the allergenic and immunogenic properties of recombinant allergens will be discussed in detail. In recent years, several successful clinical studies using recombinant wild-type or hypoallergens as active ingredients have been published and, currently, novel treatment forms with higher safety and efficacy profiles are under investigation in clinical trials. These recent developments are summarized and discussed.

  12. The IL-2 cytokine family in cancer immunotherapy.

    Science.gov (United States)

    Sim, Geok Choo; Radvanyi, Laszlo

    2014-08-01

    The use of cytokines from the IL-2 family (also called the common γ chain cytokine family) such as interleukin (IL)-2, IL-7, IL-15, and IL-21 to activate the immune system of cancer patients is one of the most important areas of current cancer immunotherapy research. The infusion of IL-2 at low or high doses for multiple cycles in patients with metastatic melanoma and renal cell carcinoma was the first successful immunotherapy for cancer proving that the immune system could completely eradicate tumor cells under certain conditions. The initial clinical success observed in some IL-2-treated patients encouraged further efforts focused on developing and improving the application of other IL-2 family cytokines (IL-4, IL-7, IL-9, IL-15, and IL-21) that have unique biological effects playing important roles in the development, proliferation, and function of specific subsets of lymphocytes at different stages of differentiation with some overlapping effects with IL-2. IL-7, IL-15, and IL-21, as well as mutant forms or variants of IL-2, are now also being actively pursued in the clinic with some measured early successes. In this review, we summarize the current knowledge on the biology of the IL-2 cytokine family focusing on IL-2, IL-15 and IL-21. We discuss the similarities and differences between the signaling pathways mediated by these cytokines and their immunomodulatory effects on different subsets of immune cells. Current clinical application of IL-2, IL-15 and IL-21 either as single agents or in combination with other biological agents and the limitation and potential drawbacks of these cytokines for cancer immunotherapy are also described. Lastly, we discuss the future direction of research on these cytokines, such as the development of new cytokine mutants and variants for improving cytokine-based immunotherapy through differential binding to specific receptor subunits.

  13. Adoptive immunotherapy via CD4+ versus CD8+ T cells

    Directory of Open Access Journals (Sweden)

    Vy Phan-Lai

    2016-04-01

    Full Text Available The goal of cancer immunotherapy is to induce specific and durable antitumor immunity. Adoptive T cell therapy (ACT has garnered wide interest, particularly in regard to strategies to improve T cell efficacy in trials. There are many types of T cells (and subsets which can be selected for use in ACT. CD4+ T cells are critical for the regulation, activation and aid of host defense mechanisms and, importantly, for enhancing the function of tumor-specific CD8+ T cells. To date, much research in cancer immunotherapy has focused on CD8+ T cells, in melanoma and other cancers. Both CD4+ T cells and CD8+ T cells have been evaluated as ACT in mice and humans, and both are effective at eliciting antitumor responses. IL-17 producing CD4+ T cells are a new subset of CD4+ T cells to be evaluated in ACT models. This review discusses the benefits of adoptive immunotherapy mediated by CD8+ and CD4+ cells. It also discusses the various type of T cells, source of T cells, and ex vivo cytokine growth factors for augmenting clinical efficacy of ACT. [Biomed Res Ther 2016; 3(4.000: 588-595

  14. Immunotherapy for malignant glioma

    Directory of Open Access Journals (Sweden)

    Carter M Suryadevara

    2015-01-01

    Full Text Available Malignant gliomas (MG are the most common type of primary malignant brain tumor. Most patients diagnosed with glioblastoma (GBM, the most common and malignant glial tumor, die within 12-15 months. Moreover, conventional treatment, which includes surgery followed by radiation and chemotherapy, can be highly toxic by causing nonspecific damage to healthy brain and other tissues. The shortcomings of standard-of-care have thus created a stimulus for the development of novel therapies that can target central nervous system (CNS-based tumors specifically and efficiently, while minimizing off-target collateral damage to normal brain. Immunotherapy represents an investigational avenue with the promise of meeting this need, already having demonstrated its potential against B-cell malignancy and solid tumors in clinical trials. T-cell engineering with tumor-specific chimeric antigen receptors (CARs is one proven approach that aims to redirect autologous patient T-cells to sites of tumor. This platform has evolved dramatically over the past two decades to include an improved construct design, and these modern CARs have only recently been translated into the clinic for brain tumors. We review here emerging immunotherapeutic platforms for the treatment of MG, focusing on the development and application of a CAR-based strategy against GBM.

  15. Therapeutic cancer vaccines and combination immunotherapies involving vaccination

    Directory of Open Access Journals (Sweden)

    Nguyen T

    2014-10-01

    Full Text Available Trang Nguyen,1 Julie Urban,1 Pawel Kalinski1–5 1Department of Surgery, 2Department of Immunology, 3Department of Microbiology and Infectious Disease, 4Department of Bioengineering, University of Pittsburgh, 5University of Pittsburgh Cancer Institute, Pittsburgh, PA, USAAbstract: Recent US Food and Drug Administration approvals of Provenge® (sipuleucel-T as the first cell-based cancer therapeutic factor and ipilimumab (Yervoy®/anticytotoxic T-lymphocyte antigen-4 as the first “checkpoint blocker” highlight recent advances in cancer immunotherapy. Positive results of the clinical trials evaluating additional checkpoint blocking agents (blockade of programmed death [PD]-1, and its ligands, PD-1 ligand 1 and 2 and of several types of cancer vaccines suggest that cancer immunotherapy may soon enter the center stage of comprehensive cancer care, supplementing surgery, radiation, and chemotherapy. This review discusses the current status of the clinical evaluation of different classes of therapeutic cancer vaccines and possible avenues for future development, focusing on enhancing the magnitude and quality of cancer-specific immunity by either the functional reprogramming of patients' endogenous dendritic cells or the use of ex vivo-manipulated dendritic cells as autologous cellular transplants. This review further discusses the available strategies aimed at promoting the entry of vaccination-induced T-cells into tumor tissues and prolonging their local antitumor activity. Finally, the recent improvements to the above three modalities for cancer immunotherapy (inducing tumor-specific T-cells, prolonging their persistence and functionality, and enhancing tumor homing of effector T-cells and rationale for their combined application in order to achieve clinically effective anticancer responses are addressed.Keywords: immunotherapy, cancer, vaccines

  16. Development of cancer immunotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Yun, Yeon Sook; Chung, H. Y.; Yi, S. Y.; Kim, K. W.; Kim, B. K.; Chung, I. S.; Park, J. Y

    1999-04-01

    To increase the curative rate of cancer patients, we developed ideal biological response modifier from medicinal plants: Ginsan, KC68IId-8, KC-8Ala, KG-30. Ginsan activated natural killer cell activity of spleen cells more than 5.4 times than lentinan, 1.4 times than picibanil. Radioprotective activity of Ginsan is stronger than WR2721, glucan, and selenium. The immunogenicity of MOPC tumor cells was augmented by treatment with IL-10 antisense oligonucleotide and by transfection with VEGF sense-, antisense gene. The immunogenicity of MOPC tumor cells was augmented by treatment with IL-10 antisense oligonucleotide and by transfection with VEGF sense-, antisense gene. The immunogenicity of A20 tumor cells was also augmented by transfection with B7.1 gene. The immunosuppression of gamma-irradiation was due to the reduction of Th1 sytokine gene expression through STAT pathway. These research will devote to develop new cancer immunotherapy and to reduce side effect of cancer radiotherapy and chemotherapy.

  17. Cancer immunotherapy in children

    Science.gov (United States)

    More often than not, cancer immunotherapies that work in adults are used in modified ways in children. Seldom are new therapies developed just for children, primarily because of the small number of pediatric patients relative to the adult cancer patient

  18. Immunotherapy for Cervical Cancer

    Science.gov (United States)

    In an early phase NCI clinical trial, two patients with metastatic cervical cancer had a complete disappearance of their tumors after receiving treatment with a form of immunotherapy called adoptive cell transfer.

  19. Cancer Immunotherapy: A Review

    Directory of Open Access Journals (Sweden)

    Anna Meiliana

    2016-04-01

    Full Text Available BACKGROUND: The goals of treating patients with cancer are to cure the disease, prolong survival, and improve quality of life. Immune cells in the tumor microenvironment have an important role in regulating tumor progression. Therefore, stimulating immune reactions to tumors can be an attractive therapeutic and prevention strategy. CONTENT: During immune surveillance, the host provides defense against foreign antigens, while ensuring it limits activation against self antigens. By targeting surface antigens expressed on tumor cells, monoclonal antibodies have demonstrated efficacy as cancer therapeutics. Recent successful antibody-based strategies have focused on enhancing antitumor immune responses by targeting immune cells, irrespective of tumor antigens. The use of antibodies to block pathways inhibiting the endogenous immune response to cancer, known as checkpoint blockade therapy, has stirred up a great deal of excitement among scientists, physicians, and patients alike. Clinical trials evaluating the safety and efficacy of antibodies that block the T cell inhibitory molecules cytotoxic T-lymphocyte-associated protein 4 (CTLA-4 and programmed cell death 1 (PD-1 have reported success in treating subsets of patients. Adoptive cell transfer (ACT is a highly personalized cancer therapy that involve administration to the cancer-bearing host of immune cells with direct anticancer activity. In addition, the ability to genetically engineer lymphocytes to express conventional T cell receptors or chimeric antigen receptors has further extended the successful application of ACT for cancer treatment. SUMMARY: For cancer treatment, 2011 marked the beginning of a new era. The underlying basis of cancer immunotherapy is to activate a patient’s own T cells so that they can kill their tumors. Reports of amazing recoveries abound, where patients remain cancer-free many years after receiving the therapy. The idea of harnessing immune cells to fight cancer is

  20. Targetless T cells in cancer immunotherapy

    DEFF Research Database (Denmark)

    thor Straten, Eivind Per; Garrido, Federico

    2016-01-01

    Attention has recently focused on new cancer immunotherapy protocols aiming to activate T cell mediated anti-tumor responses. To this end, administration of antibodies that target inhibitory molecules regulating T-cell cytotoxicity has achieved impressive clinical responses, as has adoptive cell...... infiltrate tumor tissues and destroy HLA class I positive tumor cells expressing the specific antigen. In fact, current progress in the field of cancer immune therapy is based on the capacity of T cells to kill cancer cells that present tumor antigen in the context on an HLA class I molecule. However......, it is also well established that cancer cells are often characterized by loss or down regulation of HLA class I molecules, documented in a variety of human tumors. Consequently, immune therapy building on CD8 T cells will be futile in patients harboring HLA class-I negative or deficient cancer cells...

  1. Nanochemistry-based immunotherapy for HIV-1.

    Science.gov (United States)

    Lori, F; Calarota, S A; Lisziewicz, J

    2007-01-01

    Highly active antiretroviral treatment (HAART), i.e. the combination of three or more drugs against human immunodeficiency virus type 1 (HIV-1), has greatly improved the clinical outcome of HIV-1-infected individuals. However, HAART is unable to reconstitute HIV-specific immunity and eradicate the virus. Several observations in primate models and in humans support the notion that cell-mediated immunity can control viral replication and slow disease progression. Thus, besides drugs, an immunotherapy that induces long-lasting HIV-specific T-cell responses could play a role in the treatment of HIV/AIDS. To induce such immune responses, DermaVir Patch has been developed. DermaVir consists of an HIV-1 antigen-encoding plasmid DNA that is chemically formulated in a nanoparticle. DermaVir is administered under a patch after a skin preparation that supports the delivery of the nanoparticle to Langerhans cells (LC). Epidermal LC trap and transport the nanomedicine to draining lymph nodes. While in transit, LC mature into dendritic cells (DC), which can efficiently present the DNA-encoded antigens to naïve T-cells for the induction of cellular immunity. Pre-clinical studies and Phase I clinical testing of DermaVir in HIV-1-infected individuals have demonstrated the safety and tolerability of DermaVir Patch. To further modulate cellular immunity, molecular adjuvants might be added into the nanoparticle. DermaVir Patch represents a new nanomedicine platform for immunotherapy of HIV/AIDS. In this review, the antiviral activity of DermaVir-induced cellular immunity is discussed. Furthermore, the action of some cytokines currently being tested as adjuvants are highlighted and the adjuvant effect of cytokine plasmid DNA included in the DermaVir nanoparticle is reviewed.

  2. Sublingual Immunotherapy: Recent Advances

    Directory of Open Access Journals (Sweden)

    Enrico Compalati

    2013-01-01

    Full Text Available The practice of administering sublingual immunotherapy for respiratory allergy is gaining more and more diffusion worldwide as a consequence of the robust demonstration of clinical efficacy and safety provided by recent high-powered and well-designed studies, confirming for individual seasonal allergens the results of previous metanalyses in adult and pediatric populations. Preliminary evidence derives from recent rigorous trials on perennial allergens, like house dust mites, and specifically designed studies addressed the benefits on asthma. Emerging research suggests that SLIT may have a future role in other allergic conditions such as atopic dermatitis, food, latex and venom allergy. Efforts to develop a safer and more effective SLIT for inhalant allergens have led to the development of allergoids, recombinant allergens and formulations with adjuvants and substances targeting antigens to dendritic cells that possess a crucial role in initiating immune responses. The high degree of variation in the evaluation of clinical effects and immunological changes requires further studies to identify the candidate patients to SLIT and biomarkers of short and long term efficacy. Appropriate management strategies are urgently needed to overcome the barriers to SLIT compliance.

  3. Reciprocal regulation of activating and inhibitory Fcγ receptors by TLR7/8 activation: Implications for tumor immunotherapy

    Science.gov (United States)

    Butchar, Jonathan P.; Mehta, Payal; Justiniano, Steven E.; Guenterberg, Kristan D.; Kondadasula, Sri-Vidya; Mo, Xiaokui; Chemudupati, Mahesh; Kanneganti, Thirumala-Devi; Amer, Amal; Muthusamy, Natarajan; Jarjoura, David; Marsh, Clay B.; Carson, William E.; Byrd, John C.; Tridandapani, Susheela

    2010-01-01

    Purpose Activation of Toll-like Receptors (TLR) 7 and 8 by engineered agonists has been shown to aid in combating viruses and tumors. Here, we wished to test the effect of TLR7/8 activation on monocyte Fcγ receptor (FcγR) function, as they are critical mediators of antibody therapy. Experimental Design The effect of the TLR7/8 agonist R-848 on cytokine production and antibody-dependent cellular cytotoxicity (ADCC) by human peripheral blood monocytes (PBM) was tested. Affymetrix microarrays were done to examine genomewide transcriptional responses of monocytes to R-848, and Western blots were done to measure protein levels of FcγR. Murine bone marrow-derived macrophages (BMM) from wild-type and knockout mice were examined to determine the downstream pathway involved with regulating FcγR expression. The efficacy of R-848 as an adjuvant for antibody therapy was tested using a CT26-HER2/neu solid tumor model. Results Overnight incubation with R-848 increased FcγR-mediated cytokine production and ADCC in human PBM. Expression of FcγRI, FcγRIIa and the common γ-subunit was increased. Surprisingly, expression of the inhibitory FcγRIIb was almost completely abolished. In BMM, this required TLR7 and MyD88, as R-848 did not increase expression of the γ-subunit in TLR7−/− nor MyD88−/− cells. In a mouse solid tumor model, R-848 treatment superadditively enhanced the effects of antitumor antibody. Conclusions These results demonstrate an as-yet undiscovered regulatory and functional link between the TLR7/8 and FcγR pathways. This suggests that TLR7/8 agonists may be especially beneficial during antibody therapy. PMID:20332325

  4. Advances in the understanding of cancer immunotherapy.

    Science.gov (United States)

    Shore, Neal D

    2015-09-01

    The principal role of the immune system is to prevent and eradicate pathogens and infections. The key characteristics or features of an effective immune response include specificity, trafficking, antigen spread and durability (memory). The immune system is recognised to have a critical role in controlling cancer through a dynamic relationship with tumour cells. Normally, at the early stages of tumour development, the immune system is capable of eliminating tumour cells or keeping tumour growth abated; however, tumour cells may evolve multiple pathways over time to evade immune control. Immunotherapy may be viewed as a treatment designed to boost or restore the ability of the immune system to fight cancer, infections and other diseases. Immunotherapy manifests differently from traditional cancer treatments, eliciting delayed response kinetics and thus may be more effective in patients with lower tumour burden, in whom disease progression may be less rapid, thereby allowing ample time for the immunotherapy to evolve. Because immunotherapies may have a different mechanism of action from traditional cytotoxic or targeted biological agents, immunotherapy techniques have the potential to combine synergistically with traditional therapies.

  5. Immunotherapy for Drug Abuse

    Science.gov (United States)

    Shen, Xiaoyun; Kosten, Thomas R.

    2013-01-01

    Substance use disorders continue to be major medical and social problems worldwide. Current medications for substance use disorders have many limitations such as cost, availability, medication compliance, dependence, diversion of some to illicit use and relapse to addiction after discontinuing their use. Immunotherapies using either passive monoclonal antibodies or active vaccines have distinctly different mechanisms and therapeutic utility from small molecule approaches to treatment. They have great potential to help the patient achieve and sustain abstinence and have fewer of the above limitations. This review covers the cocaine vaccine development in detail and provides an overview of directions for developing anti-addiction vaccines against the abuse of other substances. The notable success of the first placebo-controlled clinical trial of a cocaine vaccine, TA-CD, has led to an ongoing multi-site, Phase IIb clinical trial in 300 subjects. The results from these trials are encouarging further development of the cocaine vacine as one of the first anti-addiction vaccines to go forward to the U.S. Food and Drug Administration for review and approval for human use. PMID:22229313

  6. Short-, Intermediate-, and Long-Term Changes in Basophil Reactivity Induced by Venom Immunotherapy

    OpenAIRE

    Rodríguez Trabado, Ana; Cámara Hijón, Carmen; Ramos Cantariño, Alfonso; Romero-Chala, Silvia; García-Trujillo, José Antonio; Fernández Pereira, Luis Miguel

    2016-01-01

    Purpose The basophil activation test (BAT) has been used to monitor venom immunotherapy (VIT) due to its high specificity. A previous study has reported a good correlation between a significant decrease in basophil activation during 5 years of VIT and clinical protection assessed by sting challenge. The following prospective study was performed to examine changes in basophil reactivity over a complete VIT period of 5 years. Methods BAT in a dose-response curve was studied prospectively in 10 ...

  7. Strategies of mucosal immunotherapy for allergic diseases

    Institute of Scientific and Technical Information of China (English)

    Yi-Ling Ye; Ya-Hui Chuang; Bor-Luen Chiang

    2011-01-01

    Incidences of allergic disease have recently increased worldwide.Allergen-specific immunotherapy (SIT) has long been a controversial treatment for allergic diseases.Although beneficial effects on clinically relevant outcomes have been demonstrated in clinical trials by subcutaneous immunotherapy (SCIT),there remains a risk of severe and sometimes fatal anaphylaxis.Mucosal immunotherapy is one advantageous choice because of its non-injection routes of administration and lower side-effect profile.This study reviews recent progress in mucosal immunotherapy for allergic diseases.Administration routes,antigen quality and quantity,and adjuvants used are major considerations in this field.Also,direct uses of unique probiotics,or specific cytokines,have been discussed.Furthermore,some researchers have reported new therapeutic ideas that combine two or more strategies.The most important strategy for development of mucosal therapies for allergic diseases is the improvement of antigen formulation,which includes continuous searching for efficient adjuvants,collecting more information about dominant T-cell epitopes of allergens,and having the proper combination of each.In clinics,when compared to other mucosal routes,sublingual immunotherapy (SLIT) is a preferred choice for therapeutic administration,although local and systemic side effects have been reported.Additionally,not every allergen has the same beneficial effect.Further studies are needed to determine the benefits of mucosal immunotherapy for different allergic diseases after comparison of the different administration routes in children and adults.Data collected from large,well-designed,double-blind,placebo-controlled,and randomized trials,with post-treatment follow-up,can provide robust substantiation of current evidence.

  8. Novel immunotherapy approaches to food allergy

    NARCIS (Netherlands)

    Hayen, Simone M; Kostadinova, Atanaska I; Garssen, Johan; Otten, Henny G; Willemsen, Linette E M

    2014-01-01

    PURPOSE OF REVIEW: Despite reaching high percentages of desensitization using allergen-specific immunotherapy (SIT) in patients with food allergy, recent studies suggest only a low number of patients to reach persistent clinical tolerance. This review describes current developments in strategies to

  9. Novel Immunotherapies for Autoimmune Hepatitis.

    Science.gov (United States)

    Cassim, Shamir; Bilodeau, Marc; Vincent, Catherine; Lapierre, Pascal

    2017-01-01

    Autoimmune hepatitis (AIH) is a multifactorial autoimmune disease of unknown pathogenesis, characterized by a loss of immunological tolerance against liver autoantigens resulting in the progressive destruction of the hepatic parenchyma. Current treatments are based on non-specific immunosuppressive drugs. Although tremendous progress has been made using specific biological agents in other inflammatory diseases, progress has been slow to come for AIH patients. While current treatments are successful in the majority of patients, treatment discontinuation is difficult to achieve, and relapses are frequent. Lifelong immunosuppression is not without risks, especially in the pediatric population; 4% of patient with type 1 AIH will eventually develop hepatocellular carcinoma with a 2.9% probability after 10 years of treatment. Therefore, future treatments should aim to restore tolerance to hepatic autoantigens and induce long-term remission. Promising new immunotherapies have been tested in experimental models of AIH including T and B cell depletion and regulatory CD4(+) T cells infusion. Clinical studies on limited numbers of patients have also shown encouraging results using B-cell-depleting (rituximab) and anti-TNF-α (infliximab) antibodies. A better understanding of key molecular targets in AIH combined with effective site-specific immunotherapies could lead to long-term remission without blanket immunosuppression and with minimal deleterious side effects.

  10. Novel Immunotherapies for Autoimmune Hepatitis

    Science.gov (United States)

    Cassim, Shamir; Bilodeau, Marc; Vincent, Catherine; Lapierre, Pascal

    2017-01-01

    Autoimmune hepatitis (AIH) is a multifactorial autoimmune disease of unknown pathogenesis, characterized by a loss of immunological tolerance against liver autoantigens resulting in the progressive destruction of the hepatic parenchyma. Current treatments are based on non-specific immunosuppressive drugs. Although tremendous progress has been made using specific biological agents in other inflammatory diseases, progress has been slow to come for AIH patients. While current treatments are successful in the majority of patients, treatment discontinuation is difficult to achieve, and relapses are frequent. Lifelong immunosuppression is not without risks, especially in the pediatric population; 4% of patient with type 1 AIH will eventually develop hepatocellular carcinoma with a 2.9% probability after 10 years of treatment. Therefore, future treatments should aim to restore tolerance to hepatic autoantigens and induce long-term remission. Promising new immunotherapies have been tested in experimental models of AIH including T and B cell depletion and regulatory CD4+ T cells infusion. Clinical studies on limited numbers of patients have also shown encouraging results using B-cell-depleting (rituximab) and anti-TNF-α (infliximab) antibodies. A better understanding of key molecular targets in AIH combined with effective site-specific immunotherapies could lead to long-term remission without blanket immunosuppression and with minimal deleterious side effects. PMID:28184367

  11. Immunotherapy for Gastroesophageal Cancer

    Science.gov (United States)

    Goode, Emily F.; Smyth, Elizabeth C.

    2016-01-01

    Survival for patients with advanced oesophageal and stomach cancer is poor; together these cancers are responsible for more than a million deaths per year globally. As chemotherapy and targeted therapies such as trastuzumab and ramucirumab result in modest improvements in survival but not long-term cure for such patients, development of alternative treatment approaches is warranted. Novel immunotherapy drugs such as checkpoint inhibitors have been paradigm changing in melanoma, non-small cell lung cancer and urothelial cancers. In this review, we assess the early evidence for efficacy of immunotherapy in patients with gastroesophageal cancer in addition to considering biomarkers associated with response to these treatments. Early results of Anti- Programmed Cell Death Protein-1 (anti-PD-1), anti-PD-L1 and anti-Cytotoxic T-lymphocyte assosciated protein-4 (anti-CTLA4) trials are examined, and we conclude with a discussion on the future direction for immunotherapy for gastroesophageal cancer patients. PMID:27669318

  12. Immunotherapy for Gastroesophageal Cancer

    Directory of Open Access Journals (Sweden)

    Emily F. Goode

    2016-09-01

    Full Text Available Survival for patients with advanced oesophageal and stomach cancer is poor; together these cancers are responsible for more than a million deaths per year globally. As chemotherapy and targeted therapies such as trastuzumab and ramucirumab result in modest improvements in survival but not long-term cure for such patients, development of alternative treatment approaches is warranted. Novel immunotherapy drugs such as checkpoint inhibitors have been paradigm changing in melanoma, non-small cell lung cancer and urothelial cancers. In this review, we assess the early evidence for efficacy of immunotherapy in patients with gastroesophageal cancer in addition to considering biomarkers associated with response to these treatments. Early results of Anti- Programmed Cell Death Protein-1 (anti-PD-1, anti-PD-L1 and anti-Cytotoxic T-lymphocyte assosciated protein-4 (anti-CTLA4 trials are examined, and we conclude with a discussion on the future direction for immunotherapy for gastroesophageal cancer patients.

  13. Anti-CD40-mediated cancer immunotherapy

    DEFF Research Database (Denmark)

    Hassan, Sufia Butt; Sørensen, Jesper Freddie; Olsen, Barbara Nicola

    2014-01-01

    activation and thus enhancement of immune responses. Treatment with anti-CD40 monoclonal antibodies has been exploited in several cancer immunotherapy studies in mice and led to the development of anti-CD40 antibodies for clinical use. Here, Dacetuzumab and Lucatumumab are in the most advanced stage...... with other cancer immunotherapies, in particular interleukin (IL)-2. An in-depth analysis of this immunotherapy is provided elsewhere. In the present review, we provide an update of the most recent clinical trials with anti-CD40 antibodies. We present and discuss recent and ongoing clinical trials...... in this field, including clinical studies which combine anti-CD40 treatment with other cancer-treatments, such as Rituximab and Tremelimumab....

  14. Immunotherapy advances in uro-genital malignancies.

    Science.gov (United States)

    Ratta, Raffaele; Zappasodi, Roberta; Raggi, Daniele; Grassi, Paolo; Verzoni, Elena; Necchi, Andrea; Di Nicola, Massimo; Salvioni, Roberto; de Braud, Filippo; Procopio, Giuseppe

    2016-09-01

    Immunotherapy for the treatment of cancer has made significant progresses over the last 20 years. Multiple efforts have been attempted to restore immune-mediated tumor elimination, leading to the development of several targeted immunotherapies. Data from recent clinical trials suggest that these agents might improve the prognosis of patients with advanced genito-urinary (GU) malignancies. Nivolumab has been the first immune checkpoint-inhibitor approved for pre-treated patients with metastatic renal cell carcinoma. Pembrolizumab and atezolizumab have shown promising results in both phase I and II trials in urothelial carcinoma. Brentuximab vedotin has demonstrated early signals of clinical activity and immunomodulatory effects in highly pre-treated patients with testicular germ cell tumors. In this review, we have summarized the major clinical achievements of immunotherapy in GU cancers, focusing on immune checkpoint blockade as well as the new immunomodulatory monoclonal antibodies (mAbs) under clinical evaluation for these malignancies.

  15. Improving cancer immunotherapy with DNA methyltransferase inhibitors.

    Science.gov (United States)

    Saleh, Mohammad H; Wang, Lei; Goldberg, Michael S

    2016-07-01

    Immunotherapy confers durable clinical benefit to melanoma, lung, and kidney cancer patients. Challengingly, most other solid tumors, including ovarian carcinoma, are not particularly responsive to immunotherapy, so combination with a complementary therapy may be beneficial. Recent findings suggest that epigenetic modifying drugs can prime antitumor immunity by increasing expression of tumor-associated antigens, chemokines, and activating ligands by cancer cells as well as cytokines by immune cells. This review, drawing from both preclinical and clinical data, describes some of the mechanisms of action that enable DNA methyltransferase inhibitors to facilitate the establishment of antitumor immunity.

  16. Production of high specific activity silicon-32

    Energy Technology Data Exchange (ETDEWEB)

    Phillips, D.R. [Los Alamos National Lab., NM (United States); Brzezinski, M.A. [Univ. of California, Santa Barbara, CA (United States). Marine Biotechnology Center

    1998-12-31

    This is the final report of a three-year, Laboratory Directed Research and Development Project (LDRD) at Los Alamos National Laboratory (LANL). There were two primary objectives for the work performed under this project. The first was to take advantage of capabilities and facilities at Los Alamos to produce the radionuclide {sup 32}Si in unusually high specific activity. The second was to combine the radioanalytical expertise at Los Alamos with the expertise at the University of California to develop methods for the application of {sup 32}Si in biological oceanographic research related to global climate modeling. The first objective was met by developing targetry for proton spallation production of {sup 32}Si in KCl targets and chemistry for its recovery in very high specific activity. The second objective was met by developing a validated field-useable, radioanalytical technique, based upon gas-flow proportional counting, to measure the dynamics of silicon uptake by naturally occurring diatoms.

  17. An Undergraduate Laboratory Activity Demonstrating Bacteriophage Specificity

    Directory of Open Access Journals (Sweden)

    Mary E. Allen

    2013-02-01

    Full Text Available Bacteriophage are among the most diverse and numerous microbes inhabiting our planet. Yet many laboratory activities fail to engage students in meaningful exploration of their diversity, unique characteristics, and abundance. In this curriculum activity students use a standard plaque assay to enumerate bacteriophage particles from a natural sample and use the scientific method to address questions about host specificity and diversity. A raw primary sewage sample is enriched for bacteriophage using hosts in the family Enterobacteriaceae. Students hypothesize about host specificity and use quantitative data (serial dilution and plaque assay to test their hypotheses. Combined class data also help them answer questions about phage diversity. The exercise was field tested with a class of 47 students using pre- and posttests. For all learning outcomes posttest scores were higher than pretest scores at or below p = 0.01. Average individualized learning gain (G was also calculated for each learning outcome. Students’ use of scientific language in reference to bacteriophage and host interaction significantly improved (p = 0.002; G = 0.50. Improved means of expression helped students construct better hypotheses on phage host specificity (G = 0.31, p = 0.01 and to explain the plaque assay method (G = 0.33, p = 0.002. At the end of the exercise students also demonstrated improved knowledge and understanding of phage specificity as related to phage therapy in humans (p < 0.001; G = 51.

  18. Active immunotherapy combined with blockade of a coinhibitory pathway achieves regression of large tumor masses in cancer-prone mice.

    Science.gov (United States)

    Lasaro, Marcio O; Sazanovich, Marina; Giles-Davis, Wynetta; Mrass, Paulus; Bunte, Ralph M; Sewell, Duane A; Hussain, S Farzana; Fu, Yang-Xin; Weninger, Wolfgang; Paterson, Yvonne; Ertl, Hildegund Cj

    2011-09-01

    Vaccines that aim to expand tumor-specific CD8(+) T cells have yielded disappointing results in cancer patients although they showed efficacy in transplantable tumor mouse models. Using a system that more faithfully mimics a progressing cancer and its immunoinhibitory microenvironment, we here show that in transgenic mice, which gradually develop adenocarcinomas due to expression of HPV-16 E7 within their thyroid, a highly immunogenic vaccine expressing E7 only induces low E7-specific CD8(+) T-cell responses, which fail to affect the size of the tumors. In contrast, the same type of vaccine expressing E7 fused to herpes simplex virus (HSV)-1 glycoprotein D (gD), an antagonist of the coinhibitory B- and T-lymphocyte attenuator (BTLA)/CD160-herpes virus entry mediator (HVEM) pathways, stimulates potent E7-specific CD8(+) T-cell responses, which can be augmented by repeated vaccination, resulting in initial regression of even large tumor masses in all mice with sustained regression in more than half of them. These results indicate that active immunization concomitantly with blockade of the immunoinhibitory HVEM-BTLA/CD160 pathways through HSV-1 gD may result in sustained tumor regression.

  19. Targetless T cells in cancer immunotherapy

    DEFF Research Database (Denmark)

    Thor Straten, Per; Garrido, Federico

    2016-01-01

    Attention has recently focused on new cancer immunotherapy protocols aiming to activate T cell mediated anti-tumor responses. To this end, administration of antibodies that target inhibitory molecules regulating T-cell cytotoxicity has achieved impressive clinical responses, as has adoptive cell ...

  20. Biologic activity of digoxin-specific antisera.

    Science.gov (United States)

    Watson, J F; Butler, V P

    1972-03-01

    Digoxin-specific antibodies are capable of removing essentially all intracellular digoxin from rat renal cortical slices or from human erythrocytes. In removing digoxin from erythrocytes, these antibodies are capable of reversing an effect of the drug on cellular potassium transport. This study provides direct evidence that antibodies are capable of removing, and thereby reversing the biological effect of, physiologically active low molecular weight substances after they have been taken up by mammalian cells. This biologic property of digoxin-specific antibodies suggests that autidigoxin sera may prove useful in the reversal of digoxin toxicity. Rapid and essentially quantitative removal of digoxin from red cells by antibody is not accompanied by an immediate restoration of patassium influx to normal levels. Identification of the mechanism of this phenomenon may provide useful information concerning the mode of action not only of digoxin, but also of the cation transport system of human erythrocytes.

  1. Immunotherapy and gene therapy.

    Science.gov (United States)

    Simpson, Elizabeth

    2004-02-01

    The Immunotherapy and Gene Therapy meeting of the Academy of Medical Sciences reviewed the state-of-the-art and translational prospects for therapeutic interventions aimed at killing tumor cells, correcting genetic defects and developing vaccines for chronic infections. Crucial basic science concepts and information about dendritic cells, the structure and function of T-cell receptors, and manipulation of the immune response by cytokine antagonists and peptides were presented. This information underpins vaccine design and delivery, as well as attempts to immunomodulate autoimmune disease. Results from studies using anticancer DNA vaccines, which include appropriate signals for both the innate and adaptive immune response, were presented in several talks. The vaccines incorporated helper epitopes and cancer target epitopes such as immunoglobulin idiotypes (for lymphomas and myelomas), melanoma-associated antigens (for melanoma and other solid tumors) and minor histocompatibility antigens (for leukemia). The results of using vaccines employing similar principles and designed to reduce viral load in HIV/AIDS patients were also presented. The introduction of suicide genes incorporating the bacterial enzyme nitroreductase gene (ntr) targeted at tumor cells prior to administration of the prodrug CB-1954, converted by ntr into a toxic alkylating agent, was discussed against the background of clinical trials and improved suicide gene design. The introduction into hematopoietic stem cells of missing genes for the common gamma-chain, deficiency of which causes severe combined immunodeficiency (SCID), used similar retroviral transduction. The outcome of treating six SCID patients in the UK, and ten in France was successful immune reconstitution in the majority of patients, but in two of the French cases a complication of lymphoproliferative disease due to insertional mutagenesis was observed. The adoptive transfer of T-cells specific for minor histocompatibility antigens (for

  2. Low-dose ionizing radiation induces direct activation of natural killer cells and provides a novel approach for adoptive cellular immunotherapy.

    Science.gov (United States)

    Yang, Guozi; Kong, Qingyu; Wang, Guanjun; Jin, Haofan; Zhou, Lei; Yu, Dehai; Niu, Chao; Han, Wei; Li, Wei; Cui, Jiuwei

    2014-12-01

    Recent evidence indicates that limited availability and cytotoxicity have restricted the development of natural killer (NK) cells in adoptive cellular immunotherapy (ACI). While it has been reported that low-dose ionizing radiation (LDIR) could enhance the immune response in animal studies, the influence of LDIR at the cellular level has been less well defined. In this study, the authors aim to investigate the direct effects of LDIR on NK cells and the potential mechanism, and explore the application of activation and expansion of NK cells by LDIR in ACI. The authors found that expansion and cytotoxicity of NK cells were markedly augmented by LDIR. The levels of IFN-γ and TNF-α in the supernatants of cultured NK cells were significantly increased after LDIR. Additionally, the effect of the P38 inhibitor (SB203580) significantly decreased the expanded NK cell cytotoxicity, cytokine levels, and expression levels of FasL and perforin. These findings indicate that LDIR induces a direct expansion and activation of NK cells through possibly the P38-MAPK pathway, which provides a potential mechanism for stimulation of NK cells by LDIR and a novel but simplified approach for ACI.

  3. Cancer immunotherapy and breaking immune tolerance: new approaches to an old challenge.

    Science.gov (United States)

    Makkouk, Amani; Weiner, George J

    2015-01-01

    Cancer immunotherapy has proven to be challenging as it depends on overcoming multiple mechanisms that mediate immune tolerance to self-antigens. A growing understanding of immune tolerance has been the foundation for new approaches to cancer immunotherapy. Adoptive transfer of immune effectors such as antitumor mAb and chimeric antigen receptor T cells bypasses many of the mechanisms involved in immune tolerance by allowing for expansion of tumor-specific effectors ex vivo. Vaccination with whole tumor cells, protein, peptide, or dendritic cells has proven challenging, yet may be more useful when combined with other cancer immunotherapeutic strategies. Immunomodulatory approaches to cancer immunotherapy include treatment with agents that enhance and maintain T-cell activation. Recent advances in the use of checkpoint blockade to block negative signals and to maintain the antitumor response are particularly exciting. With our growing knowledge of immune tolerance and ways to overcome it, combination treatments are being developed, tested, and have particular promise. One example is in situ immunization that is designed to break tolerance within the tumor microenvironment. Progress in all these areas is continuing based on clear evidence that cancer immunotherapy designed to overcome immune tolerance can be useful for a growing number of patients with cancer.

  4. Sublingual immunotherapy in allergic asthma: Current evidence and needs to meet

    Directory of Open Access Journals (Sweden)

    Incorvaia Cristoforo

    2010-01-01

    Full Text Available Allergen-specific immunotherapy is aimed at modifying the natural history of allergy by inducing tolerance to the causative allergen. In its traditional, subcutaneous form, immunotherapy has complete evidence of efficacy in allergic asthma. However, subcutaneous immunotherapy (SCIT has a major flaw in side effects, and especially in possible anaphylactic reactions, and this prompted the search for safer ways of administration of allergen extracts. Sublingual immunotherapy (SLIT has met such need while maintaining a clinical efficacy comparable to SCIT. In fact, the safety profile, as outlined by a systematic revision of the available literature, was substantially free from serious systemic reactions. A number of meta-analyses clearly showed that SLIT is effective in allergic rhinitis by significantly reducing the clinical symptoms and the use of anti-allergic drugs, while the efficacy in allergic asthma is still debated, with some meta-analyses showing clear effectiveness but other giving contrasting results. Besides the efficacy on symptoms, the preventive activity and the cost-effectiveness are important outcomes of SLIT in asthma. The needs to meet include more data on efficacy in house dust mite asthma, optimal techniques of administration and, as previously done with SCIT, introduction of adjuvants able to enhance the immunologic response and use of recombinant allergens.

  5. Combination Immunotherapy for the Treatment of High-Risk HER2-Positive Breast Cancer

    Science.gov (United States)

    2015-10-01

    have withdrawn. Blood samples for immunologic monitoring are being collected in support of specific aims 2 and 3. 15. SUBJECT TERMS Breast cancer ...inflammatory breast cancer (MD Anderson Cancer Center Morgan Welch Inflammatory Breast Cancer Program Seed Grant)  New active grant o Immunologic ...1 AWARD NUMBER: W81XWH-14-1-0109 TITLE: Combination Immunotherapy for the Treatment of High-Risk HER2-Positive Breast Cancer PRINCIPAL

  6. A European perspective on immunotherapy for food allergies.

    Science.gov (United States)

    Beyer, Kirsten

    2012-05-01

    Food allergies are common, and frequently, the only treatment option is strict avoidance. Unfortunately, many patients accidentally ingest allergenic foods, which can result in severe anaphylactic reactions. Several immunotherapies are being developed for food allergies; these involve oral, sublingual, epicutaneous, or subcutaneous administration of small amounts of native or modified allergens to induce immune tolerance. Oral immunotherapy seems to be the most promising approach based on results from small uncontrolled and controlled studies. However, it is a challenge to compare results among immunotherapy trials because of differences in protocols. Studies conducted thus far have tested the most prevalent food allergens: it is not clear whether their results can be extended to other allergens. Sublingual administration of immunotherapy has shown some efficacy and fewer side effects than oral administration in some trials, yet neither approach can be recommended for routine practice. Controlled studies with larger numbers of subjects are needed to determine short- and long-term efficacy and side effects. In Europe immunotherapy trials for food allergies face many ethical and regulatory issues. Guidelines from the European Medicine Agency on the clinical development of products for specific immunotherapy of allergic diseases do not adequately address immunotherapy for food allergies, especially for therapies that orally administer native food or that include pediatric patients.

  7. Future directions in bladder cancer immunotherapy: towards adaptive immunity.

    Science.gov (United States)

    Smith, Sean G; Zaharoff, David A

    2016-01-01

    The clinical management of bladder cancer has not changed significantly in several decades. In particular, intravesical bacillus Calmette-Guérin (BCG) immunotherapy has been a mainstay for high-risk nonmuscle invasive bladder cancer since the late 1970s/early 1980s. This is despite the fact that bladder cancer has the highest recurrence rates of any cancer and BCG immunotherapy has not been shown to induce a tumor-specific immune response. We and others have hypothesized that immunotherapies capable of inducing tumor-specific adaptive immunity are needed to impact bladder cancer morbidity and mortality. This article summarizes the preclinical and clinical development of bladder cancer immunotherapies with an emphasis on the last 5 years. Expected progress in the near future is also discussed.

  8. Immunotherapy with the storage mite lepidoglyphus destructor.

    Science.gov (United States)

    Armentia-Medina, A; Tapias, J A; Martín, J F; Ventas, P; Fernández, A

    1995-01-01

    We carried out a double-blind clinical trial of immunotherapy on 35 patients sensitized to the storage mite Lepidoglyphus destructor (Ld). Before and after 12 months of specific hyposensitization (Abelló Lab., Spain) we performed in vivo (skin tests with Ld, methacholine and challenge tests), and in vitro tests (specific IgE, IgG, IgG1 and IgG4 to Ld and specific IgE, IgG, IgG1 and IgG4 to their major allergen Lep dI). We also monitored the efficacy and safety of the immunotherapy with clinical and analytical controls (symptoms and medication score, detection of immune complexes). After therapy we found a significant decrease in specific skin reactivity, dose of positive challenge tests, and hyperresponsiveness to methacholine. Sputum eosinophilia decreased. Specific IgE to Ld was increased and we also observed an increase in specific IgG1 and IgG4 to Ld and Lep DI. The placebo group showed no changes in these variables. There were no severe secondary reactions after treatment with the extract. Patients-self-evaluation was favourable and their labour absence decreased. No development of circulating immune complexes was associated with this immunotherapy.

  9. Role of IL-2 in cancer immunotherapy.

    Science.gov (United States)

    Jiang, Tao; Zhou, Caicun; Ren, Shengxiang

    2016-06-01

    Interleukin-2 (IL-2) is one of the key cytokines with pleiotropic effects on immune system. It has been approved for the treatment of metastatic renal cell carcinoma and metastatic melanoma. Recent progress has been made in our understanding of IL-2 in regulating lymphocytes that has led to exciting new directions for cancer immunotherapy. While improved IL-2 formulations might be used as monotherapies, their combination with other anticancer immunotherapies, such as adoptive cell transfer regimens, antigen-specific vaccination, and blockade of immune checkpoint inhibitory molecules, for example cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) mono-antibodies, would held the promise of treating metastatic cancer. Despite the comprehensive studies of IL-2 on immune system have established the application of IL-2 for cancer immunotherapy, a number of poignant obstacles remain for future research. In the present review, we will focus on the key biological features of IL-2, current applications, limitations, and future directions of IL-2 in cancer immunotherapy.

  10. Sublingual Immunotherapy for Japanese Cedar Pollinosis

    Directory of Open Access Journals (Sweden)

    Kimihiro Okubo

    2009-01-01

    Full Text Available The prevalence of pollinosis caused by cedar pollen has increased by 10% these ten years of 26.5% in the investigation of 2008 in Japan. The pharmacotherapy is a main treatment tool for pollinosis, and the surgical treatment is not acknowledged to the treatment of pollinosis internationally. Moreover, allergen immunotherapy enters a special treatment method, and is an important therapeutic procedure. The allergen immunotherapy is unique for having possibility of curing allergen specific allergic diseases. However the side effect of allergen subcutaneous immunotherapy (SCIT, such as anaphylaxis is kept at a distance in a medical situation in Japan. Then, a sublingual immunotherapy (SLIT that was safer than it, developed in Europe for pollinosis induced by grass or ragweed, but not in Japan. As a result, the effect of SLIT was proven in the cedar pollinosis in Japan as high level evidence. A whole body immunity induction is thought in the appearance of the effect, and, in addition, it is necessary to be going to be cleared the accurate mechanism of the effect in the future. Moreover, the development of a special SLIT and the import of an overseas product are needed in Japan.

  11. Bioinformatics for cancer immunology and immunotherapy.

    Science.gov (United States)

    Charoentong, Pornpimol; Angelova, Mihaela; Efremova, Mirjana; Gallasch, Ralf; Hackl, Hubert; Galon, Jerome; Trajanoski, Zlatko

    2012-11-01

    Recent mechanistic insights obtained from preclinical studies and the approval of the first immunotherapies has motivated increasing number of academic investigators and pharmaceutical/biotech companies to further elucidate the role of immunity in tumor pathogenesis and to reconsider the role of immunotherapy. Additionally, technological advances (e.g., next-generation sequencing) are providing unprecedented opportunities to draw a comprehensive picture of the tumor genomics landscape and ultimately enable individualized treatment. However, the increasing complexity of the generated data and the plethora of bioinformatics methods and tools pose considerable challenges to both tumor immunologists and clinical oncologists. In this review, we describe current concepts and future challenges for the management and analysis of data for cancer immunology and immunotherapy. We first highlight publicly available databases with specific focus on cancer immunology including databases for somatic mutations and epitope databases. We then give an overview of the bioinformatics methods for the analysis of next-generation sequencing data (whole-genome and exome sequencing), epitope prediction tools as well as methods for integrative data analysis and network modeling. Mathematical models are powerful tools that can predict and explain important patterns in the genetic and clinical progression of cancer. Therefore, a survey of mathematical models for tumor evolution and tumor-immune cell interaction is included. Finally, we discuss future challenges for individualized immunotherapy and suggest how a combined computational/experimental approaches can lead to new insights into the molecular mechanisms of cancer, improved diagnosis, and prognosis of the disease and pinpoint novel therapeutic targets.

  12. Immunotherapy: Disrupting the Cancer Treatment World

    Science.gov (United States)

    ... to create the best and most far-reaching cancer immunotherapy treatments. THE BASICS : The human immune system is ... none, abound these days – and point to why cancer immunotherapies matter. Immunotherapy is “providing options for people out ...

  13. [Immunotherapy in Latin America. From the past to the future].

    Science.gov (United States)

    Cagnani, Carlos E Baena; Lockey, Richard F; Passalacqua, Giovanni; Canonica, G Walter

    2008-01-01

    In Latin America, allergic diseases have a very high prevalence, comparable to that of many other countries of the world, and that prevalence is constantly increasing. Within the region, the number of allergy specialists is quite high, although allergy is not recognized as a full specialty in all countries. Specific immunotherapy is the only available allergen-oriented immunomodulator, capable of improving symptoms and modifying the natural course of the disease, and therefore it represents a powerful therapeutic tool for specialists. During the last 20 years, the practice of immunotherapy in Latin America has much improved, especially because of the intensive educational effort, the widespread divulgation of the international guidelines and the adoption of the paradigm of the evidence-based medicine. In this regard, indications, contraindications, and limits of immunotherapy, are currently well acknowledged. In Latin America, immunotherapy is properly prescribed for inhalant allergens and hymenoptera venom by allergy specialists, although some non-evidence based forms of immunotherapy (e.g. bacterial extracts, treatment of atopic dermatitis) are still occasionally practiced. Sublingual immunotherapy is now accepted as a viable alternative to the traditional subcutaneous administration, and it begins to be proposed and studied also in some Latin American countries. Some debate remains on the use of immunotherapy for one or few versus multiple allergens, and also the availability of standardized extracts is not uniform. Finally, this therapeutic modality is not always given for free to low income patients such is the case in some countries and the different modalities of reimbursement among countries often represent a limit to the use of this treatment. Much has been done in improving the use of immunotherapy in Latin America. The main challenges and objectives for the near future are greater diffusion of the evidence-based medicine, a better standardization of

  14. Immunotherapy for tularemia.

    Science.gov (United States)

    Skyberg, Jerod A

    2013-11-15

    Francisella tularensis is a gram-negative bacterium that causes the zoonotic disease tularemia. Francisella is highly infectious via the respiratory route (~10 CFUs) and pulmonary infections due to type A strains of F. tularensis are highly lethal in untreated patients (> 30%). In addition, no vaccines are licensed to prevent tularemia in humans. Due to the high infectivity and mortality of pulmonary tularemia, F. tularensis has been weaponized, including via the introduction of antibiotic resistance, by several countries. Because of the lack of efficacious vaccines, and concerns about F. tularensis acquiring resistance to antibiotics via natural or illicit means, augmentation of host immunity, and humoral immunotherapy have been investigated as countermeasures against tularemia. This manuscript will review advances made and challenges in the field of immunotherapy against tularemia.

  15. Immunotherapy for Alzheimer's disease

    Institute of Scientific and Technical Information of China (English)

    Weihua Wang; Liangfeng Fan; De'en Xu; Zhongmin Wen; Rong Yu; Quanhong Ma

    2012-01-01

    Alzheimer's disease (AD) is characterized by β-amyloid (Aβ) plaques consisted primarily of aggregated Aβ proteins and neurofibrillary tangles formed by hyperphosphorylated tau protein.Both Aβ and hyperphosphorylated tau are toxic both in vivo and in vitro.Immunotherapy targeting Aβ seems to provide a promising approach to reduce the toxic species in the brain.However,there is little evidence from clinical trials so far indicating the efficacy of Aβ immunotherapy in cognitive improvement.Immunization with tau peptides or anti-tau antibodies could remove the tau aggregates and improve the cognitive function in preclinical study,which provides a novel strategy of AD therapy.In this article,we will summarize the immunotherapeutic strategies targeting either Aβ or tau.

  16. Cancer immunotherapy with surgery

    Directory of Open Access Journals (Sweden)

    Orita,Kunzo

    1977-08-01

    Full Text Available With the recent advances in the immunological surveillance system, an understanding of the role of host immunity has become essential to the management of carcinogenesis, tumor proliferation, recurrence and metastasis. Although it is important to continue chemical and surgical treatment of cancer, support of the anti-tumor immune system of the host should also be considered. Long term remission has been reported in leukemia by treating with BCG after chemotherapy whereas surgical treatment is usually more effective in preventing cancer recurrence in digestive organ cancer. The first step is extirpating the tumor as thoroughly as possible and the second step is chemo-immunotherapy. Cancer immunity, however weak, constitutes the basis for other treatments in selectively attacking cancer cells remaining after surgery, chemotherapy or irradiation. Immunotherapy should thus not replace chemotherapy or radiotherapy, but these methods should be employed in combination to attain more favorable results.

  17. Effects of dust mite allergen-specific immunotherapy on prevention and cure in children with asthma and allergic rhinitis and the reasons of symptom exacerbation during specific immunotherapy.%粉尘螨特异性免疫治疗变应性哮喘合并鼻炎疗效评价及治疗期间病情反复原因分析

    Institute of Scientific and Technical Information of China (English)

    谭永强; 鲍一笑; 沈瑾; 叶桂云; 陈柳

    2012-01-01

    Objective To evaluate the effects of dust mite allergen-specific immunotherapy combined with standardized management on prevention and cure in children with asthma and allergic rhinitis and analyze the reasons of the asthma and allergic rhinitis symptom exacerbation during specific immunotherapy. Methods One hundred and two children with established diagnosis of allergic asthma and allergic rhinitis to dust mite were enrolled in this study from january 2006 to december 2010, of whom 78 children received the treatment with specific immunotherapy (SIT) combined with standardized management for 2 to 4 year (as the test group) and the other 24 served as the control group with inhaled corticosteroids according to Global Initiative for Asthma (GINA) and Allergic Rhinitis and its Impact on Asthma (ARIA) in the same time. At the beginning, 6 months, 1 year, 2 years of the treament and 1 year after the treament,the clinical symptom and acute episode, pulmonery function (Peak Expiratory Flow, PEF) and Chinese children asthma control test (Ch-CACT) of the asthmatic children, symptem scores and Visual Analogue Scale( VAS) of allergic rhinitis were analyzed, while respiratory tract infection of all the patients were recorded at the second year and after 1 year of the treatment. The reasons of the asthma and allergic rhinitis symptom exacerbation during dust mite allergen-specific immunotherapy were analyzed. The data were analyzed by SPSS15.0. Results Compared with control group, the frequency of acute episode, the frequency of respiratory tract infection in test group were significantly decreased at the 2 years of the treament and 1 year after the treament. The PEFof asthmasic children were obviously improved in the test group at the 2 years of the treament and 1 year after the treament and the Ch-CACT were more higher in the test group than the control group at 1 year after the treament. Compared with control group, the symptem scores and VAS of allergic rhinitis were

  18. Immunotherapy for Gastroesophageal Cancer

    OpenAIRE

    Emily F. Goode; Smyth, Elizabeth C.

    2016-01-01

    Survival for patients with advanced oesophageal and stomach cancer is poor; together these cancers are responsible for more than a million deaths per year globally. As chemotherapy and targeted therapies such as trastuzumab and ramucirumab result in modest improvements in survival but not long-term cure for such patients, development of alternative treatment approaches is warranted. Novel immunotherapy drugs such as checkpoint inhibitors have been paradigm changing in melanoma, non-small cell...

  19. Immunotherapy of cancer in 2012.

    Science.gov (United States)

    Kirkwood, John M; Butterfield, Lisa H; Tarhini, Ahmad A; Zarour, Hassane; Kalinski, Pawel; Ferrone, Soldano

    2012-01-01

    The immunotherapy of cancer has made significant strides in the past few years due to improved understanding of the underlying principles of tumor biology and immunology. These principles have been critical in the development of immunotherapy in the laboratory and in the implementation of immunotherapy in the clinic. This improved understanding of immunotherapy, enhanced by increased insights into the mechanism of tumor immune response and its evasion by tumors, now permits manipulation of this interaction and elucidates the therapeutic role of immunity in cancer. Also important, this improved understanding of immunotherapy and the mechanisms underlying immunity in cancer has fueled an expanding array of new therapeutic agents for a variety of cancers. Pegylated interferon-α2b as an adjuvant therapy and ipilimumab as therapy for advanced disease, both of which were approved by the United States Food and Drug Administration for melanoma in March 2011, are 2 prime examples of how an increased understanding of the principles of tumor biology and immunology have been translated successfully from the laboratory to the clinical setting. Principles that guide the development and application of immunotherapy include antibodies, cytokines, vaccines, and cellular therapies. The identification and further elucidation of the role of immunotherapy in different tumor types, and the development of strategies for combining immunotherapy with cytotoxic and molecularly targeted agents for future multimodal therapy for cancer will enable even greater progress and ultimately lead to improved outcomes for patients receiving cancer immunotherapy.

  20. An overview of sipuleucel-T: autologous cellular immunotherapy for prostate cancer.

    Science.gov (United States)

    Wesley, Johnna D; Whitmore, James; Trager, James; Sheikh, Nadeem

    2012-04-01

    Sipuleucel-T, the first autologous active cellular immunotherapy approved by the United States Food and Drug Administration, is designed to stimulate an immune response to prostate cancer. Sipuleucel-T is manufactured by culturing a patient's peripheral blood mononuclear cells (including antigen presenting cells) with a recombinant protein comprising a tumor-associated antigen (prostatic acid phosphatase) and granulocyte-macrophage colony stimulating factor. Treatment consists of 3 infusions at approximately 2-week intervals, resulting in a prime-boost pattern of immune activation, a robust antigen-specific cellular and humoral immune response, and, consequently, a survival benefit in subjects with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer. Adverse events are generally mild to moderate and resolve within 2 d. Serious adverse events occur at a low rate. As the first autologous cellular immunotherapy to demonstrate a survival benefit, sipuleucel-T is a novel oncologic therapeutic that warrants the reassessment of the current prostate cancer treatment paradigm.

  1. Targeting neoantigens for cancer immunotherapy.

    Science.gov (United States)

    Lu, Yong-Chen; Robbins, Paul F

    2016-07-01

    Studies first carried out in the 1980s have demonstrated murine T cells can recognize mutated gene products, known as neoantigens, and that these T cells are capable of mediating tumor rejection. The first human tumor antigens isolated in the early 1990s were the products of non-mutated genes expressed in a tissue-specific manner; subsequent studies have indicated that tumor-infiltrating lymphocytes that are cultured in vitro frequently recognize mutated gene products. In addition, correlative studies indicate that clinical responses to therapies involving the use of antibodies directed against checkpoint inhibitors such as CTLA-4 and PD-1 may be associated with mutational burden, providing indirect evidence that these responses may primarily be mediated by neoantigen-reactive T cells. The importance of neoantigen-reactive T cells may be elucidated by the results of ongoing and future studies aimed at leveraging information gained from mutational profiling to enhance the potency of immunotherapies.

  2. siRNA and cancer immunotherapy.

    Science.gov (United States)

    Ghafouri-Fard, Soudeh; Ghafouri-Fard, Somayyeh

    2012-09-01

    Immunotherapeutic approaches have been gaining attention in the field of cancer treatment because of their possible ability to eradicate cancer cells as well as metastases by recruiting the host immune system. On the other hand, RNA-based therapeutics with the ability to silence expression of specific targets are currently under clinical investigation for various disorders including cancer. As the mechanisms of tumor evasion from the host immune system are versatile, different molecules have the capacity to be targeted by RNAi technology in order to enhance the immune response against tumors. This technology has been used to silence specific targets in tumor cells, as well as immune cells in cancer cell lines, animal models and clinical trials. siRNAs can also stimulate innate immune responses through activation of Toll-like receptors. Although currently clinical trials of the application of siRNA in cancer immunotherapy are few, it is predicted that in future this technology will be used broadly in cancer treatment.

  3. Can calcium signaling be harnessed for cancer immunotherapy?

    Science.gov (United States)

    Rooke, Ronald

    2014-10-01

    Experimental evidence shows the importance of the immune system in controlling tumor appearance and growth. Immunotherapy is defined as the treatment of a disease by inducing, enhancing or suppressing an immune response. In the context of cancer treatment, it involves breaking tolerance to a cancer-specific self-antigen and/or enhancing the existing anti-tumor immune response, be it specific or not. Part of the complexity in developing such treatment is that cancers are selected to escape adaptive or innate immune responses. These escape mechanisms are numerous and they may cumulate in one cancer. Moreover, different cancers of a same type may present different combinations of escape mechanisms. The limited success of immunotherapeutics in the clinic as stand-alone products may in part be explained by the fact that most of them only activate one facet of the immune response. It is important to identify novel methods to broaden the efficacy of immunotherapeutics. Calcium signaling is central to numerous cellular processes, leading to immune responses, cancer growth and apoptosis induced by cancer treatments. Calcium signaling in cancer therapy and control will be integrated to current cancer immunotherapy approaches. This article is part of a Special Issue entitled: Calcium Signaling in Health and Disease. Guest Editors: Geert Bultynck, Jacques Haiech, Claus W. Heizmann, Joachim Krebs, and Marc Moreau.

  4. Advances in strategies and methodologies in cancer immunotherapy.

    Science.gov (United States)

    Lam, Samuel S K; Zhou, Feifan; Hode, Tomas; Nordquist, Robert E; Alleruzzo, Luciano; Raker, Joseph; Chen, Wei R

    2015-04-01

    Since the invention of Coley's toxin by William Coley in early 1900s, the path for cancer immunotherapy has been a convoluted one. Although still not considered standard of care, with the FDA approval of trastuzumab, Provenge and ipilimumab, the medical and scientific community has started to embrace the possibility that immunotherapy could be a new hope for cancer patients with otherwise untreatable metastatic diseases. This review aims to summarize the development of some major strategies in cancer immunotherapy, from the earliest peptide vaccine and transfer of tumor specific antibodies/T cells to the more recent dendritic cell (DC) vaccines, whole cell tumor vaccines, and checkpoint blockade therapy. Discussion of some major milestones and obstacles in the shaping of the field and the future perspectives is included. Photoimmunotherapy is also reviewed as an example of emerging new therapies combining phototherapy and immunotherapy.

  5. Allergen-containing immune complexes used for immunotherapy of allergic asthma. Preparation of complexes and evaluation of their clinical performance in guinea pigs

    DEFF Research Database (Denmark)

    Poulsen, L K; Lundberg, L; Søndergaard, I

    1989-01-01

    Guinea pigs inbred for their ability to develop respiratory anaphylaxis to experimental antigens have been used for comparison of different forms of immunotherapy (IT). Passive, active and combined (immune complexes between antigen and specific IgG) IT were compared with placebo. The bronchial...

  6. Aptamers: A Feasible Technology in Cancer Immunotherapy

    Directory of Open Access Journals (Sweden)

    M. M. Soldevilla

    2016-01-01

    Full Text Available Aptamers are single-chained RNA or DNA oligonucleotides (ODNs with three-dimensional folding structures which allow them to bind to their targets with high specificity. Aptamers normally show affinities comparable to or higher than that of antibodies. They are chemically synthesized and therefore less expensive to manufacture and produce. A variety of aptamers described to date have been shown to be reliable in modulating immune responses against cancer by either blocking or activating immune receptors. Some of them have been conjugated to other molecules to target the immune system and reduce off-target side effects. Despite the success of first-line treatments against cancer, the elevated number of relapsing cases and the tremendous side effects shown by the commonly used agents hinder conventional treatments against cancer. The advantages provided by aptamers could enhance the therapeutic index of a given strategy and therefore enhance the antitumor effect. Here we recapitulate the provided benefits of aptamers with immunomodulatory activity described to date in cancer therapy and the benefits that aptamer-based immunotherapy could provide either alone or combined with first-line treatments in cancer therapy.

  7. Aptamers: A Feasible Technology in Cancer Immunotherapy.

    Science.gov (United States)

    Soldevilla, M M; Villanueva, H; Pastor, F

    2016-01-01

    Aptamers are single-chained RNA or DNA oligonucleotides (ODNs) with three-dimensional folding structures which allow them to bind to their targets with high specificity. Aptamers normally show affinities comparable to or higher than that of antibodies. They are chemically synthesized and therefore less expensive to manufacture and produce. A variety of aptamers described to date have been shown to be reliable in modulating immune responses against cancer by either blocking or activating immune receptors. Some of them have been conjugated to other molecules to target the immune system and reduce off-target side effects. Despite the success of first-line treatments against cancer, the elevated number of relapsing cases and the tremendous side effects shown by the commonly used agents hinder conventional treatments against cancer. The advantages provided by aptamers could enhance the therapeutic index of a given strategy and therefore enhance the antitumor effect. Here we recapitulate the provided benefits of aptamers with immunomodulatory activity described to date in cancer therapy and the benefits that aptamer-based immunotherapy could provide either alone or combined with first-line treatments in cancer therapy.

  8. CANCER IMMUNOTHERAPY BASED ON THE BLOCKADE OF IMMUNE CHECKPOINTS

    Directory of Open Access Journals (Sweden)

    A. V. Bogolyubova

    2015-01-01

    Full Text Available Immune checkpoints represent the system of inhibitory mechanisms regulating the activation of the immune response, preventing the autoimmune processes and modulating the immune response by decreasing the immune cell-mediated damage of tissues and organs. Tumor cells may utilize these checkpoints to prevent the activation of tumor-specific lymphocytes, thereby acquiring resistance against the immune response. The blockade of inhibitory signal that is transduced in immune checkpoints leading to the reactivation of antitumor immune response is a promising method of tumor immunotherapy. Since the majority of immune checkpoints are based on the ligand-receptor interactions, one of contemporary modalities of anti-tumor therapy is based on the development of ligandor receptor-blocking therapeutic monoclonal antibodies, as well as soluble recombinant receptors capable of competing for a ligand and thereby modulating the signal transduction. In the past few years, this field of tumor immunotherapy experienced an impressive success; however, the potential tradeoff for altering of the natural suppressive mechanisms is the development of the autoimmune reactions.

  9. Role of Local Radiation Therapy in Cancer Immunotherapy.

    Science.gov (United States)

    Demaria, Sandra; Golden, Encouse B; Formenti, Silvia C

    2015-12-01

    The recent success of cancer immunotherapy has demonstrated the power of the immune system to clear tumors, generating renewed enthusiasm for identifying ways to induce antitumor immune responses in patients. Natural antitumor immune responses are detectable in a fraction of patients across multiple malignant neoplasms and can be reactivated by targeting rate-limiting immunosuppressive mechanisms. In most patients, however, interventions to induce a de novo antitumor immune response are necessary. We review growing evidence that radiation therapy targeted to the tumor can convert it into an in situ tumor vaccine by inducing release of antigens during cancer cell death in association with proinflammatory signals that trigger the innate immune system to activate tumor-specific T cells. In addition, radiation's effects on the tumor microenvironment enhance infiltration of activated T cells and can overcome some of the barriers to tumor rejection. Thus, the complementary effects of radiation on priming and effector phases of antitumor immunity make it an appealing strategy to generate immunity against a patient's own individual tumor, that through immunological memory, can result in long-lasting systemic responses. Several anecdotal cases have demonstrated the efficacy of combining radiation with available immunotherapies, and results of prospective trials are forthcoming.

  10. New Horizons in Allergen Immunotherapy

    DEFF Research Database (Denmark)

    Backer, Vibeke

    2016-01-01

    of active SLITcomparedwith placebo,with hazard ratios of0.69 (95%CI,0.49-0.96) for the 6 SQ-HDM group and 0.66 (95% CI, 0.47 -0.93) for the 12 SQHDM group. The absolute risk for first exacerbation was 26% (n = 62) for the 6 SQ-HDM group, 24% (n = 59) for the 12 SQHDM group, and 32% (n = 83) for the placebo...... is this outcome.Canthese results truly benefit similar patients encountered in clinical practice? Addressing these questions requires consideration ofnotjust theprimaryendpointbut alsothesecondaryoutcomesandpotentialstudylimitations.With regardtosecondaryoutcomes,thereweresignificantdifferences favoring...... treatmentwith ICS. The authors’ choice of a primary end point based on exacerbations during ICS reduction is also unique to immunotherapy trials,with previous trials ofHDMimmunotherapy focusing onmedication requirements, symptomsscores, or lung function as primary end points. Furthermore, the inclusion...

  11. Suppressive effects of antigens on the activity of specific activated lymphocytes: A test to define the specificity of activated lymphocytes

    Institute of Scientific and Technical Information of China (English)

    HU Jun; PAN Sheng-jun; CAI Zhen-jie; GUAN De-lin; LIU Xiao-cheng

    2006-01-01

    Objective:With the regular mixed lymphocytes culture (MLC) to detect the allograft rejection, the reactivity of the activated lymphocytes (primed lymphocytes) of a recipient shows sometimes increase and sometimes decrease against the antigens from the donor, which is inconsistent with the clinical results. In order to establish a convenient method for testing the specificity of the activated lymphocytes in vitro, so as to know the rejection occurred or not by testing the existence of the specific activated lymphocytes against donor's HLA antigens in the recipient's peripheral blood. Methods: Anti-IL-2 neutralizing monoclonal antibody (anti-IL-2 N-mAb) and immunosuppressors were introduced in this test system in the presence of specific stimulators and activated lymphocytes. Results: When the activated lymphocytes were chosen from the one-way MLC 4 d to undergo re-stimulation by specific stimulators, the activity of activated lymphocytes in the treatment group was suppressed significantly compared with that in the control group. The result of this test method is consistent with the biopsy in the clinical diagnosis of rejection.Conclusion :It suggests that the activated lymphocytes can be inactivated by specific antigens in certain conditions. This can be a useful tool to define the specificity of the activated lymphocytes.

  12. Immunotherapy for Prostate Cancer with Gc Protein-Derived Macrophage-Activating Factor, GcMAF1

    Science.gov (United States)

    Yamamoto, Nobuto; Suyama, Hirofumi; Yamamoto, Nobuyuki

    2008-01-01

    Serum Gc protein (known as vitamin D3-binding protein) is the precursor for the principal macrophage-activating factor (MAF). The MAF precursor activity of serum Gc protein of prostate cancer patients was lost or reduced because Gc protein was deglycosylated by serum α-N-acetylgalactosaminidase (Nagalase) secreted from cancerous cells. Therefore, macrophages of prostate cancer patients having deglycosylated Gc protein cannot be activated, leading to immunosuppression. Stepwise treatment of purified Gc protein with immobilized β-galactosidase and sialidase generated the most potent MAF (termed GcMAF) ever discovered, which produces no adverse effect in humans. Macrophages activated by GcMAF develop a considerable variation of receptors that recognize the abnormality in malignant cell surface and are highly tumoricidal. Sixteen nonanemic prostate cancer patients received weekly administration of 100 ng of GcMAF. As the MAF precursor activity increased, their serum Nagalase activity decreased. Because serum Nagalase activity is proportional to tumor burden, the entire time course analysis for GcMAF therapy was monitored by measuring the serum Nagalase activity. After 14 to 25 weekly administrations of GcMAF (100 ng/week), all 16 patients had very low serum Nagalase levels equivalent to those of healthy control values, indicating that these patients are tumor-free. No recurrence occurred for 7 years. PMID:18633461

  13. Immunotherapy of metastatic colorectal cancer with vitamin D-binding protein-derived macrophage-activating factor, GcMAF.

    Science.gov (United States)

    Yamamoto, Nobuto; Suyama, Hirofumi; Nakazato, Hiroaki; Yamamoto, Nobuyuki; Koga, Yoshihiko

    2008-07-01

    Serum vitamin D binding protein (Gc protein) is the precursor for the principal macrophage-activating factor (MAF). The MAF precursor activity of serum Gc protein of colorectal cancer patients was lost or reduced because Gc protein is deglycosylated by serum alpha-N-acetylgalactosaminidase (Nagalase) secreted from cancerous cells. Deglycosylated Gc protein cannot be converted to MAF, leading to immunosuppression. Stepwise treatment of purified Gc protein with immobilized beta-galactosidase and sialidase generated the most potent macrophage-activating factor (GcMAF) ever discovered, but it produces no side effect in humans. Macrophages treated with GcMAF (100 microg/ml) develop an enormous variation of receptors and are highly tumoricidal to a variety of cancers indiscriminately. Administration of 100 nanogram (ng)/ human maximally activates systemic macrophages that can kill cancerous cells. Since the half-life of the activated macrophages is approximately 6 days, 100 ng GcMAF was administered weekly to eight nonanemic colorectal cancer patients who had previously received tumor-resection but still carried significant amounts of metastatic tumor cells. As GcMAF therapy progressed, the MAF precursor activities of all patients increased and conversely their serum Nagalase activities decreased. Since serum Nagalase is proportional to tumor burden, serum Nagalase activity was used as a prognostic index for time course analysis of GcMAF therapy. After 32-50 weekly administrations of 100 ng GcMAF, all colorectal cancer patients exhibited healthy control levels of the serum Nagalase activity, indicating eradication of metastatic tumor cells. During 7 years after the completion of GcMAF therapy, their serum Nagalase activity did not increase, indicating no recurrence of cancer, which was also supported by the annual CT scans of these patients.

  14. Immunotherapy of HIV-infected patients with Gc protein-derived macrophage activating factor (GcMAF).

    Science.gov (United States)

    Yamamoto, Nobuto; Ushijima, Naofumi; Koga, Yoshihiko

    2009-01-01

    Serum Gc protein (known as vitamin D3-binding protein) is the precursor for the principal macrophage activating factor (MAF). The MAF precursor activity of serum Gc protein of HIV-infected patients was lost or reduced because Gc protein is deglycosylated by alpha-N-acetylgalactosaminidase (Nagalase) secreted from HIV-infected cells. Therefore, macrophages of HIV-infected patients having deglycosylated Gc protein cannot be activated, leading to immunosuppression. Since Nagalase is the intrinsic component of the envelope protein gp120, serum Nagalase activity is the sum of enzyme activities carried by both HIV virions and envelope proteins. These Nagalase carriers were already complexed with anti-HIV immunoglobulin G (IgG) but retained Nagalase activity that is required for infectivity. Stepwise treatment of purified Gc protein with immobilized beta-galactosidase and sialidase generated the most potent macrophage activating factor (termed GcMAF), which produces no side effects in humans. Macrophages activated by administration of 100 ng GcMAF develop a large amount of Fc-receptors as well as an enormous variation of receptors that recognize IgG-bound and unbound HIV virions. Since latently HIV-infected cells are unstable and constantly release HIV virions, the activated macrophages rapidly intercept the released HIV virions to prevent reinfection resulting in exhaustion of infected cells. After less than 18 weekly administrations of 100 ng GcMAF for nonanemic patients, they exhibited low serum Nagalase activities equivalent to healthy controls, indicating eradication of HIV-infection, which was also confirmed by no infectious center formation by provirus inducing agent-treated patient PBMCs. No recurrence occurred and their healthy CD + cell counts were maintained for 7 years.

  15. Immunotherapy of metastatic breast cancer patients with vitamin D-binding protein-derived macrophage activating factor (GcMAF).

    Science.gov (United States)

    Yamamoto, Nobuto; Suyama, Hirofumi; Yamamoto, Nobuyuki; Ushijima, Naofumi

    2008-01-15

    Serum vitamin D3-binding protein (Gc protein) is the precursor for the principal macrophage activating factor (MAF). The MAF precursor activity of serum Gc protein of breast cancer patients was lost or reduced because Gc protein was deglycosylated by serum alpha-N-acetylgalactosaminidase (Nagalase) secreted from cancerous cells. Patient serum Nagalase activity is proportional to tumor burden. The deglycosylated Gc protein cannot be converted to MAF, resulting in no macrophage activation and immunosuppression. Stepwise incubation of purified Gc protein with immobilized beta-galactosidase and sialidase generated probably the most potent macrophage activating factor (termed GcMAF) ever discovered, which produces no adverse effect in humans. Macrophages treated in vitro with GcMAF (100 pg/ml) are highly tumoricidal to mammary adenocarcinomas. Efficacy of GcMAF for treatment of metastatic breast cancer was investigated with 16 nonanemic patients who received weekly administration of GcMAF (100 ng). As GcMAF therapy progresses, the MAF precursor activity of patient Gc protein increased with a concomitant decrease in serum Nagalase. Because of proportionality of serum Nagalase activity to tumor burden, the time course progress of GcMAF therapy was assessed by serum Nagalase activity as a prognostic index. These patients had the initial Nagalase activities ranging from 2.32 to 6.28 nmole/min/mg protein. After about 16-22 administrations (approximately 3.5-5 months) of GcMAF, these patients had insignificantly low serum enzyme levels equivalent to healthy control enzyme levels, ranging from 0.38 to 0.63 nmole/min/mg protein, indicating eradication of the tumors. This therapeutic procedure resulted in no recurrence for more than 4 years.

  16. 466 Bee venom Immunotherapy with Standardized Extract, Two Case Comunication and Clinical Progress

    Science.gov (United States)

    Cardona, Aristoteles Alvarez; Nieto, Leticia Hernandez; Melendez, Alvaro Pedroza

    2012-01-01

    Background Bee venom immunotherapy is a safe and effective treatment, indicated in patients with previous history of severe systemic reactions to bee venom, demonstrating succesful desensitization in more than 90% of cases with standardized extract. Currently in Mexico there is no standardized extract commercially available for treatment, despite of having high activity of beekeeping and occupational exposure with at least 17,478 registered stings per year and an annually honey production of nearly 70 tons. Methods We present the clinical progress of 2 patients with history of severe systemic reactions to bee venom and occupational exposure, both with demonstrated sensitization by specific IgE and who underwent specific immunotherapy with standardized extract (Alk-US) reaching a maintenance weekly dose of 100 mcg (PLA2) for the last 4 years. Results Both patients sufered of accidental stings after reached the maintenance dose presenting mild local reactions to stings. Both patients had very different clinical course presenting a wide variety of adverse reactions during desensitization protocol; from mild local to generalized reactions all generally well tolerated allowed to reach the maintenance dose with succesful desensitization proved by accidental exposure without severe systemic reactions. Conclusions Bee venom specific immunotherapy with standardized extract is a well tolerated and efective treatment preventing the development of life threathening reactions in sensitized patients. It is important to promote the use and availability of standardized extract in developing countries with poor safety measures and high occupational exposure.

  17. New directions in immunotherapy.

    Science.gov (United States)

    Cox, Linda; Compalati, Enrico; Kundig, Thomas; Larche, Mark

    2013-04-01

    Allergen immunotherapy (AIT) is effective in reducing the clinical symptoms associated with allergic rhinitis, asthma and venom-induced anaphylaxis. Subcutaneous (SCIT) and sublingual immunotherapy (SLIT) with unmodified allergen extracts are the most widely prescribed AIT regimens. The efficacy of these 2 routes appears comparable, but the safety profile with SLIT is more favorable allowing for home administration and requiring less patient time. However, both require that the treatment is taken regularly over several years, e.g., monthly in a supervised medical setting with SCIT and daily at home with SLIT. Despite the difference in treatment settings, poor adherence has been reported with both routes. Emerging evidence suggests that AIT may be effective in other allergic conditions such as atopic dermatitis, venom sting-induced large local reactions, and food allergy. Research with oral immunotherapy (OIT) for food allergies suggest that many patients can be desensitized during treatment, but questions remain about whether this can produce long term tolerance. Further studies are needed to identify appropriate patients and treatment regimens with these conditions. Efforts to develop safer and more effective AIT for inhalant allergies have led to investigations with modified allergens and alternate routes. Intralymphatic (ILIT) has been shown to produce long-lasting clinical benefits after three injections comparable to a 3-year course of SCIT. Epicutaneous (EPIT) has demonstrated promising results for food and inhalant allergies. Vaccine modifications, such as T cell epitopes or the use of viral-like particles as an adjuvant, have been shown to provide sustained clinical benefits after a relatively short course of treatment compared to the currently available AIT treatments, SLIT and SCIT. These newer approaches may increase the utilization and adherence to AIT because the multi-year treatment requirement of currently available AIT is a likely deterrent for

  18. CCL21 Cancer Immunotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Lin, Yuan, E-mail: yuanlin@mednet.ucla.edu [Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA 90095 (United States); Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA 90095 (United States); UCLA Head and Neck Cancer Program, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA 90095 (United States); Clinical and Translational Science Institute, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA 90095 (United States); Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine at UCLA, 37-131 CHS, 10833 Le Conte Avenue, Los Angeles, CA 90095 (United States); Sharma, Sherven [Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA 90095 (United States); Clinical and Translational Science Institute, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA 90095 (United States); Division of Pulmonary and Critical Care Medicine, Department of Medicine, David Geffen School of Medicine at UCLA, 37-131 CHS, 10833 Le Conte Avenue, Los Angeles, CA 90095 (United States); Veterans’ Affairs Greater Los Angeles Healthcare System, Los Angeles, CA 90073 (United States); John, Maie St. [Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA 90095 (United States); Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA 90095 (United States); UCLA Head and Neck Cancer Program, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA 90095 (United States); Clinical and Translational Science Institute, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA 90095 (United States)

    2014-05-07

    Cancer, a major health problem, affects 12 million people worldwide every year. With surgery and chemo-radiation the long term survival rate for the majority of cancer patients is dismal. Thus novel treatments are urgently needed. Immunotherapy, the harnessing of the immune system to destroy cancer cells is an attractive option with potential for long term anti-tumor benefit. Cytokines are biological response modifiers that stimulate anti-tumor immune responses. In this review, we discuss the anti-tumor efficacy of the chemotactic cytokine CCL21 and its pre-clinical and clinical application in cancer.

  19. Immune targets and neoantigens for cancer immunotherapy and precision medicine.

    Science.gov (United States)

    Wang, Rong-Fu; Wang, Helen Y

    2017-01-01

    Harnessing the immune system to eradicate malignant cells is becoming a most powerful new approach to cancer therapy. FDA approval of the immunotherapy-based drugs, sipuleucel-T (Provenge), ipilimumab (Yervoy, anti-CTLA-4), and more recently, the programmed cell death (PD)-1 antibody (pembrolizumab, Keytruda), for the treatment of multiple types of cancer has greatly advanced research and clinical studies in the field of cancer immunotherapy. Furthermore, recent clinical trials, using NY-ESO-1-specific T cell receptor (TCR) or CD19-chimeric antigen receptor (CAR), have shown promising clinical results for patients with metastatic cancer. Current success of cancer immunotherapy is built upon the work of cancer antigens and co-inhibitory signaling molecules identified 20 years ago. Among the large numbers of target antigens, CD19 is the best target for CAR T cell therapy for blood cancer, but CAR-engineered T cell immunotherapy does not yet work in solid cancer. NY-ESO-1 is one of the best targets for TCR-based immunotherapy in solid cancer. Despite the great success of checkpoint blockade therapy, more than 50% of cancer patients fail to respond to blockade therapy. The advent of new technologies such as next-generation sequencing has enhanced our ability to search for new immune targets in onco-immunology and accelerated the development of immunotherapy with potentially broader coverage of cancer patients. In this review, we will discuss the recent progresses of cancer immunotherapy and novel strategies in the identification of new immune targets and mutation-derived antigens (neoantigens) for cancer immunotherapy and immunoprecision medicine.

  20. Advances and Prospects in Cancer Immunotherapy

    Directory of Open Access Journals (Sweden)

    Juhua Zhou

    2014-01-01

    Full Text Available Cancer immunotherapy is a promising and effective treatment modality for patients with cancers. Cytokine, anticytokine, and antibody therapies appear to be effective in treating various forms of cancer. The human papillomavirus vaccine is protective for cervical cancer, and this discovery has paved the way to the development of cancer vaccines for other forms of virus-associated cancers such as liver cancer and Merkel cell carcinoma. Clinical trials have demonstrated that adoptive cell therapy using tumor-infiltrating lymphocytes can induce tumor regression in approximately 75% of metastatic melanoma patients, suggesting the possibility of using similar technique to effectively treat breast, lung, and renal cancers in the near future. Besides, genetically engineered T cells transduced with genes encoding specific T cell receptors and chimeric antigen receptors have been shown effective in the treatment of cancer patients. These studies suggest that combination therapies are superior choices in cancer immunotherapy for patients.

  1. Era of cancer immunotherapy has come.

    Science.gov (United States)

    Nakatsura, Tetsuya

    2016-01-01

      The dramatic and long durable anti-tumor effect of immune checkpoint blockade, such as anti-CTLA-4 Ab, anti-PD-1 Ab, and anti-PD-L1 Ab was surprised the world. In addition, CAR-T cell therapy that target the CD19 indicates a very high response rate to the CD19-positive hematologic malignancies. Now, no one doubts the presence of immunity against cancer.  Further, accordingly, tumor-specific neoantigen are attention now, the clinical trials of individualized peptide vaccination that target patient individual neoantigens has begun in the Western. On the other hand, the peptide vaccine therapy that target common self-antigen is not yet been approved in Japan, the development is struggling.  In this paper, I overview the cancer immunotherapy and neoantigen and introduce some development of cancer immunotherapy in Japan.

  2. RNA-Based Vaccines in Cancer Immunotherapy.

    Science.gov (United States)

    McNamara, Megan A; Nair, Smita K; Holl, Eda K

    2015-01-01

    RNA vaccines traditionally consist of messenger RNA synthesized by in vitro transcription using a bacteriophage RNA polymerase and template DNA that encodes the antigen(s) of interest. Once administered and internalized by host cells, the mRNA transcripts are translated directly in the cytoplasm and then the resulting antigens are presented to antigen presenting cells to stimulate an immune response. Alternatively, dendritic cells can be loaded with either tumor associated antigen mRNA or total tumor RNA and delivered to the host to elicit a specific immune response. In this review, we will explain why RNA vaccines represent an attractive platform for cancer immunotherapy, discuss modifications to RNA structure that have been developed to optimize mRNA vaccine stability and translational efficiency, and describe strategies for nonviral delivery of mRNA vaccines, highlighting key preclinical and clinical data related to cancer immunotherapy.

  3. RNA-Based Vaccines in Cancer Immunotherapy

    Directory of Open Access Journals (Sweden)

    Megan A. McNamara

    2015-01-01

    Full Text Available RNA vaccines traditionally consist of messenger RNA synthesized by in vitro transcription using a bacteriophage RNA polymerase and template DNA that encodes the antigen(s of interest. Once administered and internalized by host cells, the mRNA transcripts are translated directly in the cytoplasm and then the resulting antigens are presented to antigen presenting cells to stimulate an immune response. Alternatively, dendritic cells can be loaded with either tumor associated antigen mRNA or total tumor RNA and delivered to the host to elicit a specific immune response. In this review, we will explain why RNA vaccines represent an attractive platform for cancer immunotherapy, discuss modifications to RNA structure that have been developed to optimize mRNA vaccine stability and translational efficiency, and describe strategies for nonviral delivery of mRNA vaccines, highlighting key preclinical and clinical data related to cancer immunotherapy.

  4. Oncolytic viruses: a step into cancer immunotherapy

    Directory of Open Access Journals (Sweden)

    Pol JG

    2011-12-01

    Full Text Available Jonathan G Pol, Julien Rességuier, Brian D LichtyMcMaster Immunology Research Centre, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, CanadaAbstract: Oncolytic virotherapy is currently under investigation in phase I–III clinical trials for approval as a new cancer treatment. Oncolytic viruses (OVs selectively infect, replicate in, and kill tumor cells. For a long time, the therapeutic efficacy was thought to depend on the direct viral oncolysis (virocentric view. The host immune system was considered as a brake that impaired virus delivery and spread. Attention was paid primarily to approaches enhancing virus tumor selectivity and cytotoxicity and/or that limited antiviral responses. Thinking has changed over the past few years with the discovery that OV therapy was also inducing indirect oncolysis mechanisms. Among them, induction of an antitumor immunity following OV injection appeared to be a key factor for an efficient therapeutic activity (immunocentric view. Indeed, tumor-specific immune cells persist post-therapy and can search and destroy any tumor cells that escape the OVs, and thus immune memory may prevent relapse of the disease. Various strategies, which are summarized in this manuscript, have been developed to enhance the efficacy of OV therapy with a focus on its immunotherapeutic aspects. These include genetic engineering and combination with existing cancer treatments. Several are currently being evaluated in human patients and already display promising efficacy.Keywords: oncolytic virus, cancer immunotherapy, tumor antigen, cancer vaccine, combination strategies

  5. Active immunotherapy of allergic asthma with a recombinant human interleukin-5 protein as vaccine in a murine model

    Institute of Scientific and Technical Information of China (English)

    TAN Guang-hong; WANG Cai-chun; HUANG Feng-ying; WANG Hua; HUANG Yong-hao; LIN Ying-ying

    2007-01-01

    Background Eosinophils are highly related to allergic asthma inflammation. Interleukin (IL)-5 is the major chemokine of eosinophils, inhibition of the activity of IL-5 thus seems to be a potential approach to asthma therapy. The current study was performed to determine whether a recombinant human IL-5 protein as a xenogeneic vaccine has the capability of inducing anti-asthma activities.Methods Recombinant human IL-5 was used as a protein vaccine. Mouse asthma model was established to observe the anti-asthma activities. Lung histology was observed; eosinophils in blood and bronchoalveolar lavage were stained and counted. Airway hyperresponsiveness was determined by whole body plethysmograph. Antibody characters and cytokines were detected with enzyme linked immunosorbent assay (ELISA) and Western blot assay.Results Vaccination with recombinant human IL-5 protein as vaccine significantly reduced airway inflammation and airway hyperresponsiveness, and shifted the cytokine production from Th2 (IL-4) to Th1 (INF-γ) in mice allergic-asthma model. Immunization with recombinant human IL-5 protein vaccine bypassed the immunological tolerance and induced production of polyclonal antibodies that were cross-reactive with murine IL-5.Conclusions Active immunization with xenogeneic homologous IL-5 may be a possible therapeutic approach to the treatment of asthma and potentially of other eosinophilic disorders.

  6. Human task-specific somatosensory activation.

    Science.gov (United States)

    Ginsberg, M D; Yoshii, F; Vibulsresth, S; Chang, J Y; Duara, R; Barker, W W; Boothe, T E

    1987-08-01

    We used positron emission tomography to study normal patterns of local cortical metabolic activation induced by somatosensory stimuli. Palpation and sorting of mah-jongg tiles by textured design increased local glucose metabolic rate (lCMRgl), by 18% on average, in contralateral somatosensory cortex. A graphesthesia task gave a similar result. In contrast, vigorous vibrotactile stimulation of fingers, face, or knee did not produce a consistent focus of activation. Our results indicate that lCMRgl activation is best achieved by somatosensory tasks requiring an active perceptual effort.

  7. Homing of radiolabelled recombinant interleukin-2 activated natural killer cells and their efficacy in adoptive immunotherapy against murine fibrosarcoma

    Indian Academy of Sciences (India)

    Anuradha Rai; Ashim K Chakravarty

    2007-12-01

    Natural killer (NK) cells are spontaneously cytotoxic against tumour target cells. Their number was found to be four times more in the spleen of tumour-bearing Swiss albino mice. After activation with recombinant interleukin-2 (rIL-2), NK cells were tested and found to seek out the tumour site when injected intravenously in tumour-bearing mice. Their potential for fighting tumours in vivo was further seen following adoptive transfer of rIL-2 activated NK (A-NK) cells in tumour-bearing mice. After surgical removal of tumour load, adoptive transfer of A-NK cells inhibited tumour recurrence in 92.3% cases, thereby suggesting the use of this protocol for therapeutic purposes to obtain a better outcome.

  8. Study of Immunotherapy with Endogenous Opiod (Met-Enkephalin Activated TILs in Fibrosarcoma Induced Balb/C Mice

    Directory of Open Access Journals (Sweden)

    Abbas Ali Amini

    2010-01-01

    Full Text Available Objective: In this study the effects of met-enkephalin on tumor infiltrating lymphocytesfor cancer treatment in fibrosarcoma bearing mice was evaluated.Materials and Methods: Initially, to obtain the most effective dose and treating time forthe inductionof CD25, splenocytes were cultured with several doses of met-enkephalin.Flowcytometry was used to evaluate CD25 expression. The best dose and treatingtime were used to stimulate tumor infiltrating lymphocytes (TILs. To obtain pure CD4+and CD8+ cells, TILs were taken from tumors by enzymatic tissue disaggregation andpurified by magnet bead cell separation. After TILs stimulation they were re-injectedinto three groups of other fibrosarcoma bearing mice. The first group received onlyCD4+ TILs, the second group received only CD8+ TILs, and the third group receivedboth CD4+ and CD8+ TILs. A fourth group that served as the control group receivedonly phosphate buffered saline (PBS. The effect of this treatment on tumor volume,mice survival, effector cells, regulatory T cells and serum level Bcl-2were evaluated.To analyze data in both the experimental and control groups one way ANOVA wasused followed by the Tukey test. P value <0.05 was considered significant.Results: Treatment with met-enkephalin at a dose of 10-10 M for 6 hours was most effectivein CD25 induction on the splenocytes of Balb/C mice. There were a significantdecrease in tumors growth in both the CD8+ and CD4+ activated TILs injected groups(p<0.044 and p<0.017, respectively. The result of the CD4+ plus CD8+ activated TILsinjected group was not significantly different from control group (p<0.661. There wasan improvement in survival amongst the mice in all treated groups (p<0.001 for allthree groups. FoxP3 levels in all groups were significantly low (p<0.001, p<0.002and p<0.001 for the CD4+, CD8+ and CD4+ plus CD8+ activated TILs injected groups,respectively. CD25 and Bcl-2 expressions were higher in the treated groups, but onlythe CD4

  9. Modified immunotherapy for alopecia areata.

    Science.gov (United States)

    Yoshimasu, Takashi; Furukawa, Fukumi

    2016-07-01

    Squaric acid dibutylester (SADBE) is a commonly used contact sensitizer in immunotherapy for alopecia areata (AA). Severe contact dermatitis is induced by the currently high recommended sensitization dose of 1%-2% SADBE, often decreasing patient compliance. We assessed a modified immunotherapy for AA using SADBE at a starting concentration of 0.01% without sensitization. After one or two weeks of initial 0.01% SADBE application, the concentration of SADBE was increased gradually to 0.025%, 0.05%, 0.1%, 0.25%, 0.5%, 1% and 2% until the patients felt itching or erythema at the AA lesion site. The modified immunotherapy showed a response rate of 69.4% (25/36), equivalent to conventional immunotherapy using SADBE starting at 1%-2% sensitization. Furthermore, we investigated the combination therapy of SADBE and multiple courses of steroid pulses for AA. The response rate for combination therapy was 73.7% (28/38); however, the group receiving combination therapy showed a significant prevalence of severe AA compared with the group receiving modified immunotherapy only. We reviewed the efficacy and safety of modified immunotherapy without initial sensitization and combination therapy with immunotherapy and multiple courses of pulses for AA.

  10. Molecular biomarkers for grass pollen immunotherapy.

    Science.gov (United States)

    Popescu, Florin-Dan

    2014-03-26

    Grass pollen allergy represents a significant cause of allergic morbidity worldwide. Component-resolved diagnosis biomarkers are increasingly used in allergy practice in order to evaluate the sensitization to grass pollen allergens, allowing the clinician to confirm genuine sensitization to the corresponding allergen plant sources and supporting an accurate prescription of allergy immunotherapy (AIT), an important approach in many regions of the world with great plant biodiversity and/or where pollen seasons may overlap. The search for candidate predictive biomarkers for grass pollen immunotherapy (tolerogenic dendritic cells and regulatory T cells biomarkers, serum blocking antibodies biomarkers, especially functional ones, immune activation and immune tolerance soluble biomarkers and apoptosis biomarkers) opens new opportunities for the early detection of clinical responders for AIT, for the follow-up of these patients and for the development of new allergy vaccines.

  11. Preclinical activity of anti-CCR7 immunotherapy in patients with high-risk chronic lymphocytic leukemia.

    Science.gov (United States)

    Cuesta-Mateos, Carlos; Loscertales, Javier; Kreutzman, Anna; Colom-Fernández, Beatriz; Portero-Sáinz, Itxaso; Pérez-Villar, Juan José; Terrón, Fernando; Muñoz-Calleja, Cecilia

    2015-06-01

    Chronic lymphocytic leukemia (CLL) with deletions of the p53 locus on chromosome 17 and/or refractory to fludarabine chemoimmunotherapy remains a major clinical problem with few therapeutic options. Currently, these types of CLL are treated with approaches that do not target the p53 pathway, such as small molecules and monoclonal antibodies (mAb). We have previously postulated anti-CCR7 mAb therapy as a novel CLL treatment. In the present study, we evaluated the in vitro efficacy of anti-CCR7 mAb as a single agent in CLL patients with high-risk cytogenetics and/or refractory to fludarabine, by measuring CCR7 surface expression and complement-dependent cytotoxicity. Our results demonstrate that CCR7 is highly expressed in challenging and heavily treated CLL patients. In addition, the complement-mediated mechanism of action of this mAb effectively eradicates CLL cells while sparing subsets of T cells in these patients. Moreover, this mAb outperformed the activity of alemtuzumab, the mAb with the highest efficacy in these groups. Finally, in vitro activity was also demonstrated in patients with a disease refractory to both fludarabine and alemtuzumab, and patients harboring 11q22 deletion. Our results propose that anti-CCR7 mAb is an effective and promising future treatment in high-risk CLL.

  12. Immunotherapy for nasopharyngeal cancer-a review.

    Science.gov (United States)

    Jain, Amit; Chia, Whay Kuang; Toh, Han Chong

    2016-04-01

    Nasopharyngeal carcinoma (NPC) is associated with the Epstein-Barr virus (EBV) and characterized by peritumoral immune infiltrate. Advanced NPC has high lethality. Immunotherapy directed against EBV antigen targets has been previously explored in clinical trials, and is likely to be validated as an important target in NPC as randomized data emerges in the future. Cancer vaccines and adoptive T cell therapy have been explored in the clinic, with the latter showing the greatest success. Recent advances in gene sequencing technology now allow personalized tumor epitope mapping, whilst the advent of immune checkpoint inhibitors targeting the PD-1/PD-L1 axis offers the opportunity to activate adaptive T cell response in vivo. Anti-PD1 antibodies have shown promising activity in early phase clinical trials, and randomized studies against chemotherapy are underway. As immunotherapy is incorporated into standard treatment paradigms, issues of optimal combinations with targeting agents, immune adjuvants, and sequence with chemotherapy and radiation therapy will need to be addressed. Effective strategies to increase tumor antigenicity, improve immunological memory and reduce immune escape, will need to be developed to improve treatment outcomes. Here we present a brief history of the evolution of immunotherapy in NPC, and highlight key concepts relevant to its further development in the clinic.

  13. Effects of dendritic cell vaccine activated with protein components of toxoplasma gondii on tumor specific CD8+ T-cells

    Directory of Open Access Journals (Sweden)

    Amari A

    2009-12-01

    Full Text Available "n Normal 0 false false false EN-US X-NONE AR-SA MicrosoftInternetExplorer4 /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:Arial; mso-bidi-theme-font:minor-bidi;} Background: Dendritic Cell (DC is an important antigen-presenting cell that present tumor antigen to CD8+ and CD4+ T- Lymphocytes and induce specific anti-tumor immunity. In order to induce effective anti-tumor response, an option is increasing the efficiency of antigen presentation of dendritic cells and T cell activation capacity. The aim of the present study was to investigate the effect of dendritic cell maturation with protein components of toxoplasma gondii on cytotoxic T lymphocyte activity and their infiltration in to the tumor."n"nMethods: For DC generation, bone marrow cells were cultured in the presence of GM-CSF and IL-4 for five days. After that, LPS, protein components and whole extract of toxoplasma gondii were added to the culture media and incubated for another two days for DC maturation. To generate tumor, mices were injected subcutaneously with WEHI-164 cell line. For immunotherapy 106 DCs matured with different compounds were injected around the tumor site. Infiltration of CD8+ T cells were determined by flow cytometry and cytotoxic activity was measured by LDH detection kit."n"nResults: Immunotherapy with DCs treated with protein components of toxoplasma gondii led to a significant increase in the

  14. Laser immunotherapy of canine and feline neoplasia

    Science.gov (United States)

    Woods, J. P.; Bartels, Kenneth E.; Davidson, Ellen B.; Ritchey, Jerry W.; Lehenbauer, Terry W.; Nordquist, Robert E.; Chen, Wei R.

    1998-07-01

    The major cause of treatment failure in human and veterinary cancer patients is tumor invasion and metastasis. The inability of local therapy (surgery, radiation, photodynamic therapy) to eradicate a metastatic cancer presents a challenge in the therapy of residual or micrometastatic disease. Because of its local therapy limitations, chromophore-enhanced selective photothermal laser treatment has been augmented with a superimposed laser-induced systemic photobiological reaction, laser immunotherapy. Laser immunotherapy is a novel cancer treatment consisting of: (1) a laser in the infrared wavelength range (i.e. 805 nm solid state laser); (2) a photosensitizer of the corresponding absorption peak [i.e. indocyanine green (ICG)]; and (3) an immunoadjuvant [i.e. glycated chitosan gel (GCG)]. The intratumor injection of the photosensitizer (ICG) and immunoadjuvant (GCG) solution is followed by noninvasive laser irradiation. The laser energy causes tumor cell destruction by photothermal interaction to reduce the tumor burden and at the same time exposes tumor antigens. The immunoadjuvant concomitantly stimulates the host to mount a systemic anti-tumor immune response against the remaining cells of the tumor and to induce a long-term, tumor-specific immunity. This study investigates the feasibility of utilizing laser immunotherapy as an adjunctive therapy for the control of feline fibrosarcoma in future.

  15. Immunotherapy in Lung Cancer.

    Science.gov (United States)

    Castellanos, Emily H; Horn, Leora

    2016-01-01

    Lung cancer has not traditionally been viewed as an immune-responsive tumor. However, it is becoming evident that tumor-induced immune suppression is vital to malignant progression. Immunotherapies act by enhancing the patient's innate immune response and hold promise for inducing long-term responses in select patients with non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Immune checkpoint inhibitors, in particular, inhibitors to cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) and programmed death receptor ligand 1 (PD-L1) have shown promise in early studies and are currently in clinical trials in both small cell lung cancer and non-small cell lung cancer patients. Two large randomized phase III trials recently demonstrated superior overall survival (OS) in patients treated with anti-PD-1 therapy compared to chemotherapy in the second-line setting.

  16. Checkpoint Blockade in Cancer Immunotherapy

    Science.gov (United States)

    Korman, Alan J.; Peggs, Karl S.; Allison, James P.

    2007-01-01

    The progression of a productive immune response requires that a number of immunological checkpoints be passed. Passage may require the presence of excitatory costimulatory signals or the avoidance of negative or coinhibitory signals, which act to dampen or terminate immune activity. The immunoglobulin superfamily occupies a central importance in this coordination of immune responses, and the CD28/cytotoxic T-lymphocyte antigen-4 (CTLA-4):B7.1/B7.2 receptor/ligand grouping represents the archetypal example of these immune regulators. In part the role of these checkpoints is to guard against the possibility of unwanted and harmful self-directed activities. While this is a necessary function, aiding in the prevention of autoimmunity, it may act as a barrier to successful immunotherapies aimed at targeting malignant self-cells that largely display the same array of surface molecules as the cells from which they derive. Therapies aimed at overcoming these mechanisms of peripheral tolerance, in particular by blocking the inhibitory checkpoints, offer the potential to generate antitumor activity, either as monotherapies or in synergism with other therapies that directly or indirectly enhance presentation of tumor epitopes to the immune system. Such immunological molecular adjuvants are showing promise in early clinical trials. This review focuses on the results of the archetypal example of checkpoint blockade, anti-CTLA-4, in preclinical tumor models and clinical trials, while also highlighting other possible targets for immunological checkpoint blockade. PMID:16730267

  17. Immunotherapy for Bone and Soft Tissue Sarcomas

    Directory of Open Access Journals (Sweden)

    Takenori Uehara

    2015-01-01

    Full Text Available Although multimodal therapies including surgery, chemotherapy, and radiotherapy have improved clinical outcomes of patients with bone and soft tissue sarcomas, the prognosis of patients has plateaued over these 20 years. Immunotherapies have shown the effectiveness for several types of advanced tumors. Immunotherapies, such as cytokine therapies, vaccinations, and adoptive cell transfers, have also been investigated for bone and soft tissue sarcomas. Cytokine therapies with interleukin-2 or interferons have limited efficacy because of their cytotoxicities. Liposomal muramyl tripeptide phosphatidylethanolamine (L-MTP-PE, an activator of the innate immune system, has been approved as adjuvant therapeutics in combination with conventional chemotherapy in Europe, which has improved the 5-year overall survival of patients. Vaccinations and transfer of T cells transduced to express chimeric antigen receptors have shown some efficacy for sarcomas. Ipilimumab and nivolumab are monoclonal antibodies designed to inhibit immune checkpoint mechanisms. These antibodies have recently been shown to be effective for patients with melanoma and also investigated for patients with sarcomas. In this review, we provide an overview of various trials of immunotherapies for bone and soft tissue sarcomas, and discuss their potential as adjuvant therapies in combination with conventional therapies.

  18. Targeted immunotherapy in Hodgkin lymphoma

    DEFF Research Database (Denmark)

    Hutchings, Martin

    2015-01-01

    In this issue of Blood, Rothe et al introduce a new principle of targeted Hodgkin lymphoma (HL) immunotherapy in their report from a phase 1 study of the bispecific anti-CD30/CD16A antibody construct AFM13.......In this issue of Blood, Rothe et al introduce a new principle of targeted Hodgkin lymphoma (HL) immunotherapy in their report from a phase 1 study of the bispecific anti-CD30/CD16A antibody construct AFM13....

  19. Novel ways for immune intervention in immunotherapy: mucosal allergy vaccines.

    Science.gov (United States)

    Mascarell, Laurent; Van Overtvelt, Laurence; Moingeon, Philippe

    2006-05-01

    Allergen-specific immunotherapy is currently the only curative treatment for allergy. Subcutaneous immunotherapy (SCIT) has been successfully used to treat patients who are allergic to insect venom, house dust mites, or tree or grass pollens. In the context of potentially severe, albeit infrequent, side effects associated with SCIT, mucosal routes of administration are being investigated to conduct allergenic desensitization. This article reviews recent developments in the field of nasal, oral, and sublingual immunotherapy as they relate to safety, clinical efficacy, and immune mechanisms of action. Implications for the design and development of improved allergy vaccines that could be used through such nonparenteral routes are discussed. Specifically, allergen presentation platforms and adjuvants facilitating the targeting of immune cells at mucosal surfaces to promote tolerance induction are reviewed.

  20. Dendritic Cells as Pharmacological Tools for Cancer Immunotherapy.

    Science.gov (United States)

    Anguille, Sébastien; Smits, Evelien L; Bryant, Christian; Van Acker, Heleen H; Goossens, Herman; Lion, Eva; Fromm, Phillip D; Hart, Derek N; Van Tendeloo, Viggo F; Berneman, Zwi N

    2015-10-01

    Although the earliest—rudimentary—attempts at exploiting the immune system for cancer therapy can be traced back to the late 18th Century, it was not until the past decade that cancer immunotherapeutics have truly entered mainstream clinical practice. Given their potential to stimulate both adaptive and innate antitumor immune responses, dendritic cells (DCs) have come under intense scrutiny in recent years as pharmacological tools for cancer immunotherapy. Conceptually, the clinical effectiveness of this form of active immunotherapy relies on the completion of three critical steps: 1) the DCs used as immunotherapeutic vehicles must properly activate the antitumor immune effector cells of the host, 2) these immune effector cells must be receptive to stimulation by the DCs and be competent to mediate their antitumor effects, which 3) requires overcoming the various immune-inhibitory mechanisms used by the tumor cells. In this review, following a brief overview of the pivotal milestones in the history of cancer immunotherapy, we will introduce the reader to the basic immunobiological and pharmacological principles of active cancer immunotherapy using DCs. We will then discuss how current research is trying to define the optimal parameters for each of the above steps to realize the full clinical potential of DC therapeutics. Given its high suitability for immune interventions, acute myeloid leukemia was chosen here to showcase the latest research trends driving the field of DC-based cancer immunotherapy.

  1. The INIS Study. International Neonatal Immunotherapy Study: non-specific intravenous immunoglobulin therapy for suspected or proven neonatal sepsis: an international, placebo controlled, multicentre randomised trial

    Directory of Open Access Journals (Sweden)

    2008-12-01

    Full Text Available Abstract Background Sepsis is an important cause of neonatal death and perinatal brain damage, particularly in preterm infants. While effective antibiotic treatment is essential treatment for sepsis, resistance to antibiotics is increasing. Adjuvant therapies, such as intravenous immunoglobulin, therefore offer an important additional strategy. Three Cochrane systematic reviews of randomised controlled trials in nearly 6,000 patients suggest that non-specific, polyclonal intravenous immunoglobulin is safe and reduces sepsis by about 15% when used as prophylaxis but does not reduce mortality in this situation. When intravenous immunoglobulin is used in the acute treatment of neonatal sepsis, however, there is a suggestion that it may reduce mortality by 45%. However, the existing trials of treatment were small and lacked long-term follow-up data. This study will assess reliably whether treatment of neonatal sepsis with intravenous immunoglobulin reduces mortality and adverse neuro-developmental outcome. Methods and design A randomised, placebo controlled, double blind trial. Babies with suspected or proven neonatal sepsis will be randomised to receive intravenous immunoglobulin therapy or placebo. Eligibility criteria Babies must be receiving antibiotics and have proven or suspected serious infection AND have at least one of the following: birthweight less than 1500 g OR evidence of infection in blood culture, cerebrospinal fluid or usually sterile body fluid OR be receiving respiratory support via an endotracheal tube AND there is substantial uncertainty that intravenous immunoglobulin is indicated. Exclusion criteria Babies are excluded if intravenous immunoglobulin has already been given OR intravenous immunoglobulin is thought to be needed OR contra-indicated. Trial treatment Babies will be given either 10 ml/kg of intravenous immunoglobulin or identical placebo solution over 4–6 hours, repeated 48 hours later. Primary outcome Mortality or

  2. Requirements for acquiring a high-quality house dust mite extract for allergen immunotherapy

    Directory of Open Access Journals (Sweden)

    Frati F

    2012-05-01

    Full Text Available Franco Frati,1 Cristoforo Incorvaia,2 Marie David,3 Silvia Scurati,3 Simona Seta,4 Guglielmo Padua,4 Eleonora Cattaneo,1 Carlo Cavaliere,5 Alessia Di Rienzo,6 Ilaria Dell'Albani,1 Paola Puccinelli11Medical and Scientific and Regulatory Department, Stallergenes, Milan, Italy; 2Allergy/Pulmonary Rehabilitation, ICP Hospital, Milan, Italy; 3Laboratoire Stallergenes, Antony, France; 4Marketing Department, Stallergenes, Milan, Italy; 5Ear, Nose and Throat Department, University Sapienza, Rome, Italy; 6Azienda Sanitaria Locale, Allergology Service, Frosinone, ItalyAbstract: The house dust mite is a major cause of respiratory allergy worldwide. The management of mite allergy is based on avoidance measures, drug treatment, and allergen immunotherapy, but only allergen immunotherapy is able to modify the natural history of the disease. Injectable subcutaneous immunotherapy was introduced a century ago, while sublingual immunotherapy was proposed in the 1980s and emerged in the ensuing years as an effective and safe option to subcutaneous immunotherapy. However, the quality of the extracts to be used in allergen immunotherapy is crucial for the success of treatment. The mite extract for sublingual immunotherapy known as Staloral 300 was developed to offer optimal characteristics concerning the mite culture medium, standardization, and allergen dose. Double-blind, placebo-controlled trials with Staloral 300 have provided a substantial part of the clinical evidence analyzed in a meta-analysis of the efficacy of allergen immunotherapy in mite-induced rhinitis and asthma. Safety and tolerability are very good, mild local reactions in the mouth being the most common side effect. This makes it feasible to carry out sublingual immunotherapy for the 3–5-year duration needed to achieve long-lasting tolerance to the specific allergen. The performance of Staloral 300 may provide optimal conditions for an effective and safe sublingual immunotherapy in patients with

  3. Therapeutic Response in Patients with Advanced Malignancies Treated with Combined Dendritic Cell–Activated T Cell Based Immunotherapy and Intensity–Modulated Radiotherapy

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    Hasumi, Kenichiro; Aoki, Yukimasa; Watanabe, Ryuko [Hasumi International Research Foundation, Tokyo Research Center, 1-44-6 Asagaya-kita, Suginami- ku, Tokyo 166-0001 (Japan); Hankey, Kim G.; Mann, Dean L., E-mail: dmann001@umaryland.edu [Department of Pathology, University of Maryland School of Medicine, MSTF Room 700, 10 South Pine Street, Baltimore, Maryland 21040 (United States)

    2011-04-28

    Successful cancer immunotherapy is confounded by the magnitude of the tumor burden and the presence of immunoregulatory elements that suppress an immune response. To approach these issues, 26 patients with advanced treatment refractory cancer were enrolled in a safety/feasibility study wherein a conventional treatment modality, intensity modulated radiotherapy (IMRT), was combined with dendritic cell-based immunotherapy. We hypothesized that radiation would lower the tumor burdens, decrease the number/function of regulatory cells in the tumor environment, and release products of tumor cells that could be acquired by intratumoral injected immature dendritic cells (iDC). Metastatic lesions identified by CT (computed tomography) were injected with autologous iDC combined with a cytokine-based adjuvant and KLH (keyhole limpet hemocyanin), followed 24 h later by IV-infused T-cells expanded with anti-CD3 and IL-2 (AT). After three to five days, each of the injected lesions was treated with fractionated doses of IMRT followed by another injection of intratumoral iDC and IV-infused AT. No toxicity was observed with cell infusion while radiation-related toxicity was observed in seven patients. Five patients had progressive disease, eight demonstrated complete resolution at treated sites but developed recurrent disease at other sites, and 13 showed complete response at various follow-up times with an overall estimated Kaplan-Meier disease-free survival of 345 days. Most patients developed KLH antibodies supporting our hypothesis that the co-injected iDC are functional with the capacity to acquire antigens from their environment and generate an adaptive immune response. These results demonstrate the safety and effectiveness of this multimodality strategy combining immunotherapy and IMRT in patients with advanced malignancies.

  4. Past, present and future targets for immunotherapy in ovarian cancer.

    Science.gov (United States)

    Schwab, Carlton L; English, Diana P; Roque, Dana M; Pasternak, Monica; Santin, Alessandro D

    2014-01-01

    Ovarian cancer is the leading cause of death from gynecologic malignancy in the US. Treatments have improved with conventional cytotoxic chemotherapy and advanced surgical techniques but disease recurrence is common and fatal in nearly all cases. Current evidence suggests that the immune system and its ability to recognize and eliminate microscopic disease is paramount in preventing recurrence. Ovarian cancer immunotherapy is targeting tumors through active, passive and adoptive approaches. The goal of immunotherapy is to balance the activation of the immune system against cancer while preventing the potential for tremendous toxicity elicited by immune modulation. In this paper we will review the different immunotherapies available for ovarian cancer as well as current ongoing studies and potential future directions.

  5. Th1 cytokine-based immunotherapy for cancer

    Institute of Scientific and Technical Information of China (English)

    Hong-Mei Xu

    2014-01-01

    Cytokine-based immunotherapy is executed by harnessing cytokines to activate the immune system to suppress tumors. Th1-type cytokines including IL-1, IL-2, IL-12 and granulocyte-macrophage colony-stimulating factor are potent stimulators of Th1 differentiation and Th1-based antitumor response. Many preclinical studies demonstrated the antitumor effects of Th1 cytokines but their clinical efficacy is limited. Multiple factors influence the efficacy of immunotherapy for tumors. For instance immunosuppressive cells in the tumor microenvironment can produce inhibitory cytokines which suppress antitumor immune response. Most studies on cytokine immunotherapy focused on how to boost Th1 response; many studies combined cytokine-based therapy with other treatments to reverse immunosuppression in tumor microenvironment. In addition, cytokines have pleiotropic functions and some cytokines show paradoxical activities under different settings. Better understanding the physiological and pathological functions of cytokines helps clinicians to design Th1-based cancer therapy in clinical practice.

  6. [The role of immunotherapy in the prevention of allergic diseases].

    Science.gov (United States)

    Lugović-Mihić, Liborija; Duvancić, Tomislav

    2011-01-01

    Immunotherapy through repeated administration of allergens and augmentation of doses (hyposensibilization) with the purpose of decreasing the severity of type I allergic reactions or even its complete elimination is known already for a longer period of time. This type of therapy is especially beneficial in allergies to Hymenoptera venom, allergic rhinoconjunctivitis, allergic asthma and is implemented in patients with previously proven allergy to appropriate allergens (insects, pollen, house dust mite, pet dander and other). The most common form of therapy is subcutaneous immunotherapy which includes a series of injections containing specific allergens (allergy vaccines) with increasingly larger doses administered subcutaneously during a period of 3-5 years. There are also other forms of immunotherapy (for instance sublingual immunotherapy) although these are less effective. Repetition of the hyposensibilization procedure leads to further reduction in severity of allergy disease in the majority of patients. The efficacy of immunotherapy is also proven by a lower risk of allergic rhinitis patients developing asthma as well as by prevention of new sensibilizations.

  7. [Satisfaction with immunotherapy in patients with advanced cancer].

    Science.gov (United States)

    Moriyama, Yoshiaki; Fujisawa, Fumika; Kotani, Junko; Ohnishi, Masayuki; Watanabe, Toru

    2015-04-01

    Patient satisfaction with cancer immunotherapy, which is not covered by health insurance in Japan, was evaluated among 65 patients with advanced cancer who had received immunotherapy in our hospital for 2 years. Satisfaction measures were based on patients' expectations for medical care, cost, and staff services, and involved a questionnaire consisting of 25 items. Results of the questionnaire analysis showed that most patients, who expected much of antigen-specific vaccination such as dendritic cells (DC) pulsed tumor-associated antigens, were dissatisfied with the high cost of private immunotherapy(i. e., not covered by medical insurance), and were unable to perceive the effectiveness of the treatment because there was no quantitative analysis of killer T cells induced by immunotherapy. Therefore, it is critically important for us to confirm the safety and efficiency of cancer immunotherapy, before introducing medical insurance for cancer patients in Japan. In addition, the quantitative measurement of killer T cells induced by DC peptide vaccines should be considered, to meet patients' expectations.

  8. Cancer Immunotherapy Targeting the Telomerase Reverse Transcriptase

    Institute of Scientific and Technical Information of China (English)

    Longfei Huo; Janice WS Tang; Junjian Huang; Peitang Huang; Cuifen Huang; Hsiang-fu Kung; Marie C. Lin

    2006-01-01

    The human telomerase reverse transcriptase (hTERT) is expressed in more than 85% of tumor cells but is usually not found in normal cells, which makes hTERT as an ideal tumor-associate antigen (TAA) to develop potential vaccine specifically destroying cancers without impairing normal tissues in human cancer immunotherapy. Here are reviewed the fundamental advances of studies on immunogenicity of hTERT or its peptides and the early clinical trials using the hTERT vaccine approach in the last decades.

  9. Clinical efficacy of a standardized specific immunotherapy against house dust mite in 85 asthmatic children%尘螨标准化免疫治疗85例哮喘儿童疗效相关指标分析

    Institute of Scientific and Technical Information of China (English)

    张璇; 李孟荣; 王超; 王晓宁; 张海邻; 林剑; 金可; 李迎春

    2010-01-01

    目的 观察哮喘特异性免疫治疗(Specific immunotherapy,SIT)过程中变应原注射时间、变应原累积注射量及糖皮质激素吸入剂量、最高呼气流量、总IgE、螨特异性IgE等的变化.方法 根据纳入标准选择2005年2月-2008年6月我院哮喘免疫治疗中心就诊的过敏性哮喘患儿,进行同期对照回顾性分析,其中治疗组接受尘螨标准化变应原特异性免疫治疗,以每4次变应原注射为观察点,历时3.4年,观察治疗时间、变应原累积注射量、糖皮质激素吸入量、最高呼气流量变化、总IgE和螨特异性IgE变化,对照组仅行药物治疗,比较两组糖皮质激素吸入量及哮喘发作情况,并在SIT结束时评估疗效.结果 SIT组85例,男45例,女40例,年龄(7.6±1.4)岁,对照组病例50例,单纯药物治疗,男28例,女22例,年龄(7.7±1.5)岁.SIT第20次注射、治疗(38.7±2.4)周时,变应原累积注射量达(69.7±4.8)μg,糖皮质激素吸入量明显少于对照组(t=2.359,P<0.05);SIT组最高呼气流量较治疗前升高,有统计学意义(F=7.874,P<0.05);SIT前后总IgE变化无统计学意义(t=0.313,P>0.05),螨特异性IgE变化无统计学意义(tDerp=0.517,tDerf=0.717,P>0.05);SIT组疗程结束时患儿家长对病情主观评价:45.9%表示明显好转,36.5%表示中度好转,16.5%表示稍有好转,1.1%表示无改变;两组患儿在治疗结束时进行疗效评估,SIT组控制率达85.5%,对照组为62.0%,两组比较差异有统计学意义(x2=10.150,P<0.01),提示SIT有效..结论 哮喘特异性免疫治疗第20次注射后,螨过敏性哮喘患儿糖皮质激素吸入剂量显著减少;85%以上患儿在SIT结束时哮喘得到控制;总IgE和螨特异性IgE变化无统计学意义.%Objective The scientific basis and the clinical effectiveness of allergen specific immunotherapy (SIT) administered by subcutaneous injection are well established. This study aimed to observe the changes in amount of inhaled corticosteroids

  10. Biologic Therapy (Immunotherapy) for Kidney Cancer

    Science.gov (United States)

    ... Stage for Kidney Cancer Kidney Cancer Treating Kidney Cancer Biologic Therapy (Immunotherapy) for Kidney Cancer The goal of biologic therapy ... Therapy for Kidney Cancer Targeted Therapies for Kidney Cancer Biologic Therapy (Immunotherapy) for Kidney Cancer Chemotherapy for Kidney Cancer Pain ...

  11. Gene-modified hematopoietic stem cells for cancer immunotherapy.

    Science.gov (United States)

    Larson, Sarah; De Oliveira, Satiro N

    2014-01-01

    The rapid expansion of available cancer immunotherapies has resulted in favorable early outcomes. Specifically the use of gene therapy to introduce chimeric antigen receptors (CARs) and T cell receptors (TCRs) in T cells creates new immunotherapy options for patients. While showing early success with these approaches, limitations remain that can be overcome by the use of modification of hematopoietic stem cells (HSCs) to express CARs and TCRs. With modern gene therapy technologies, increased safety and control of the modification of the HSCs can be achieved through the use of a suicide gene.

  12. IMMUNOTHERAPY FOR EPSTEIN-BARR VIRUS-RELATED LYMPHOMAS

    Directory of Open Access Journals (Sweden)

    Alana Kennedy-Nasser

    2009-11-01

    Full Text Available Latent EBV infection is associated with several malignancies, including EBV post-transplant lymphoproliferative disorders (LPD, Hodgkin and non-Hodgkin lymphomas, nasopharyngeal carcinoma and Burkitt lymphoma. The range of expression of latent EBV antigens varies in these tumors, which influences how susceptible the tumors are to immunotherapeutic approaches. Tumors expressing type III latency, such as in LPD, express the widest array of EBV antigens making them the most susceptible to immunotherapy. Treatment strategies for EBV-related tumors include restoring normal cellular immunity by adoptive immunotherapy with EBV-specific T cells and targeting the malignant B cells with monoclonal antibodies. We review the current immunotherapies and future studies aimed at targeting EBV antigen expression in these tumors.

  13. Strategies to genetically engineer T cells for cancer immunotherapy.

    Science.gov (United States)

    Spear, Timothy T; Nagato, Kaoru; Nishimura, Michael I

    2016-06-01

    Immunotherapy is one of the most promising and innovative approaches to treat cancer, viral infections, and other immune-modulated diseases. Adoptive immunotherapy using gene-modified T cells is an exciting and rapidly evolving field. Exploiting knowledge of basic T cell biology and immune cell receptor function has fostered innovative approaches to modify immune cell function. Highly translatable clinical technologies have been developed to redirect T cell specificity by introducing designed receptors. The ability to engineer T cells to manifest desired phenotypes and functions is now a thrilling reality. In this review, we focus on outlining different varieties of genetically engineered T cells, their respective advantages and disadvantages as tools for immunotherapy, and their promise and drawbacks in the clinic.

  14. Immunotherapy and lung cancer: current developments and novel targeted therapies.

    Science.gov (United States)

    Domingues, Duarte; Turner, Alice; Silva, Maria Dília; Marques, Dânia Sofia; Mellidez, Juan Carlos; Wannesson, Luciano; Mountzios, Giannis; de Mello, Ramon Andrade

    2014-01-01

    Non-small-cell lung cancer (NSCLC) is a highly prevalent and aggressive disease. In the metastatic setting, major advances include the incorporation of immunotherapy and targeted therapies into the clinician's therapeutic armamentarium. Standard chemotherapeutic regimens have long been reported to interfere with the immune response to the tumor; conversely, antitumor immunity may add to the effects of those therapies. The aim of immunotherapy is to specifically enhance the immune response directed to the tumor. Recently, many trials addressed the role of such therapies for metastatic NSCLC treatment: ipilimumab, tremelimumab, nivolumab and lambrolizumab are immunotherapeutic agents of main interest in this field. In addition, anti-tumor vaccines, such as MAGE-A3, Tecetomide, TG4010, CIMAvax, ganglioside vaccines, tumor cell vaccines and dendritic cell vaccines, emerged as potent inducers of immune response against the tumor. The current work aims to address the most recent developments regarding these innovative immunotherapies and their implementation in the treatment of metastatic NSCLC.

  15. Treating allergic rhinitis by sublingual immunotherapy: a review

    Directory of Open Access Journals (Sweden)

    Cristoforo Incorvaia

    2012-06-01

    Full Text Available OBJECTIVE: Allergic rhinitis (AR is a disease with high and increasing prevalence. The management of AR includes allergen avoidance, anti-allergic drugs, and allergen specific immunotherapy (AIT, but only the latter works on the causes of allergy and, due to its mechanisms of action, modifies the natural history of the disease. Sublingual immunotherapy (SLIT was proposed in the 1990s as an option to traditional, subcutaneous immunotherapy. MATERIAL AND METHODS: We reviewed all the available controlled trials on the efficacy and safety of SLIT. RESULTS AND CONCLUSION: Thus far, more than 60 trials, globally evaluated in 6 meta-analyses, showed that SLIT is an effective and safe treatment for AR. However, it must be noted that to expect clinical efficacy in the current practice SLIT has to be performed following the indications from controlled trials, that is, sufficiently high doses to be regularly administered for at least 3 consecutive years.

  16. Propionibacterium acnes in the pathogenesis and immunotherapy of acne vulgaris.

    Science.gov (United States)

    Liu, Pei-Feng; Hsieh, Yao-Dung; Lin, Ya-Ching; Two, Aimee; Shu, Chih-Wen; Huang, Chun-Ming

    2015-01-01

    Acne vulgaris, a multi-factorial disease, is one of the most common skin diseases, affecting an estimated 80% of Americans at some point during their lives. The gram-positive and anaerobic Propionibacterium acnes (P. acnes) bacterium has been implicated in acne inflammation and pathogenesis. Therapies for acne vulgaris using antibiotics generally lack bacterial specificity, promote the generation of antibiotic-resistant bacterial strains, and cause adverse effects. Immunotherapy against P. acnes or its antigens (sialidase and CAMP factor) has been demonstrated to be effective in mice, attenuating P. acnes-induced inflammation; thus, this method may be applied to develop a potential vaccine targeting P. acnes for acne vulgaris treatment. This review summarizes reports describing the role of P. acnes in the pathogenesis of acne and various immunotherapy-based approaches targeting P. acnes, suggesting the potential effectiveness of immunotherapy for acne vulgaris as well as P. acnes-associated diseases.

  17. Immunotherapy of multiple sclerosis: the state of the art.

    Science.gov (United States)

    Karussis, Dimitrios

    2013-04-01

    It is widely accepted that the main common pathogenetic pathway in multiple sclerosis (MS) involves an immune-mediated cascade initiated in the peripheral immune system and targeting CNS myelin. Logically, therefore, the therapeutic approaches to the disease include modalities aiming at downregulation of the various immune elements that are involved in this immunologic cascade. Since the introduction of interferons in 1993, which were the first registered treatments for MS, huge steps have been made in the field of MS immunotherapy. More efficious and specific immunoactive drugs have been introduced and it appears that the increased specificity for MS of these new treatments is paralleled by greater efficacy. Unfortunately, this seemingly increased efficacy has been accompanied by more safety issues. The immunotherapeutic modalities can be divided into two main groups: those affecting the acute stages (relapses) of the disease and the long-term treatments that are aimed at preventing the appearance of relapses and the progression in disability. Immunomodulating treatments may also be classified according to the level of the 'immune axis' where they exert their main effect. Since, in MS, a neurodegenerative process runs in parallel and as a consequence of inflammation, early immune intervention is warranted to prevent progression of relapses of MS and the accumulation of disability. The use of neuroimaging (MRI) techniques that allow the detection of silent inflammatory activity of MS and neurodegeneration has provided an important tool for the substantiation of the clinical efficacy of treatments and the early diagnosis of MS. This review summarizes in detail the existing information on all the available immunotherapies for MS, old and new, classifies them according to their immunologic mechanisms of action and proposes a structured algorithm/therapeutic scheme for the management of the disease.

  18. Exploiting the Immunomodulatory Properties of Chemotherapeutic Drugs to Improve the Success of Cancer Immunotherapy.

    Science.gov (United States)

    Kersten, Kelly; Salvagno, Camilla; de Visser, Karin E

    2015-01-01

    Cancer immunotherapy is gaining momentum in the clinic. The current challenge is to understand why a proportion of cancer patients do not respond to cancer immunotherapy, and how this can be translated into the rational design of combinatorial cancer immunotherapy strategies aimed at maximizing success of immunotherapy. Here, we discuss how tumors orchestrate an immunosuppressive microenvironment, which contributes to their escape from immune attack. Relieving the immunosuppressive networks in cancer patients is an attractive strategy to extend the clinical success of cancer immunotherapy. Since the clinical availability of drugs specifically targeting immunosuppressive cells or mediators is still limited, an alternative strategy is to use conventional chemotherapy drugs with immunomodulatory properties to improve cancer immunotherapy. We summarize the preclinical and clinical studies that illustrate how the anti-tumor T cell response can be enhanced by chemotherapy-induced relief of immunosuppressive networks. Treatment strategies aimed at combining chemotherapy-induced relief of immunosuppression and T cell-boosting checkpoint inhibitors provide an attractive and clinically feasible approach to overcome intrinsic and acquired resistance to cancer immunotherapy, and to extend the clinical success of cancer immunotherapy.

  19. Non-Specific Immunotherapies and Adjuvants

    Science.gov (United States)

    ... Center Volunteer Learning Center Follow Us Twitter Facebook Instagram Cancer Information, Answers, and Hope. Available Every Minute ... 227.2345 Live Chat Follow Us Twitter Facebook Instagram help site map privacy accessibility terms of use ...

  20. Innovative Strategies for Breast Cancer Immunotherapy

    Science.gov (United States)

    2014-09-01

    AWARD NUMBER: W81XWH-12-1-0223 TITLE: Innovative Strategies for Breast Cancer Immunotherapy ...studies (2). A promising approach in cancer treatment is adoptive immunotherapy using chimeric antigen receptor (CAR)-engineered T cells to redirect...multiple tissues. DISCUSSION Adoptive immunotherapy is a promising approach for the treatment of cancer , and observations from preclinical and

  1. Cancer testis antigen and immunotherapy

    Directory of Open Access Journals (Sweden)

    Krishnadas DK

    2013-04-01

    Full Text Available Deepa Kolaseri Krishnadas, Fanqi Bai, Kenneth G Lucas Department of Pediatrics, Division of Hematology/Oncology, University of Louisville, KY, USA Abstract: The identification of cancer testis (CT antigens has been an important advance in determining potential targets for cancer immunotherapy. Multiple previous studies have shown that CT antigen vaccines, using both peptides and dendritic cell vaccines, can elicit clinical and immunologic responses in several different tumors. This review details the expression of melanoma antigen family A, 1 (MAGE-A1, melanoma antigen family A, 3 (MAGE-A3, and New York esophageal squamous cell carcinoma-1 (NY-ESO-1 in various malignancies, and presents our current understanding of CT antigen based immunotherapy. Keywords: cancer testis antigens, immunotherapy, vaccine

  2. Emerging nanotechnologies for cancer immunotherapy.

    Science.gov (United States)

    Shukla, Sourabh; Steinmetz, Nicole F

    2016-05-01

    Founded on the growing insight into the complex cancer-immune system interactions, adjuvant immunotherapies are rapidly emerging and being adapted for the treatment of various human malignancies. Immune checkpoint inhibitors, for example, have already shown clinical success. Nevertheless, many approaches are not optimized, require frequent administration, are associated with systemic toxicities and only show modest efficacy as monotherapies. Nanotechnology can potentially enhance the efficacy of such immunotherapies by improving the delivery, retention and release of immunostimulatory agents and biologicals in targeted cell populations and tissues. This review presents the current status and emerging trends in such nanotechnology-based cancer immunotherapies including the role of nanoparticles as carriers of immunomodulators, nanoparticles-based cancer vaccines, and depots for sustained immunostimulation. Also highlighted are key translational challenges and opportunities in this rapidly growing field.

  3. Current status of cancer immunotherapy

    Directory of Open Access Journals (Sweden)

    Kono K

    2014-04-01

    Full Text Available To prove clinical benefits of cancer vaccine is currently difficult, except for one phase III trial has documented improved overall survival with the vaccine, Sipuleucel‑T, although induction of anti-tumor immune responses through cancer vaccine is theoretically promising and would be straightforward. In contrast, immune checkpoint blockade with anti-CTLA4 mAb and anti-PD‑1 mAb has demonstrated clear evidence of objective responses including improved overall survival and tumor shrinkage, driving renewed enthusiasm for cancer immunotherapy in multi­ple cancer types. In addition, there is a promising novel cancer immunotherapy, CAR therapy—a personalized treatment that involves genetically modifying a patient’s T- cells to make them target tumor cells. We are now facing new era of cancer immunotherapy.

  4. Immunotherapy for Urothelial Carcinoma: Current Status and Perspectives

    Directory of Open Access Journals (Sweden)

    Taiji Tsukamoto

    2011-07-01

    Full Text Available Intravesical instillation of bacillus Calmette Guérin (BCG for the treatment of urothelial carcinoma (UC of the bladder is based on the BCG-induced immune response, which eradicates and prevents bladder cancer. The results of recent studies have suggested that not only major histocompatibility complex (MHC-nonrestricted immune cells such as natural killer cells, macrophages, neutrophils, etc., but also MHC-restricted CD8+ T cells play an important role and are one of the main effectors in this therapy. Better understanding of the mechanism of BCG immunotherapy supports the idea that active immunotherapy through its augmented T cell response can have great potential for the treatment of advanced UC. In this review, progress in immunotherapy for UC is discussed based on data from basic, translational and clinical studies. We also review the escape mechanism of cancer cells from the immune system, and down-regulation of MHC class I molecules.

  5. Advances in Immunotherapies for Non-small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Yuan HE

    2014-03-01

    Full Text Available Globally, Lung cancer is the leading cause of cancer-related death of high morbidity and mortality with poor prognosis, which needs some more effective and less toxic therapies. The immunotherapies offer a novel approach for the treatment of patients with non-small cell lung cancer (NSCLC in both the adjuvant and palliative disease settings. A number of promising immunotherapies based on different mechanism have now been evaluated showing an increasing response rate. Moreover, further phase II/III clinical trials will be indicated to explore its value. These include checkpoint inhibitors (anti-CTLA4 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, active vaccination (L-BLP25 liposome vaccine, Belagenpumatucel-L vaccine, MAGE-A3 protein vaccine and adoptive vaccination (CIK cells. The purpose of this paper will draw a summary on the theory, clinical trials, toxicity and problems to be solved of the immunotherapies in NSCLC.

  6. Immunotherapy for Urothelial Carcinoma: Current Status and Perspectives

    Energy Technology Data Exchange (ETDEWEB)

    Kitamura, Hiroshi, E-mail: hkitamu@sapmed.ac.jp; Tsukamoto, Taiji [Department of Urology, Sapporo Medical University School of Medicine, South 1 West 16, Chuo-ku, Sapporo 060-8543 (Japan)

    2011-07-29

    Intravesical instillation of bacillus Calmette Guérin (BCG) for the treatment of urothelial carcinoma (UC) of the bladder is based on the BCG-induced immune response, which eradicates and prevents bladder cancer. The results of recent studies have suggested that not only major histocompatibility complex (MHC)-nonrestricted immune cells such as natural killer cells, macrophages, neutrophils, etc., but also MHC-restricted CD8{sup +} T cells play an important role and are one of the main effectors in this therapy. Better understanding of the mechanism of BCG immunotherapy supports the idea that active immunotherapy through its augmented T cell response can have great potential for the treatment of advanced UC. In this review, progress in immunotherapy for UC is discussed based on data from basic, translational and clinical studies. We also review the escape mechanism of cancer cells from the immune system, and down-regulation of MHC class I molecules.

  7. How can nanotechnology help membrane vesicle-based cancer immunotherapy development?

    Science.gov (United States)

    Tian, Xin; Zhu, Motao; Nie, Guangjun

    2013-01-01

    Exosomes are nanosized vesicles originating from endosomal compartments and secreted by most living cells. In the past decade, exosomes have emerged as potent tools for cancer immunotherapy due to their important roles in modulation of immune responses, and promising results have been achieved in exosome-based immunotherapy. The recent rapid progress of nanotechnology, especially on tailored design of nanocarriers for drug delivery based on both passive and active targeting strategies, sheds light on re-engineering native membrane vesicles for enhanced immune regulation and therapy. Applications of nanotechnology toolkits might provide new opportunity not only for value-added therapeutic or diagnostic strategies based on exosomes in cancer immunotherapy, but also new insights for biogenesis and biological relevance of membrane vesicles. This commentary focuses on the recent development and limitations of using exosomes in cancer immunotherapy and our perspectives on how nanomaterials with potential immune regulatory effects could be introduced into exosome-based immunotherapy.

  8. 以VEGF及VEGFR2为靶位的抗肿瘤血管生成主动免疫治疗的研究进展%Research Progress of Active Immunotherapies against Tumor Angiogenisis Targeting on VEGF and VEGFR2

    Institute of Scientific and Technical Information of China (English)

    王伟; 殷小涛; 田仁礼; 阎瑾琦; 高江平; 于继云

    2013-01-01

    Tumor cells stimulate angiogenesis to meet increasing nutrient and oxygen demands. Therefore, the dependence of growing tumors on new blood vessel formation has made anti-angiogenesis become one of the most appealing strategy in cancer research and therapeutics of clinical oncology. Among all of the factors stimulating angiogenesis, vascular endothelial growth factor (VEGF) and its receptor VEGFR2 (also called fetal liver kinse-1 [Flk-1] in mice, kinase-containing domain receptor [KDR] in humans) are critically important to the angiogenesis associated with tumor growth, metastasis and relapse. In addition, active anti-tumor immunotherapy has provided a novel strategy through interrupting tumor-mediated immune escape and suppression. By combining the two strategies, active anti-angiogenic immunotherapy might offer the possibility to more robustly inhibit tumor angiogenesis. This combination application of immunotherapy and anti-angiogenic treatment might represent a promising avenue for future research. This review summarized latest researches of active immunotherapy targeting tumor angiogenesis through interrupting the signal passway of VEGF/VEGFR2. This paper discussed three different types of vaccines utilized as anti-cancer therapeutics-cell vaccines, protein/peptide vaccines and gene/DNA vaccines-with a specific focus on angiogenesis suppression. And future research directions for this field are also outlined.%肿瘤细胞通过刺激新生血管生成来满足对营养及供氧的不断增长的需求,因此,肿瘤组织生长对于新生血管形成的依赖性使得抗血肿瘤管生成已经成为肿瘤学基础研究与临床治疗领域中最吸引人的策略之一.在众多的促血管生成因子中,血管内皮生长因子(VEGF)及其受体VEGFR2(鼠和人中也分别称为Flk-1和KDR)对于与肿瘤生长、转移及复发相关的血管生成是至关重要的.此外,通过打破肿瘤组织自身介导的免疫耐受与逃避,主动免疫治疗已

  9. An approach for activity-based DEVS model specification

    DEFF Research Database (Denmark)

    Alshareef, Abdurrahman; Sarjoughian, Hessam S.; Zarrin, Bahram

    2016-01-01

    activity-based behavior modeling of parallel DEVS atomic models. We consider UML activities and actions as fundamental units of behavior modeling, especially in the presence of recent advances in the UML 2.5 specifications. We describe in detail how to approach activity modeling with a set of elemental...

  10. Allergenic Characterization of New Mutant Forms of Pru p 3 as New Immunotherapy Vaccines

    Directory of Open Access Journals (Sweden)

    C. Gómez-Casado

    2013-01-01

    Full Text Available Nowadays, treatment of food allergy only considered the avoidance of the specific food. However, the possibility of cross-reactivity makes this practice not very effective. Immunotherapy may exhibit as a good alternative to food allergy treatment. The use of hypoallergenic molecules with reduced IgE binding capacity but with ability to stimulate the immune system is a promising tool which could be developed for immunotherapy. In this study, three mutants of Pru p 3, the principal allergen of peach, were produced based on the described mimotope and T cell epitopes, by changing the specific residues to alanine, named as Pru p 3.01, Pru p 3.02, and Pru p 3.03. Pru p 3.01 showed very similar allergenic activity as the wild type by in vitro assays. However, Pru p 3.02 and Pru p 3.03 presented reduced IgE binding with respect to the native form, by in vitro, ex vivo, and in vivo assays. In addition, Pru p 3.03 had affected the IgG4 binding capacity and presented a random circular dichroism, which was reflected in the nonrecognition by specific antibodies anti-Pru p 3. Nevertheless, both Pru p 3.02 and Pru p 3.03 maintained the binding to IgG1 and their ability to activate T lymphocytes. Thus, Pru p 3.02 and Pru p 3.03 could be good candidates for potential immunotherapy in peach-allergic patients.

  11. Cancer immunotherapy using tumor cryoablation.

    Science.gov (United States)

    Sidana, Abhinav

    2014-01-01

    Cryoablation is increasingly being used as a primary treatment for localized cancers and as a salvage therapy for metastatic cancers. Anecdotal clinical reports and animal experiments have confirmed an induction of systemic antitumor immune response by tumor cryoablation. To capitalize on the stimulatory effects of cryoablation for cancer immunotherapy, this response must be intensified using other immunomodulatory agents. This article reviews the preclinical and clinical evidence and discusses the mechanism of the antitumor immune response generated by cryoablation. The rationale and evidence behind several immunotherapy approaches that can be combined with cryoablation to devise a cryoimmunotherapeutic strategy with a potential to impact the progression of metastatic disease are described.

  12. NK cell mediated antibody-dependent cellular cytotoxicity in cancer immunotherapy

    Directory of Open Access Journals (Sweden)

    Wei eWang

    2015-07-01

    Full Text Available Natural killer (NK cells play a major role in cancer immunotherapies that involve tumor-antigen targeting by monoclonal antibodies (mAbs. NK cells express a variety of activating and inhibitory receptors that serve to regulate the function and activity of the cells. In the context of targeting cells, NK cells can be specifically activated through certain Fc receptors that are expressed on their cell surface. NK cells can express FcγRIIIA and/or FcγRIIC, which can bind to the Fc portion of immunoglobulins, transmitting activating signals within NK cells. Once activated through Fc receptors by antibodies bound to target cells, NK cells are able to lyse target cells without priming, and secrete cytokines like interferon gamma to recruit adaptive immune cells. This antibody-dependent cell-mediated cytotoxicity (ADCC of tumor cells is utilized in the treatment of various cancers overexpressing unique antigens, such as neuroblastoma, breast cancer, B cell lymphoma, and others. NK cells also express a family of receptors called Killer Immunoglobulin-like Receptors (KIRs, which regulate the function and response of NK cells towards target cells through their interaction with their cognate ligands that are expressed on tumor cells. Genetic polymorphisms in KIR and KIR ligands, as well as FcγRs may influence NK cell responsiveness in conjunction with mAb immunotherapies. This review focuses on current therapeutic mAbs, different strategies to augment the anti-tumor efficacy of ADCC, and genotypic factors that may influence patient responses to antibody-dependent immunotherapies.

  13. The specific activation of TRPC4 by Gi protein subtype.

    Science.gov (United States)

    Jeon, Jae-Pyo; Lee, Kyu Pil; Park, Eun Jung; Sung, Tae Sik; Kim, Byung Joo; Jeon, Ju-Hong; So, Insuk

    2008-12-12

    The classical type of transient receptor potential channel (TRPC) is a molecular candidate for Ca(2+)-permeable cation channels in mammalian cells. Especially, TRPC4 has the similar properties to Ca(2+)-permeable nonselective cation channels (NSCCs) activated by muscarinic stimulation in visceral smooth muscles. In visceral smooth muscles, NSCCs activated by muscarinic stimulation were blocked by anti-Galphai/o antibodies. However, there is still no report which Galpha proteins are involved in the activation process of TRPC4. Among Galpha proteins, only Galphai protein can activate TRPC4 channel. The activation effect of Galphai was specific for TRPC4 because Galphai has no activation effect on TRPC5, TRPC6 and TRPV6. Coexpression with muscarinic receptor M2 induced TRPC4 current activation by muscarinic stimulation with carbachol, which was inhibited by pertussis toxin. These results suggest that Galphai is involved specifically in the activation of TRPC4.

  14. Immunotherapy and immunoescape in colorectal cancer

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Immunotherapy encompasses a variety of interventions and techniques with the common goal of eliciting tumor cell destructive immune responses. Colorectal carcinoma often presents as metastatic disease that impedes curative surgery. Novel strategies such as active immunization with dendritic cells (DCs), gene transfer of cytokines into tumor cells or administration of immunostimulatory monoclonal antibodies (such as anti-CD137 or anti-CTLA-4) have been assessed in preclinical studies and are at an early clinical development stage. Importantly, there is accumulating evidence that chemotherapy and immunotherapy can be combined in the treatment of some cases with colorectal cancer, with synergistic potentiation as a result of antigens cross-presented by dendritic cells and/or elimination of competitor or suppressive T lymphocyte populations (regulatory T-cells). However, genetic and epigenetic unstable carcinoma cells frequently evolve mechanisms of immunoevasion that are the result of either loss of antigen presentation, or an active expression of immunosuppressive substances. Some of these actively immunosuppressive mechanisms are inducible by cytokines that signify the arrival of an effector immune response. For example, induction of 2, 3 indoleamine dioxygenase (IDO) by IFNy in colorectal carcinoma cells. Combinational and balanced strategies fostering antigen presentation, T-cell costimulation and interference with immune regulatory mechanisms will probably take the stage in translational research in the treatment of colorectal carcinoma.

  15. Dendritic cell-tumor cell hybrids and immunotherapy

    DEFF Research Database (Denmark)

    Cathelin, Dominique; Nicolas, Alexandra; Bouchot, André

    2011-01-01

    Dendritic cells (DC) are professional antigen-presenting cells currently being used as a cellular adjuvant in cancer immunotherapy strategies. Unfortunately, DC-based vaccines have not demonstrated spectacular clinical results. DC loading with tumor antigens and DC differentiation and activation...

  16. Specific activity of radioiodine-labelled human chorionic gonadotropin ligand

    Energy Technology Data Exchange (ETDEWEB)

    Crespi, M. (South African Inst. for Medical Research, Sandringham. National Inst. for Virology); Kay, G.W.; Van der Walt, L.A. (South African Inst. for Medical Research, Johannesburg. Dept. of Pathology)

    1983-10-01

    The article deals with the determination of the specific activity of radioiodine-labelled human chorionic gonadotropin ligand. The iodiation of human chorionic gonadotropin and the counting efficiency of /sup 125/I are discussed.

  17. Cancer immunotherapy: sipuleucel-T and beyond.

    Science.gov (United States)

    Hammerstrom, Aimee E; Cauley, Diana H; Atkinson, Bradley J; Sharma, Padmanee

    2011-08-01

    In April 2010, sipuleucel-T became the first anticancer vaccine approved by the United States Food and Drug Administration. Different from the traditional chemotherapy agents that produce widespread cytotoxicity to kill tumor cells, anticancer vaccines and immunotherapies focus on empowering the immune system to overcome the tumor. The immune system consists of innate and adaptive components. The CD4(+) and CD8(+) T cells are the most crucial components of the adaptive arm of the immune system that act to mediate antitumor responses. However, T-cell responses are regulated by intrinsic and extrinsic mechanisms, which may interfere with effective antitumor responses. Many anticancer immunotherapies use tumor-associated antigens as vaccines in order to stimulate an immune response against tumor cells. Sipuleucel-T is composed of autologous mononuclear cells incubated with a fusion protein consisting of a common prostate cancer antigen (prostatic acid phosphatase) linked to an adjuvant (granulocyte-macrophage colony-stimulating factor). It is postulated that when the vaccine is infused into the patient, the activated antigen-presenting cells displaying the fusion protein will induce an immune response against the tumor antigen. In a recent randomized, double-blind, placebo-controlled, phase III clinical trial, sipuleucel-T significantly improved median overall survival by 4.1 months in men with metastatic castration-resistant prostate cancer compared with placebo. Although overall survival was improved, none of the three phase III clinical trials found a significant difference in time to disease progression. This, along with cost and logistic issues, has led to an active discussion. Although sipuleucel-T was studied in the metastatic setting, its ideal place in therapy is unknown, and clinical trials are being conducted in patients at different stages of disease and in combination with radiation therapy, antiandrogen therapy, and chemotherapy. Various other anticancer

  18. Immunotherapy strategies for spinal cord injury.

    Science.gov (United States)

    Wang, Yong-Tang; Lu, Xiu-Min; Chen, Kai-Ting; Shu, Ya-Hai; Qiu, Chun-Hong

    2015-01-01

    Regeneration in the central nervous system (CNS) of adult mammalian after traumatic injury is limited, which often causes permanent functional motor and sensory loss. After spinal cord injury (SCI), the lack of regeneration is mainly attributed to the presence of a hostile microenvironment, glial scarring, and cavitation. Besides, inflammation has also been proved to play a crucial role in secondary degeneration following SCI. The more prominent treatment strategies in experimental models focus mainly on drugs and cell therapies, however, only a few strategies applied in clinical studies and therapies still have only limited effects on the repair of SCI. Recently, the interests in immunotherapy strategies for CNS are increasing in number and breadth. Immunotherapy strategies have made good progresses in treating many CNS degenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), stroke, and multiple sclerosis (MS). However, the strategies begin to be considered to the treatment of SCI and other neurological disorders in recent years. Besides anti-inflamatory therapy, immunization with protein vaccines and DNA vaccines has emerged as a novel therapy strategy because of the simplicity of preparation and application. An inflammatory response followed by spinal cord injury, and is controled by specific signaling molecules, such as some cytokines playing a crucial role. As a result, appropriate immunoregulation, the expression of pro-inflammatory cytokines and anti-inflammatory cytokines may be an effective therapy strategy for earlier injury of spinal cord. In addition, myelinassociated inhibitors (MAIs) in the injured spinal cord, such as Nogo, myelin-associated glycoprotein (MAG) and oligodendrocyte- myelin glycoprotein (OMgp) are known to prevent axonal regeneration through their co-receptors, and to trigger demyelinating autoimmunity through T cell-mediated harmful autoimmune response. The antagonism of the MAIs through vaccinating with

  19. Integrated Immunotherapy for Breast Cancer

    Science.gov (United States)

    2013-09-01

    CSF. J Clin Invest 117, 1902 (Jul, 2007). 32. H. Yamaguchi et al., Milk fat globule EGF factor 8 in the serum of human patients of systemic lupus erythematosus . J Leukoc Biol 83, 1300 (May, 2008). ...comprehensive and systematic manner is the underlying principle of my goal to develop ’rational combination immunotherapy’ for breast cancer, one

  20. Allergen immunotherapy for allergic rhinoconjunctivitis

    DEFF Research Database (Denmark)

    Dhami, Sangeeta; Nurmatov, Ulugbek; Roberts, Graham;

    2016-01-01

    BACKGROUND: The European Academy of Allergy and Clinical Immunology (EAACI) is in the process of developing the EAACI Guidelines for Allergen Immunotherapy (AIT) for the Management of Allergic Rhinoconjunctivitis. We seek to critically assess the effectiveness, cost-effectiveness and safety of AIT...

  1. Safety of specific immunotherapy with standardized house-dust mite vaccine in asthmatic children%标准化屋尘螨提取液治疗儿童支气管哮喘的安全性研究

    Institute of Scientific and Technical Information of China (English)

    郝创利; 陶慧; 沈美菊; 侯政

    2008-01-01

    目的 通过观察进行标准化屋尘螨特异性免疫治疗(脱敏治疗)的支气管哮喘(简称哮喘)患儿,在脱敏治疗过程中出现的不良反应,评价脱敏治疗的安全性.方法 对在苏州大学附属儿童医院哮喘专科门诊临床确诊的110例哮喘患儿,应用(丹麦ALK-Abell(o)公司安脱达)标准化屋尘螨提取液进行皮下注射脱敏治疗.观察每次注射后不良反应发生情况,统计脱敏治疗的不良反应发生率.结果 在110例患儿共接受免疫注射2332人次,发生局部不良反应291人次(发生率12.48%),其中速发型局部不良反应146人次(6.26%),迟发型局部不良反应145人次(6.22%).局部不良反应在20~800SQU、2000~80 000SQU、100 000 SQU阶段的发生率分别是:1.05%(6/569)、12.05%(97/805)和19.62%(188/958),差异有统计学意义.发生全身不良反应79人次(3.39%),1例次为3级非致命性全身反应,其余均为轻度全身反应(包括哮喘、过敏性鼻炎,过敏性结膜炎、过敏性皮炎),其中速发型全身不良反应49人次(2.10%).迟发型全身不良反应为30人次(1.29%).全身不良反应在20~800 SQU、2 000~80 000 SQU、100 000 SQU阶段的发生率分别是:0.35%(2/569)、6.71%(54/805)和2.51%(24/958),差异有统计学意义.结论 哮喘患儿对标准化屋尘螨提取液特异性免疫治疗耐受性良好.绝大多数局部不良反应为轻度,其发生率随注射提取物浓度增高而增高.全身不良反应绝大多数为轻度,以发生在2 000~80 000 SQU剂量明显上升阶段为最多,在此阶段多加注意.全身不良反应以注射浓度2 000~80 000 SQU为最高.而局部不良反应以100 000 SQU组为最高,提示局部不良反应和全身不良反应不平行.局部不良反应发生不提示全身不良反应发生.%Objective To evaluate the safety of specific immunotherapy(SIT)with standardized house dust mite(HDM)vaccine on allergic asthmatic children.Methods 110 patients with mild to moderate

  2. Development of a hypoallergenic recombinant parvalbumin for first-in-man subcutaneous immunotherapy of fish allergy

    DEFF Research Database (Denmark)

    Zuidmeer-Jongejan, Laurian; Huber, Hans; Swoboda, Ines;

    2015-01-01

    BACKGROUND: The FAST (food allergy-specific immunotherapy) project aims at developing safe and effective subcutaneous immunotherapy for fish allergy, using recombinant hypoallergenic carp parvalbumin, Cyp c 1. OBJECTIVES: Preclinical characterization and good manufacturing practice (GMP) production...... PBMCs. Toxicity studies revealed no toxic effects and real-time stability studies on the Al(OH)3-adsorbed drug product demonstrated at least 20 months of stability. CONCLUSION: The GMP drug product developed for treatment of fish allergy has the characteristics targeted for in FAST: i.......e. hypoallergenicity with retained immunogenicity. These results have warranted first-in-man immunotherapy studies to evaluate the safety of this innovative vaccine....

  3. UML activity diagrams in requirements specification of logic controllers

    Science.gov (United States)

    Grobelna, Iwona; Grobelny, Michał

    2015-12-01

    Logic controller specification can be prepared using various techniques. One of them is the wide understandable and user-friendly UML language and its activity diagrams. Using formal methods during the design phase increases the assurance that implemented system meets the project requirements. In the approach we use the model checking technique to formally verify a specification against user-defined behavioral requirements. The properties are usually defined as temporal logic formulas. In the paper we propose to use UML activity diagrams in requirements definition and then to formalize them as temporal logic formulas. As a result, UML activity diagrams can be used both for logic controller specification and for requirements definition, what simplifies the specification and verification process.

  4. 舌下含服粉尘螨滴剂治疗支气管哮喘伴变应性鼻炎的疗效%Efficacy of Specific Sublingual Immunotherapy with Dermatophagoides Farinae Drops on Bronchitic Asthma and Allergic Rhinitis in Children

    Institute of Scientific and Technical Information of China (English)

    谢庆玲; 甄宏; 谭颖; 温志红; 胡琼燕; 李东云; 李柳青; 梁珍花

    2011-01-01

    Objective To explore the efficacy and safety of specific sublingual immunotherapy with dermatophagoides farinae drops on bronchitic asthma and allergic rhinitis in children. Methods Five hundred and sixteen children aged 4 - 13 years old with asthma and allergic rhinitis were involved in the study. Among them, 291 cases had received specific sublingual immunotherapy for 1 year( immunotherapy group) and the other (225 cases) had not received specific sublingual immunotherapy as control group. Skin prick test with 10 common allergens were taken in all subjects and positive reaction to dermatophagoides was confirmed. Immunotherapy group were assigned into 4 subgroups according to the results of skin prick test:only sensitized to mites group(80 cases), sensitized to mites and cockroach group(71 cases), sensitized to mites and pollen group(74 cases) ,sensitized to mites and dog hair group(66 cases). Dermatophagoides farinae drops(DFD) was used for sublingual immunotherapy. Asthma control questionnaire (ACQ) scores, rhinitis symptoms scores, drug use before and after treatment and side reaction were recorded. Results 1. After 12 months treatment of sublingual immunotherapy ,the ACQ scores in immunotherapy group and control group were 0. 28 ± 0. 33 and 1.07 ± 0.68, and they were decreased separately by (74.03 ± 37.66 ) % and ( 29.32 ± 44.53 ) % compared with those before treatment ( 1.76 ±0. 75 and 1.55 ±0.62 ) ,which showed extremely significant decreased ACQ grading in the irnmunotherapy patients ( Z = - 154. 109 ,P < 0.000 1 ). 2. After 12 months treatment of sublingual immunotherapy, the rhinitis symptoms scores in immunotherapy group and control group were 0. 337 ± 0.479 and 0. 560 ± 0. 634, and they were decreased by 70.8% and 39.1% compared with those before treatment (0. 899 ± 0.667 and 0. 892 ± 0. 688 ), and there was significant difference between both groups (x2 =51. 949,P < 0. 000 1 ). 3. After 12 months treatment of sublingual

  5. Peptide immunotherapy in experimental autoimmune encephalomyelitis

    Directory of Open Access Journals (Sweden)

    Stephen M Anderton

    2015-06-01

    Full Text Available We now have potent drugs available to treat the inflammatory component of multiple sclerosis (MS. However, not all patients respond, the drugs are not curative, and the associated risks to beneficial immune surveillance are considerable. A more desirable approach is to specifically target those comparatively rare T lymphocytes that are orchestrating the autoimmune attack. Using the autoantigen itself to instill immune tolerance in those cells remains a holy grail of immunotherapy. Peptide immunotherapy (PIT is highly effective at silencing autoimmune responses in experimental autoimmune encephalomyelitis (EAE, and clinical trials of PIT are underway in MS. This review discusses the current paradigms for PIT-induced tolerance in naïve T cells. It highlights the need for better understanding of the mode of action of PIT upon memory and effector T cells that are responsible for driving/sustaining ongoing autoimmune pathology. Recent studies in EAEsuggest genetic and epigenetic changes in these pathogenic T-cell populations in response to PIT. Finally, future challenges to effective translation of PIT to the clinic are considered.

  6. Cancer immunotherapy: avoiding the road to perdition

    Directory of Open Access Journals (Sweden)

    Bright Robert K

    2004-07-01

    Full Text Available Abstract The hypothesis that human cancers express antigens that can be specifically targeted by cell mediated immunity has become a scientifically justifiable rationale for the design and clinical testing of novel tumor-associated antigens (TAA. Although a number of TAA have been recognized and it has been suggested that they could be useful in the immunological treatment of cancer, the complexity of human beings leads us to reflect on the need to establish new criteria for validating their real applicability. Herein, we show a system level-based approach that includes morphological and molecular techniques, which is specifically required to improve the capacity to produce desired results and to allow cancer immunotherapy to re-emerge from the mist in which it is currently shrouded.

  7. [Development of Nucleic Acid-Based Adjuvant for Cancer Immunotherapy].

    Science.gov (United States)

    Kobiyama, Kouji; Ishii, Ken J

    2015-09-01

    Since the discovery of the human T cell-defined tumor antigen, the cancer immunotherapy field has rapidly progressed, with the research and development of cancer immunotherapy, including cancer vaccines, being conducted actively. However, the disadvantages of most cancer vaccines include relatively weak immunogenicity and immune escape or exhaustion. Adjuvants with innate immunostimulatory activities have been used to overcome these issues, and these agents have been shown to enhance the immunogenicity of cancer vaccines and to act as mono-therapeutic anti-tumor agents. CpG ODN, an agonist for TLR9, is one of the promising nucleic acid-based adjuvants, and it is a potent inducer of innate immune effector functions. CpG ODN suppresses tumor growth in the absence of tumor antigens and peptide administration. Therefore, CpG ODN is expected to be useful as a cancer vaccine adjuvant as well as a cancer immunotherapy agent. In this review, we discuss the potential therapeutic applications and mechanisms of CpG ODN for cancer immunotherapy.

  8. Combining targeted therapy with immunotherapy in BRAF-mutant melanoma: promise and challenges.

    Science.gov (United States)

    Hu-Lieskovan, Siwen; Robert, Lidia; Homet Moreno, Blanca; Ribas, Antoni

    2014-07-20

    Recent breakthroughs in the treatment of advanced melanoma are based on scientific advances in understanding oncogenic signaling and the immunobiology of this cancer. Targeted therapy can successfully block oncogenic signaling in BRAF(V600)-mutant melanoma with high initial clinical responses, but relapse rates are also high. Activation of an immune response by releasing inhibitory check points can induce durable responses in a subset of patients with melanoma. These advances have driven interest in combining both modes of therapy with the goal of achieving high response rates with prolonged duration. Combining BRAF inhibitors and immunotherapy can specifically target the BRAF(V600) driver mutation in the tumor cells and potentially sensitize the immune system to target tumors. However, it is becoming evident that the effects of paradoxical mitogen-activated protein kinase pathway activation by BRAF inhibitors in non-BRAF-mutant cells needs to be taken into account, which may be implicated in the problems encountered in the first clinical trial testing a combination of the BRAF inhibitor vemurafenib with ipilimumab (anti-CTLA4), with significant liver toxicities. Here, we present the concept and potential mechanisms of combinatorial activity of targeted therapy and immunotherapy, review the literature for evidence to support the combination, and discuss the potential challenges and future directions for rational conduct of clinical trials.

  9. Sipuleucel-T: immunotherapy for advanced prostate cancer

    Directory of Open Access Journals (Sweden)

    Olson BM

    2011-05-01

    Full Text Available Brian M Olson, Douglas G McNeelUniversity of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI, USAAbstract: Prostate cancer continues to be one of the most serious afflictions of men of advanced age, remaining the most commonly diagnosed and second leading cause of cancer-related deaths in American men. The treatment options for patients with incurable metastatic, castrate-resistant disease have long focused on various chemotherapeutic approaches, which provide a slight survival benefit while being associated with potentially significant side effects. However, the recent approval of sipuleucel-T has given patients with advanced disease an additional treatment option that has demonstrated benefit without the side effects associated with chemotherapy. Sipuleucel-T is an antigen-presenting cell-based active immunotherapy that utilizes a patient's own immune cells, presumably to activate an antigen-specific immune response against tumor cells. This review focuses on the development and implementation of sipuleucel-T as a therapy for prostate cancer. Specifically, we present some of the issues associated with the management of advanced prostate cancer, the research and development that led to the approval of sipuleucel-T, how the approval of sipuleucel-T could change the clinical management of prostate cancer, and current and future areas of investigation that are being pursued with regard to sipuleucel-T and other treatments for advanced prostate cancer.Keywords: sipuleucel-T, prostatic acid phosphatase, granulocyte-macrophage colonystimulating factor

  10. Sipuleucel-T: immunotherapy for advanced prostate cancer.

    Science.gov (United States)

    Olson, Brian M; McNeel, Douglas G

    2011-05-03

    Prostate cancer continues to be one of the most serious afflictions of men of advanced age, remaining the most commonly diagnosed and second leading cause of cancer-related deaths in American men. The treatment options for patients with incurable metastatic, castrate-resistant disease have long focused on various chemotherapeutic approaches, which provide a slight survival benefit while being associated with potentially significant side effects. However, the recent approval of sipuleucel-T has given patients with advanced disease an additional treatment option that has demonstrated benefit without the side effects associated with chemotherapy. Sipuleucel-T is an antigen-presenting cell-based active immunotherapy that utilizes a patient's own immune cells, presumably to activate an antigen-specific immune response against tumor cells. This review focuses on the development and implementation of sipuleucel-T as a therapy for prostate cancer. Specifically, we present some of the issues associated with the management of advanced prostate cancer, the research and development that led to the approval of sipuleucel-T, how the approval of sipuleucel-T could change the clinical management of prostate cancer, and current and future areas of investigation that are being pursued with regard to sipuleucel-T and other treatments for advanced prostate cancer.

  11. 2015 Guidance on cancer immunotherapy development in early-phase clinical studies.

    Science.gov (United States)

    2015-12-01

    The development of cancer immunotherapies is progressing rapidly with a variety of technological approaches. They consist of "cancer vaccines", which are based on the idea of vaccination, "effector cell therapy", classified as passive immunotherapy, and "inhibition of immunosuppression", which intends to break immunological tolerance to autoantigens or immunosuppressive environments characterizing antitumor immune responses. Recent reports showing clinical evidence of efficacy of immune checkpoint inhibitors and adoptive immunotherapies with tumor-infiltrating lymphocytes and tumor-specific receptor gene-modified T cells indicate the beginning of a new era for cancer immunotherapy. This guidance summarizes ideas that will be helpful to those who plan to develop cancer immunotherapy. The aims of this guidance are to discuss and offer important points in early phase clinical studies of innovative cancer immunotherapy, with future progress in this field, and to contribute to the effective development of cancer immunotherapy aligned with the scope of regulatory science. This guidance covers cancer vaccines, effector cell therapy, and inhibition of immunosuppression, including immune checkpoint inhibitors.

  12. Immunotherapy Treatments of Warm Autoimmune Hemolytic Anemia

    Directory of Open Access Journals (Sweden)

    Bainan Liu

    2013-01-01

    Full Text Available Warm autoimmune hemolytic anemia (WAIHA is one of four clinical types of autoimmune hemolytic anemia (AIHA, with the characteristics of autoantibodies maximally active at body temperature. It produces a variable anemia—sometimes mild and sometimes severe. With respect to the absence or presence of an underlying condition, WAIHA is either idiopathic (primary or secondary, which determines the treatment strategies in practice. Conventional treatments include immune suppression with corticosteroids and, in some cases, splenectomy. In recent years, the number of clinical studies with monoclonal antibodies and immunosuppressants in the treatment of WAIHA increased as the knowledge of autoimmunity mechanisms extended. This thread of developing new tools of treating WAIHA is well exemplified with the success in using anti-CD20 monoclonal antibody, Rituximab. Following this success, other treatment methods based on the immune mechanisms of WAIHA have emerged. We reviewed these newly developed immunotherapy treatments here in order to provide the clinicians with more options in selecting the best therapy for patients with WAIHA, hoping to stimulate researchers to find more novel immunotherapy strategies.

  13. Long-term effect evaluation of antigen specific immunotherapy for patients with pollen allergy%抗原特异性免疫治疗对花粉症的长期疗效

    Institute of Scientific and Technical Information of China (English)

    林小平; 何韶衡; 高军; 迟秀丽

    2005-01-01

    目的:探讨抗原特异性免疫治疗(specific immunotherapy,SIT)对花粉症患者的疗效及作用机制.方法:选择对夏秋季豚草(Ragweed)和蒿草(Atremisa vulgaris)过敏的花粉症患者(过敏性鼻炎或哮喘)235例,随机分为SIT组:包括过敏性鼻炎组(n=65);过敏性鼻炎+哮喘组(n=60);对症治疗组(symptomatic therapy,ST),同样包括过敏性鼻炎组(n=56),和过敏性鼻炎+哮喘组(n=54).健康对照组(n=43).应用UniCAPsystem免疫荧光法、双抗体夹心ELISA法、放射比浊法和瑞氏染色法分别测定血清特异性IgE(sIgE)、总IgE(tIgE)、嗜酸性粒细胞阳离子蛋白(ECP)、IgG水平和外周血嗜酸性粒细胞(Eos)计数.分别比较二组治疗前、后上述各种参数、肺功能指标、症状评分和皮肤试验指数的变化.结果:治疗前,患者血清sIgE、tIgE、ECP水平、血Eos计数、tIgE:IgG值均明显升高(P<0.01).经SIT治疗后,上述指标均明显下降,而IgG含量明显上升(P<0.01).肺功能指标、症状评分和皮肤试验指数均在治疗后有明显改善(P<0.05).其中临床控制率40%,有效率57.7%(显效46.4%,好转11.3%),无效率仅为2.3%,不良反应8.9%.ST组治疗前、后上述各种参数无明显改变,其中23%的过敏性鼻炎患者发生了哮喘.ST组以上各种参数无改变.结论:SIT能明显改善过敏性鼻炎和哮喘的临床症状,增加血清IgG水平,减少IgE的生成并抑制Eos的募集.

  14. Adoptive immunotherapy of cancer with polyclonal, 108-fold hyperexpanded, CD4+ and CD8+ T cells

    Directory of Open Access Journals (Sweden)

    Kim Julian A

    2004-11-01

    Full Text Available Abstract T cell-mediated cancer immunotherapy is dose dependent and optimally requires participation of antigen-specific CD4+ and CD8+ T cells. Here, we isolated tumor-sensitized T cells and activated them in vitro using conditions that led to greater than 108-fold numerical hyperexpansion of either the CD4+ or CD8+ subset while retaining their capacity for in vivo therapeutic efficacy. Murine tumor-draining lymph node (TDLN cells were segregated to purify the CD62Llow subset, or the CD4+ subset thereof. Cells were then propagated through multiple cycles of anti-CD3 activation with IL-2 + IL-7 for the CD8+ subset, or IL-7 + IL-23 for the CD4+ subset. A broad repertoire of TCR Vβ families was maintained throughout hyperexpansion, which was similar to the starting population. Adoptive transfer of hyper-expanded CD8+ T cells eliminated established pulmonary metastases, in an immunologically specific fashion without the requirement for adjunct IL-2. Hyper-expanded CD4+ T cells cured established tumors in intracranial or subcutaneous sites that were not susceptible to CD8+ T cells alone. Because accessibility and antigen presentation within metastases varies according to anatomic site, maintenance of a broad repertoire of both CD4+ and CD8+ T effector cells will augment the overall systemic efficacy of adoptive immunotherapy.

  15. Improving the clinical impact of biomaterials in cancer immunotherapy.

    Science.gov (United States)

    Gammon, Joshua M; Dold, Neil M; Jewell, Christopher M

    2016-03-29

    Immunotherapies for cancer have progressed enormously over the past few decades, and hold great promise for the future. The successes of these therapies, with some patients showing durable and complete remission, demonstrate the power of harnessing the immune system to eradicate tumors. However, the effectiveness of current immunotherapies is limited by hurdles ranging from immunosuppressive strategies employed by tumors, to inadequate specificity of existing therapies, to heterogeneity of disease. Further, the vast majority of approved immunotherapies employ systemic delivery of immunomodulators or cells that make addressing some of these challenges more difficult. Natural and synthetic biomaterials - such as biocompatible polymers, self-assembled lipid particles, and implantable biodegradable devices - offer unique potential to address these hurdles by harnessing the benefits of therapeutic targeting, tissue engineering, co-delivery, controlled release, and sensing. However, despite the enormous investment in new materials and nanotechnology, translation of these ideas to the clinic is still an uncommon outcome. Here we review the major challenges facing immunotherapies and discuss how the newest biomaterials and nanotechnologies could help overcome these challenges to create new clinical options for patients.

  16. Seasonal versus perennial immunotherapy: evaluation after three years of treatment.

    Science.gov (United States)

    Muñoz Lejarazu, D; Bernaola, G; Fernández, E; Audícana, M; Ventas, P; Martín, S; Fernández de Corres, L

    1993-01-01

    We have performed a comparative study to evaluate seasonal and perennial schedules after 3 years of immunotherapy. Sixty patients suffering from rhinitis and/or asthma due to grass pollen sensitization were randomly allocated to receive a semi-depot extract of Phleum pratense according to a perennial or seasonal schedule. The last year of the study, 14 patients were recruited as a control group without immunotherapy. The cumulative dose was 602 BU in the perennial group and 372 BU in the seasonal group. The frequency and severity of side-effects were similar and very low in both treated groups. The IgE level was significantly lower after perennial immunotherapy at the end of the first 2 years. A seasonal decrease in specific IgG levels was observed in patients who interrupted immunotherapy, while this was not observed in patients under the perennial schedule. Symptoms and medication scores did not show differences between groups. Nevertheless, we found a significant difference between treated patients and the control group.

  17. Experimental studies of tumor immunotherapy. II. Tumor immunotherapy following tumor extirpation

    Directory of Open Access Journals (Sweden)

    Hayashi,Shigeo

    1976-06-01

    Full Text Available In order to approach human cancer immunotherapy, the author carried out the immunotherapy with BCG on mice having homotransplanted cancer, observed the posttransplantation results with lapse of time, conduced daily macrophage inhibition test (MI test and found the immunotherapy to be effective. At the same time the MI test proved to be a useful criterion in determining the course of cancer progress and effectiveness of the immunotherapy.

  18. [Cancer immunotherapy by immuno-checkpoint blockade].

    Science.gov (United States)

    Kawakami, Yutaka

    2015-10-01

    As cancer immunotherapies utilizing anti-tumor T-cell responses, immuno-checkpoint blockade and adoptive T-cell immunotherapy have recently achieved durable responses even in advanced cancer patients with metastases. Administration of antibodies on the T-cell surface, CTLA-4 and PD-1 (or PD-1 ligand PD-L1), resulted in tumor regression of not only melanoma and renal cell cancer which were known to be relatively sensitive to immunotherapy, but also various malignancies including lung, bladder, ovarian, gastric, and head and neck cancers, as well as hematological malignancies such as Hodgkin and B-cell malignant lymphomas. These findings have changed the status of immunotherapy in the development of cancer treatments. Currently, development of combinations employing cancer immunotherapy with immuno-checkpoint blockade, as well as personalized cancer immunotherapy based on the evaluation of pretreatment immune status, are in progress.

  19. Intraperitoneal alpha-radioimmunotherapy in mice using different specific activities

    DEFF Research Database (Denmark)

    Elgqvist, Jörgen; Andersson, Håkan; Haglund, Elin;

    2009-01-01

    The aim of this study was to investigate the therapeutic efficacy of the alpha-radioimmunotherapy of ovarian cancer in mice, using different specific activities. This study was performed by using the monoclonal antibody, MX35 F(ab')(2), labeled with the alpha-particle-emitter, 211At.......The aim of this study was to investigate the therapeutic efficacy of the alpha-radioimmunotherapy of ovarian cancer in mice, using different specific activities. This study was performed by using the monoclonal antibody, MX35 F(ab')(2), labeled with the alpha-particle-emitter, 211At....

  20. High efficiency cell-specific targeting of cytokine activity

    Science.gov (United States)

    Garcin, Geneviève; Paul, Franciane; Staufenbiel, Markus; Bordat, Yann; van der Heyden, José; Wilmes, Stephan; Cartron, Guillaume; Apparailly, Florence; de Koker, Stefaan; Piehler, Jacob; Tavernier, Jan; Uzé, Gilles

    2014-01-01

    Systemic toxicity currently prevents exploiting the huge potential of many cytokines for medical applications. Here we present a novel strategy to engineer immunocytokines with very high targeting efficacies. The method lies in the use of mutants of toxic cytokines that markedly reduce their receptor-binding affinities, and that are thus rendered essentially inactive. Upon fusion to nanobodies specifically binding to marker proteins, activity of these cytokines is selectively restored for cell populations expressing this marker. This ‘activity-by-targeting’ concept was validated for type I interferons and leptin. In the case of interferon, activity can be directed to target cells in vitro and to selected cell populations in mice, with up to 1,000-fold increased specific activity. This targeting strategy holds promise to revitalize the clinical potential of many cytokines.

  1. Lentiviral vectors in cancer immunotherapy.

    Science.gov (United States)

    Oldham, Robyn Aa; Berinstein, Elliot M; Medin, Jeffrey A

    2015-01-01

    Basic science advances in cancer immunotherapy have resulted in various treatments that have recently shown success in the clinic. Many of these therapies require the insertion of genes into cells to directly kill them or to redirect the host's cells to induce potent immune responses. Other analogous therapies work by modifying effector cells for improved targeting and enhanced killing of tumor cells. Initial studies done using γ-retroviruses were promising, but safety concerns centered on the potential for insertional mutagenesis have highlighted the desire to develop other options for gene delivery. Lentiviral vectors (LVs) have been identified as potentially more effective and safer alternative delivery vehicles. LVs are now in use in clinical trials for many different types of inherited and acquired disorders, including cancer. This review will discuss current knowledge of LVs and the applications of this viral vector-based delivery vehicle to cancer immunotherapy.

  2. Cancer immunotherapy: the beginning of the end of cancer?

    Science.gov (United States)

    Farkona, Sofia; Diamandis, Eleftherios P; Blasutig, Ivan M

    2016-05-05

    These are exciting times for cancer immunotherapy. After many years of disappointing results, the tide has finally changed and immunotherapy has become a clinically validated treatment for many cancers. Immunotherapeutic strategies include cancer vaccines, oncolytic viruses, adoptive transfer of ex vivo activated T and natural killer cells, and administration of antibodies or recombinant proteins that either costimulate cells or block the so-called immune checkpoint pathways. The recent success of several immunotherapeutic regimes, such as monoclonal antibody blocking of cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD1), has boosted the development of this treatment modality, with the consequence that new therapeutic targets and schemes which combine various immunological agents are now being described at a breathtaking pace. In this review, we outline some of the main strategies in cancer immunotherapy (cancer vaccines, adoptive cellular immunotherapy, immune checkpoint blockade, and oncolytic viruses) and discuss the progress in the synergistic design of immune-targeting combination therapies.

  3. Melanoma immunotherapy: dendritic cell vaccines

    OpenAIRE

    Lozada-Requena, Ivan; Laboratorios de Inmunología #108, Laboratorio de investigación y Desarrollo, Facultad de Ciencieas y Filosofía, Universidad Cayetano Heredia. Lima, Perú Empresa de Investigación y Desarrollo en Cáncer (EMINDES) SAC. Lima, Perú.; Núñez, César; Empresa de Investigación y Desarrollo en Cáncer (EMINDES) SAC. Lima, Perú.; Aguilar, José Luis; Laboratorios de Inmunología #108, Laboratorio de investigación y Desarrollo, Facultad de Ciencieas y Filosofía, Universidad Cayetano Heredia. Lima, Perú.

    2015-01-01

    This is a narrative review that shows accessible information to the scientific community about melanoma and immunotherapy.Dendritic cells have the ability to participate in innate and adaptive immunity, but are not unfamiliar to the immune evasion oftumors. Knowing the biology and role has led to generate in vitro several prospects of autologous cell vaccines against diversetypes of cancer in humans and animal models. However, given the low efficiency they have shown, we must implementstrateg...

  4. Immunotherapy for metastatic colorectal cancer

    DEFF Research Database (Denmark)

    Ellebaek, Eva; Andersen, Mads Hald; Svane, Inge Marie

    2012-01-01

    and presents the most interesting strategies investigated so far: cancer vaccination including antigen-defined vaccination and dendritic cell vaccination, chemo-immunotherapy, and adoptive cell transfer. Future treatment options as well as the possibility of combining existing therapies will be discussed along......Although no immunotherapeutic treatment is approved for colorectal cancer (CRC) patients, promising results from clinical trials suggest that several immunotherapeutic strategies may prove efficacious and applicable to this group of patients. This review describes the immunogenicity of CRC...

  5. Novel Approaches and Perspectives in Allergen Immunotherapy

    DEFF Research Database (Denmark)

    Hoffmann, Hans Jürgen; Valovirta, Erkka; Pfaar, Oliver;

    2017-01-01

    In this review we report on relevant current topics in allergen immunotherapy (AIT) which were broadly discussed during the 1(st) Aarhus Immunotherapy Symposium (Aarhus, Denmark) in December, 2015 by leading clinicians, scientists and industry representatives in the field. The aim of this symposium...... have substantiated proof of effectiveness of this disease-modifying therapeutic option. Novel treatments like peptide immunotherapy, intralymphatic immunotherapy and use of recombinant allergens herald a new age in which AIT may address treatment of allergy as a public health issue by reaching a large...

  6. Liver-specific activities of FGF19 require Klotho beta.

    Science.gov (United States)

    Lin, Benjamin C; Wang, Manping; Blackmore, Craig; Desnoyers, Luc R

    2007-09-14

    Hepatocyte function is regulated by members of the fibroblast growth factor (FGF) family of proteins, but little is known about the specific molecular mechanisms of this endocrine pathway. FGF19 regulates bile acid homeostasis and gall bladder filling; FGF19 binds only to FGF receptor 4 (FGFR4), but its liver-specific activity cannot be explained solely by the distribution of this receptor. Although it has been suggested that Klotho beta (KLB) may have a role in mediating FGF19 activity, we have provided for the first time definitive evidence that KLB is required for FGF19 binding to FGFR4, intracellular signaling, and downstream modulation of gene expression. We have shown that FGFR4 is widely distributed in mouse, whereas KLB distribution is more restricted. Liver was the only organ in which both genes were abundantly expressed. We show that in mice, FGF19 injection triggers liver-specific induction of c-Fos and repression of CYP7A1. The tissue-specific activity of FGF19 supports the unique intersection of KLB and FGFR4 distribution in liver. These studies define KLB as a novel FGFR4 coreceptor required for FGF19 liver specific functions.

  7. Immunotherapy for B-cell lymphoma: current status and prospective advances

    Directory of Open Access Journals (Sweden)

    Nurit eHollander

    2012-01-01

    Full Text Available Therapy for non-Hodgkin's lymphoma has progressed significantly over the last decades. However, the majority of patients remain incurable, and novel therapies are needed. Because immunotherapy ideally offers target selectivity, an ever increasing number of immunotherapies, both passive and active, are undergoing development. The champion of passive immunotherapy to date is the anti-CD20 monoclonal antibody rituximab that revolutionized the standard of care for lymphoma. The great success of rituximab catalyzed the development of new passive immunotherapy strategies that are currently undergoing clinical evaluation. These include improvement of rituximab efficacy, newer generation anti-CD20 antibodies, drug-conjugated and radiolabelled anti-CD20 antibodies, monoclonal antibodies targeting non-CD20 lymphoma antigens, and bispecific antibodies. Active immunotherapy aims at inducing long-lasting antitumor immunity, thereby limiting the likelihood of relapse. Current clinical studies of active immunotherapy for lymphoma consist largely of vaccination and immune checkpoint blockade. A variety of protein- and cell-based vaccines are being tested in ongoing clinical studies. Recently completed phase III clinical trials of an idiotype protein vaccine suggest that the vaccine may have clinical activity in a subset of patients. Efforts to enhance the efficacy of active immunotherapy are ongoing with an emphasis on optimization of antigen delivery and presentation of vaccines and modulation of the immune system toward counteracting immunosuppression, using antibodies against immune regulatory checkpoints. This article discusses results of the various immunotherapy approaches applied to date for B-cell lymphoma and the ongoing trials to improve their effect.

  8. 40 CFR 60.759 - Specifications for active collection systems.

    Science.gov (United States)

    2010-07-01

    ..., fiberglass, stainless steel, or other nonporous corrosion resistant material of suitable dimensions to... 40 Protection of Environment 6 2010-07-01 2010-07-01 false Specifications for active collection systems. 60.759 Section 60.759 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED)...

  9. Specific Activity and Impurities in Irradiated Natural Nickel Target

    Institute of Scientific and Technical Information of China (English)

    2011-01-01

    In this paper, the specific activity of the 63Ni which is produced by irradiating natural nickel in a nuclear reactor is calculated. And in the 1 g irradiated natural nickel target, the species of the key impurity nuclides were analyzed,

  10. Unconscious Semantic Activation Depends on Feature-Specific Attention Allocation

    Science.gov (United States)

    Spruyt, Adriaan; De Houwer, Jan; Everaert, Tom; Hermans, Dirk

    2012-01-01

    We examined whether semantic activation by subliminally presented stimuli is dependent upon the extent to which participants assign attention to specific semantic stimulus features and stimulus dimensions. Participants pronounced visible target words that were preceded by briefly presented, masked prime words. Both affective and non-affective…

  11. Eradication of intractable malignant ascites by abdominocentesis, reinfusion of concentrated ascites, and adoptive immunotherapy with dendritic cells and activated killer cells in a patient with recurrent lung cancer: a case report

    Directory of Open Access Journals (Sweden)

    Kimura Hideki

    2008-12-01

    Full Text Available Abstract Introduction Malignant ascites is often a sign of a terminal stage in several malignant diseases. To control ascites, drainage and intra-abdominal chemotherapy are often used in those patients but eradication of ascites is difficult and prognosis is poor. Case presentation A 55-year-old woman was admitted to our hospital on 26 January 2007 with dyspnea, abdominal distention and oliguria. Abdominocentesis revealed peritoneal carcinomatosis resulting from abdominal recurrence from lung cancer. To alleviate the dyspnea and abdominal distention, we drained the ascites aseptically and infused them intravenously back into the patient after removal of tumor cells by centrifugation, and then concentration by apheresis. After the drainage of ascites, we intraperitoneally infused activated killer cells and dendritic cells from the patient's tumor-draining lymph nodes, together with 4.5 × 105U interleukin-2 in 50 ml saline by 2.1 ml/hour infuser balloon. Drastic decreases in the tumor cell count and in ascite retention were observed after several courses of ascites drainage, intravenous infusion and intraperitoneal immunotherapy. The plasma protein level was maintained during the treatment notwithstanding the repeated drainage of ascites. Cell surface marker analysis, cytotoxic activities against autologous tumor cells and interferon-gamma examination of ascites suggested the possibility that these effects were mediated by immunological responses of activated killer cells and dendritic cells infused intraperitoneally. Conclusion Combination of local administration of immune cells and infusion of concentrated cell free ascites may be applicable for patients afflicted with refractory ascites.

  12. Targeting tumor-associated immune suppression with selective protein kinase A type I (PKAI) inhibitors may enhance cancer immunotherapy.

    Science.gov (United States)

    Hussain, Muzammal; Shah, Zahir; Abbas, Nasir; Javeed, Aqeel; Mukhtar, Muhammad Mahmood; Zhang, Jiancun

    2016-01-01

    Despite the tremendous progress in last few years, the cancer immunotherapy has not yet improved disease-free because of the tumor-associated immune suppression being a major barrier. Novel trends to enhance cancer immunotherapy aims at harnessing the therapeutic manipulation of signaling pathways mediating the tumor-associated immune suppression, with the general aims of: (a) reversing the tumor immune suppression; (b) enhancing the innate and adaptive components of anti-tumor immunosurveillance, and (c) protecting immune cells from the suppressive effects of T regulatory cells (Tregs) and the tumor-derived immunoinhibitory mediators. A particular striking example in this context is the cyclic adenosine monophosphate (cAMP)-dependent protein kinase A type I (PKAI) pathway. Oncogenic cAMP/PKAI signaling has long been implicated in the initiation and progression of several human cancers. Emerging data indicate that cAMP/PKAI signaling also contributes to tumor- and Tregs-derived suppression of innate and adaptive arms of anti-tumor immunosurveillance. Therapeutically, selective PKAI inhibitors have been developed which have shown promising anti-cancer activity in pre-clinical and clinical settings. Rp-8-Br-cAMPS is a selective PKAI antagonist that is widely used as a biochemical tool in signal transduction research. Collateral data indicate that Rp-8-Br-cAMPS has shown immune-rescuing potential in terms of enhancing the innate and adaptive anti-tumor immunity, as well as protecting adaptive T cells from the suppressive effects of Tregs. Therefore, this proposal specifically implicates that combining selective PKAI antagonists/inhibitors with cancer immunotherapy may have multifaceted benefits, such as rescuing the endogenous anti-tumor immunity, enhancing the efficacy of cancer immunotherapy, and direct anti-cancer effects.

  13. PROFILIN ACTIVATES BACILLUS THURINGIENSIS PHOSPHOINOSITIDE SPECIFIC PHOSPHOLIPASE C

    Directory of Open Access Journals (Sweden)

    Sandeepta Burgula

    2012-08-01

    Full Text Available Many extracellular signaling molecules including hormones, growth factors, neurotransmitters andimmunoglobulins elicit intracellular responses by activating phosphatidylinositol-specific phospholipase C (PI-PLCupon binding to their cell surface receptors. Activated PLC catalyses the hydrolysis of Phosphotidylinositol 4,5-bisphosphate (PIP2 to generate DAG and IP3 , which act as signaling molecules that control various cellular processes.Exploring the mechanism of regulation of PLC activity may lead to understanding various signaling events thatregulate cell growth and differentiation. One of the dramatic effects of profilin is inhibition of PIP2 hydrolysis by PLC-γ in eukaryotic cells. In the present study, the effect of profilin on Phosphotidylinositol specific phospholipase C (PI-PLC purified from Bacillus thuringiensis (Bt was examined. Assay of PI-PLC activity indicated that Bovine profilinactivated the hydrolysis of phosphotidylinositol (PI by BtPI-PLC in a concentration dependent manner under in vitroconditions. A 250 % increase in activity was noted in the presence of profilin but not in presence of phosphoprofilin. Inthe presence of profilin more proteins are observed in the soluble fraction. In conclusion it can be stated that thatprofilin activates bacterial PLC activity towards PI hydrolysis

  14. 主动免疫治疗加用地屈孕酮治疗复发性流产的临床观察%Clinical Observation on Curative Effect of Active Immunotherapy Combined with Dydrogesterone on Recurrent Spontaneous Abortion

    Institute of Scientific and Technical Information of China (English)

    张娟; 方小玲; 贺艳坤; 谭小军; 黄向红

    2012-01-01

    Objective To explore the clinical efficacy of lymphocytes active immunotherapy combined with dydrogesterone on treating recurrent spontaneous abortion. Methods Seventy patients with recurrent spontaneous abortion were randomly divided into two groups (each n= 35). The patients in observation group were given active immunotherapy combined with dydrogesterone, while the patients in control group received dydrogesterone. Serum E2, P, and HCG levels of the patients of two groups were detected to evaluate the treatment outcomes. The pregnancy results were recorded and then analyzed statistically. Results There was no statistically significant difference in age, pregnancies, parity, and spontaneous abortion time between the two groups (P >0.05). And no statistically significant difference was found in serum E2, P, and HCG levels before 8 weeks or between 8 to 12 weeks (P>0.05). Among 35 patients of observation group, 34 (97.1%) succeeded in giving full - term birth. Among 35 patients of control group, 27 (77.1 % ) succeeded in giving full - term birth. There were statistically significant differences between the two groups (P<0.05). Conclusions Lymphocytes active immunotherapy combined with dydrogesterone can significantly improve the ongoing pregnancy rate in patients with recurrent spontaneous abortion.%目的 探讨淋巴细胞主动免疫治疗加用地屈孕酮治疗复发性流产的临床疗效观察.方法 2008年3月-2011年3年将70例有复发性流产患者被随机分为两组,35名要求接受淋巴细胞主动免疫治疗和地屈孕酮的患者为观察组,35名接受地屈孕酮的患者为对照组;检测两组患者血清E2、P和HCG水平,以评估治疗结果,记录妊娠结果进行统计学分析.结果 两组在年龄、孕次、产次、前次自然流产时间方面差异无统计学意义(P>0.05);两组在血清E2、P和HCG的水平在8周前及8~12周差异均无统计学意义(P>0.05).妊娠情况:淋巴细胞主

  15. Peptide immunotherapy for childhood allergy - addressing translational challenges

    Directory of Open Access Journals (Sweden)

    Mackenzie Karen J

    2011-11-01

    Full Text Available Abstract Allergic sensitisation usually begins early in life. The number of allergens a patient is sensitised to can increase over time and the development of additional allergic conditions is increasingly recognised. Targeting allergic disease in childhood is thus likely to be the most efficacious means of reducing the overall burden of allergic disease. Specific immunotherapy involves administering protein allergen to tolerise allergen reactive CD4+ T cells, thought key in driving allergic responses. Yet specific immunotherapy risks allergic reactions including anaphylaxis as a consequence of preformed allergen-specific IgE antibodies binding to the protein, subsequent cross-linking and mast cell degranulation. CD4+ T cells direct their responses to short "immunodominant" peptides within the allergen. Such peptides can be given therapeutically to induce T cell tolerance without facilitating IgE cross-linking. Peptide immunotherapy (PIT offers attractive treatment potential for allergic disease. However, PIT has not yet been shown to be effective in children. This review discusses the immunological mechanisms implicated in PIT and briefly covers outcomes from adult PIT trials. This provides a context for discussion of the challenges for the application of PIT, both generally and more specifically in relation to children.

  16. FAST: towards safe and effective subcutaneous immunotherapy of persistent life-threatening food allergies.

    Science.gov (United States)

    Zuidmeer-Jongejan, Laurian; Fernandez-Rivas, Montserrat; Poulsen, Lars K; Neubauer, Angela; Asturias, Juan; Blom, Lars; Boye, Joyce; Bindslev-Jensen, Carsten; Clausen, Michael; Ferrara, Rosa; Garosi, Paula; Huber, Hans; Jensen, Bettina M; Koppelman, Stef; Kowalski, Marek L; Lewandowska-Polak, Anna; Linhart, Birgit; Maillere, Bernard; Mari, Adriano; Martinez, Alberto; Mills, Clare En; Nicoletti, Claudio; Opstelten, Dirk-Jan; Papadopoulos, Nikos G; Portoles, Antonio; Rigby, Neil; Scala, Enrico; Schnoor, Heidi J; Sigurdardottir, Sigurveig T; Stavroulakis, George; Stolz, Frank; Swoboda, Ines; Valenta, Rudolf; van den Hout, Rob; Versteeg, Serge A; Witten, Marianne; van Ree, Ronald

    2012-03-09

    The FAST project (Food Allergy Specific Immunotherapy) aims at the development of safe and effective treatment of food allergies, targeting prevalent, persistent and severe allergy to fish and peach. Classical allergen-specific immunotherapy (SIT), using subcutaneous injections with aqueous food extracts may be effective but has proven to be accompanied by too many anaphylactic side-effects. FAST aims to develop a safe alternative by replacing food extracts with hypoallergenic recombinant major allergens as the active ingredients of SIT. Both severe fish and peach allergy are caused by a single major allergen, parvalbumin (Cyp c 1) and lipid transfer protein (Pru p 3), respectively. Two approaches are being evaluated for achieving hypoallergenicity, i.e. site-directed mutagenesis and chemical modification. The most promising hypoallergens will be produced under GMP conditions. After pre-clinical testing (toxicology testing and efficacy in mouse models), SCIT with alum-absorbed hypoallergens will be evaluated in phase I/IIa and IIb randomized double-blind placebo-controlled (DBPC) clinical trials, with the DBPC food challenge as primary read-out. To understand the underlying immune mechanisms in depth serological and cellular immune analyses will be performed, allowing identification of novel biomarkers for monitoring treatment efficacy. FAST aims at improving the quality of life of food allergic patients by providing a safe and effective treatment that will significantly lower their threshold for fish or peach intake, thereby decreasing their anxiety and dependence on rescue medication.

  17. FAST: towards safe and effective subcutaneous immunotherapy of persistent life-threatening food allergies

    Science.gov (United States)

    2012-01-01

    The FAST project (Food Allergy Specific Immunotherapy) aims at the development of safe and effective treatment of food allergies, targeting prevalent, persistent and severe allergy to fish and peach. Classical allergen-specific immunotherapy (SIT), using subcutaneous injections with aqueous food extracts may be effective but has proven to be accompanied by too many anaphylactic side-effects. FAST aims to develop a safe alternative by replacing food extracts with hypoallergenic recombinant major allergens as the active ingredients of SIT. Both severe fish and peach allergy are caused by a single major allergen, parvalbumin (Cyp c 1) and lipid transfer protein (Pru p 3), respectively. Two approaches are being evaluated for achieving hypoallergenicity, i.e. site-directed mutagenesis and chemical modification. The most promising hypoallergens will be produced under GMP conditions. After pre-clinical testing (toxicology testing and efficacy in mouse models), SCIT with alum-absorbed hypoallergens will be evaluated in phase I/IIa and IIb randomized double-blind placebo-controlled (DBPC) clinical trials, with the DBPC food challenge as primary read-out. To understand the underlying immune mechanisms in depth serological and cellular immune analyses will be performed, allowing identification of novel biomarkers for monitoring treatment efficacy. FAST aims at improving the quality of life of food allergic patients by providing a safe and effective treatment that will significantly lower their threshold for fish or peach intake, thereby decreasing their anxiety and dependence on rescue medication. PMID:22409908

  18. FAST: towards safe and effective subcutaneous immunotherapy of persistent life-threatening food allergies

    Directory of Open Access Journals (Sweden)

    Zuidmeer-Jongejan Laurian

    2012-03-01

    Full Text Available Abstract The FAST project (Food Allergy Specific Immunotherapy aims at the development of safe and effective treatment of food allergies, targeting prevalent, persistent and severe allergy to fish and peach. Classical allergen-specific immunotherapy (SIT, using subcutaneous injections with aqueous food extracts may be effective but has proven to be accompanied by too many anaphylactic side-effects. FAST aims to develop a safe alternative by replacing food extracts with hypoallergenic recombinant major allergens as the active ingredients of SIT. Both severe fish and peach allergy are caused by a single major allergen, parvalbumin (Cyp c 1 and lipid transfer protein (Pru p 3, respectively. Two approaches are being evaluated for achieving hypoallergenicity, i.e. site-directed mutagenesis and chemical modification. The most promising hypoallergens will be produced under GMP conditions. After pre-clinical testing (toxicology testing and efficacy in mouse models, SCIT with alum-absorbed hypoallergens will be evaluated in phase I/IIa and IIb randomized double-blind placebo-controlled (DBPC clinical trials, with the DBPC food challenge as primary read-out. To understand the underlying immune mechanisms in depth serological and cellular immune analyses will be performed, allowing identification of novel biomarkers for monitoring treatment efficacy. FAST aims at improving the quality of life of food allergic patients by providing a safe and effective treatment that will significantly lower their threshold for fish or peach intake, thereby decreasing their anxiety and dependence on rescue medication.

  19. Immunology in the Clinic Review Series; focus on allergies: immunotherapy for food allergy.

    Science.gov (United States)

    Mousallem, T; Burks, A W

    2012-01-01

    There is no approved therapy for food allergy. The current standard of care is elimination of the triggering food from the diet and accessibility to epinephrine. Immunotherapy is a promising treatment approach. While desensitization to most foods seems feasible, it remains unclear if a permanent state of tolerance is achievable. The research team at Duke is pioneering immunotherapy for food allergies. Work here has evolved over time from small open-label pilot studies to larger randomized designs. Our data show that immunological changes associated with immunotherapy include reduction in mast cell reactivity, decreased basophil responses, decreased specific-immunoglobulin (Ig)E, increased IgG4 and induction of regulatory T cells. Immunotherapy has generated much excitement in the food allergy community; however, further studies are needed before it is ready for clinical use.

  20. The effect of immunotherapy with gynandropsis gynandra pollen in atopic asthma patients

    Directory of Open Access Journals (Sweden)

    Latha G

    2007-01-01

    Full Text Available Background: Immunotherapy (IT was first described by Noon and Freeman in 1911. The mechanism underlying successful immunotherapy is however not known. The protection from allergy is achieved long before IgE levels are de-creased, and they are indeed not frequently increased. Continued therapy may decrease IgE and skin reaction, although it may take years. Objective: The evaluation of effect of immunotherapy with specific pollen Gyn-andropsis gynandra. Material & Methods: Clinical subjects like skin test response, symptoms score, drugs intake and total sIgE levels were studied in sixty patients. Results: Both immediate and delayed skin test responses were highly significant. The intensity of symptoms score and medication was reduced and total sIgE levels were inconsistent after the course of IT. Conclusion: The decrease in clinical subjects may be attributed to the beneficial effect of immunotherapy with Gynandropsis gynandra.

  1. Induction of Eosinophilic Esophagitis by Sublingual Pollen Immunotherapy

    Directory of Open Access Journals (Sweden)

    Stephan Miehlke

    2013-09-01

    Full Text Available Sublingual immunotherapy (SLIT is increasingly investigated and utilized for the treatment of food and pollen allergies. Previous case reports suggested that eosinophilic esophagitis (EoE might develop as a long-term complication in children after completion of oral immunotherapy. Here, we describe a 44-year-old female with a medical history of pollinosis who for the first time in her life developed complete manifestation of EoE (peak eosinophils 164/high power field 4 weeks after initiation of SLIT using specific soluble allergens (hazelnut, birch, alder according to previous specific serum IgE testing. After discontinuation of SLIT, EoE resolved completely within 4 weeks without any other medical intervention. During a follow-up of 12 months the patient remained free of any esophageal symptoms. This is the first case report demonstrating a close and therefore likely causative association between pollen SLIT and EoE in an adult patient.

  2. Dual Roles of IL-27 in Cancer Biology and Immunotherapy

    Science.gov (United States)

    Fabbi, Marina; Carbotti, Grazia

    2017-01-01

    IL-27 is a pleiotropic two-chain cytokine, composed of EBI3 and IL-27p28 subunits, which is structurally related to both IL-12 and IL-6 cytokine families. IL-27 acts through a heterodimer receptor consisting of IL-27Rα (WSX1) and gp130 chains, which mediate signaling predominantly through STAT1 and STAT3. IL-27 was initially reported as an immune-enhancing cytokine that supports CD4+ T cell proliferation, T helper (Th)1 cell differentiation, and IFN-γ production, acting in concert with IL-12. However, subsequent studies demonstrated that IL-27 displays complex immune-regulatory functions, which may result in either proinflammatory or anti-inflammatory effects in relationship to the biological context and experimental models considered. Several pieces of evidence, obtained in preclinical tumor models, indicated that IL-27 has a potent antitumor activity, related not only to the induction of tumor-specific Th1 and cytotoxic T lymphocyte (CTL) responses but also to direct inhibitory effects on tumor cell proliferation, survival, invasiveness, and angiogenic potential. Nonetheless, given its immune-regulatory functions, the effects of IL-27 on cancer may be dual and protumor effects may also occur. Here, we will summarize IL-27 biological activities and its functional overlaps with the IFNs and discuss its dual role in tumors in the light of potential applications to cancer immunotherapy. PMID:28255204

  3. Functional Specificity of the Visual Word Form Area: General Activation for Words and Symbols but Specific Network Activation for Words

    Science.gov (United States)

    Reinke, Karen; Fernandes, Myra; Schwindt, Graeme; O'Craven, Kathleen; Grady, Cheryl L.

    2008-01-01

    The functional specificity of the brain region known as the Visual Word Form Area (VWFA) was examined using fMRI. We explored whether this area serves a general role in processing symbolic stimuli, rather than being selective for the processing of words. Brain activity was measured during a visual 1-back task to English words, meaningful symbols…

  4. Cancer immunotherapy: a future paradigm shift in the treatment of non-small cell lung cancer.

    Science.gov (United States)

    Anagnostou, Valsamo K; Brahmer, Julie R

    2015-03-01

    Emerging evidence on the role of the antitumor activity of the immune system has generated great interest in immunotherapy even for tumors that were historically considered as nonimmunogenic. Immunotherapy is emerging as a major modality in non-small cell lung cancer (NSCLC) treatment focusing on vaccine approaches to elicit specific immune responses and development of inhibitors of the molecular mediators of cancer-induced immunosuppression (immune checkpoints) to boost antitumor immune responses. Amplification of the host response against evolving tumors through vaccination is being investigated in ongoing clinical trials with tumor cell vaccines; however, the clinical efficacy of these agents has been limited. Blocking inhibitory pathways such as the CTL antigen 4 (CTLA-4) and programmed cell death 1 (PD-1) checkpoint pathways with mAbs has generated antitumor immune responses that are transforming cancer therapeutics. PD-1 and programmed cell death ligand 1 (PD-L1) antibodies have shown durable responses in NSCLC, with a favorable safety profile and manageable side effects. The activity of immune checkpoint inhibitors is currently been assessed in treatment-naïve patients with PD-L1-positive advanced NSCLC. Combinatorial approaches with other immune checkpoint inhibitors, chemotherapy, or targeted agents are being explored in ongoing clinical trials, and may improve outcome in NSCLC.

  5. Immuno-pharmacodynamics for evaluating mechanism of action and developing immunotherapy combinations.

    Science.gov (United States)

    Parchment, Ralph E; Voth, Andrea Regier; Doroshow, James H; Berzofsky, Jay A

    2016-08-01

    Immunotherapy has become a major modality of cancer treatment, with multiple new classes of immunotherapeutics recently entering the clinic and obtaining market approval from regulatory agencies. While the promise of these therapies is great, so is the number of possible combinations not only with each other but also with small molecule therapeutics. Furthermore, the observation of unusual dose-response relationships suggests a critical dependency of drug effectiveness on the dosage regimen (dose and schedule). Clinical pharmacodynamic (PD) biomarkers will be useful endpoints for confirming drug mechanism of action, evaluating combination therapies for synergy or antagonism, and identifying optimal dosage regimens. In contrast to conventional PD in which drug action occurs entirely within a single target cell (ie, is self-contained within the malignant cell), immunotherapy involves a complex mechanism of action with sequential steps that propagate through multiple cell types, both normal and malignant. Its intercellular pharmacology begins with molecular target engagement either on an immune effector cell or a malignant cell, followed by stimulatory biochemical and biological signals in immune effector cells, and then finally ends with activation of cell death mechanisms in malignant cells lying within a certain distance from the activated effector cells (immune cell-tumor cell proximity). Evaluating such "trans-cellular pharmacology," in which different steps of drug action are distributed across multiple cell types, requires novel microscopy and image analysis tools capable of quantifying PD-biomarker responses, mapping the responses onto the cellular geography of the tumor using phenotypic biomarkers to identify specific cell types, and finally analyzing the spatial relationships between biomarkers in the context of each cell's biological role. We have termed this form of nearest neighbor image analysis of drug action "proximity PD microscopy," to indicate the

  6. Experimental Research of 1,25(OH)2D3 and Specificity Immunotherapy Therapy on Mice With Allergic Rhinitis%活性维生素 D3与特异性脱敏疗法治疗小鼠过敏性鼻炎的实验性研究

    Institute of Scientific and Technical Information of China (English)

    李莹; 肖小军; 何韶衡; 刘志刚; 柴文戍

    2015-01-01

    疗组血清中 sIgE、sIgG2a 及脾脏细胞培养液上清液中 IL -4、INF -γ水平高于 PBS 空白对照组(P <0.05);pTSX2脱敏治疗组、活性维生素 D3治疗组 sIgE、IL -4水平低于模型组,sIgG2a、INF -γ水平高于模型组(P <0.05);活性维生素 D3治疗组 sIgE 水平高于 pTSX2脱敏治疗组,INF -γ水平低于 pTSX2脱敏治疗组(P <0.05)。鼻黏膜病理改变中,pTSX2脱敏治疗组比活性维生素 D3治疗组炎症更轻微。结论活性维生素 D3与特异性脱敏疗法治疗小鼠过敏性鼻炎均有效,两种疗法相比,症状改善虽无差异,但细胞因子水平控制方面特异性脱敏疗法效果较好,故特异性脱敏疗法疗效较活性维生素 D3疗效更佳。%Objective To investigate the differences between 1,25(OH)2 D3 and specificity immunotherapy therapy on mice with allergic rhinitis. Methods From July to December in 2014,32 SPF female BALB/ c mice were selected as research subjects. The crude extract of humulus scandens pollen was prepared,and cloned expression was made for pTSX2 protein. SDS - PAGE was used to test the protein components and pTSX2 protein activity of the crude extract of humulus scandens pollen. Using simple random sampling method,the 32 mice were divided into 4 groups:PBS blank control group,model group, pTSX2 immunotherapy group and 1,25(OH)2 D3 group. Each group had 8 mice and was administrated with different treatment methods. By the comparison of nasal symptoms,behavioral scores,airway hyperresponsiveness,serum sIgE and sIgG2a levels, IL - 4 level,IFN - γ level and the pathological changes of nasal mucosa,the differences between the two therapies were evaluated. Results The model group,the pTSX2 immunotherapy group and the 1,25(OH)2 D3 group were higher than the PBS blank control group in the scores of rhinocnesmus,sneeze,nasal secreta,behavior and total score(P < 0. 05);the pTSX2 immunotherapy group and the 1,25( OH)2 D3 group were lower than the model

  7. Rush immunotherapy in an experimental model of feline allergic asthma.

    Science.gov (United States)

    Reinero, Carol R; Byerly, Jenni R; Berghaus, Roy D; Berghaus, Londa J; Schelegle, Edward S; Hyde, Dallas M; Gershwin, Laurel J

    2006-03-15

    Specific allergen immunotherapy represents the only curative treatment of allergy. No studies have evaluated its efficacy in feline allergic asthma. We hypothesized that an abbreviated course of immunotherapy (rush immunotherapy, RIT) would blunt eosinophilic airways inflammation in experimental feline asthma induced with Bermuda grass allergen (BGA). The 6-month study included asthmatic-RIT treated cats; asthmatic-no RIT treated cats; and non-asthmatic cats. RIT involved increasing parenteral doses (20-200 microg) of BGA over 2 days. Numbers of eosinophils in bronchoalveolar lavage fluid (BALF), serum and BALF immunoglobulins, lymphocyte blastogenesis assays, and cytokines in blood and BALF were evaluated. BALF eosinophils decreased (P=0.048) only in asthmatic-RIT treated cats (baseline 1.1 x 10(6); Month 6, 2.4 x 10(5)). Serum BGA-specific IgG was higher (Peosinophilic airways inflammation in cats with experimental asthma. The mechanism of RIT may involve changes in allergen-specific immunoglobulins, induction of hyporesponsive lymphocytes, or alteration of cytokine profiles.

  8. ErbB-targeted CAR T-cell immunotherapy of cancer.

    Science.gov (United States)

    Whilding, Lynsey M; Maher, John

    2015-01-01

    Chimeric antigen receptor (CAR) based immunotherapy has been under development for the last 25 years and is now a promising new treatment modality in the field of cancer immunotherapy. The approach involves genetically engineering T cells to target malignant cells through expression of a bespoke fusion receptor that couples an HLA-independent antigen recognition domain to one or more intracellular T-cell activating modules. Multiple clinical trials are now underway in several centers to investigate CAR T-cell immunotherapy of diverse hematologic and solid tumor types. The most successful results have been achieved in the treatment of patients with B-cell malignancies, in whom several complete and durable responses have been achieved. This review focuses on the preclinical and clinical development of CAR T-cell immunotherapy of solid cancers, targeted against members of the ErbB family.

  9. Phosphoinositide isoforms determine compartment-specific ion channel activity.

    Science.gov (United States)

    Zhang, Xiaoli; Li, Xinran; Xu, Haoxing

    2012-07-10

    Phosphoinositides serve as address labels for recruiting peripheral cytoplasmic proteins to specific subcellular compartments, and as endogenous factors for modulating the activity of integral membrane proteins. Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P(2)) is a plasma-membrane (PM)-specific phosphoinositide and a positive cofactor required for the activity of most PM channels and transporters. This requirement for phosphoinositide cofactors has been proposed to prevent PM channel/transporter activity during passage through the biosynthetic/secretory and endocytic pathways. To determine whether intracellularly localized channels are similarly "inactivated" at the PM, we studied PIP(2) modulation of intracellular TRPML1 channels. TRPML1 channels are primarily localized in lysosomes, but can also be detected temporarily in the PM upon lysosomal exocytosis. By directly patch-clamping isolated lysosomes, we previously found that lysosomal, but not PM-localized, TRPML1 is active with PI(3,5)P(2), a lysosome-specific PIP(2), as the underlying positive cofactor. Here we found that "silent" PM-localized TRPML1 could be activated by depleting PI(4,5)P(2) levels and/or by adding PI(3,5)P(2) to inside-out membrane patches. Unlike PM channels, surface-expressed TRPML1 underwent a unique and characteristic run-up upon patch excision, and was potently inhibited by a low micromolar concentration of PI(4,5)P(2). Conversely, depletion of PI(4,5)P(2) by either depolarization-induced activation or chemically induced translocation of 5'-phosphatase potentiated whole-cell TRPML1 currents. PI(3,5)P(2) activation and PI(4,5)P(2) inhibition of TRPML1 were mediated by distinct basic amino acid residues in a common PIP(2)-interacting domain. Thus, PI(4,5)P(2) may serve as a negative cofactor for intracellular channels such as TRPML1. Based on these results, we propose that phosphoinositide regulation sets compartment-specific activity codes for membrane channels and transporters.

  10. Specific activation of the paralemniscal pathway during nociception.

    Science.gov (United States)

    Frangeul, Laura; Porrero, Cesar; Garcia-Amado, Maria; Maimone, Benedetta; Maniglier, Madlyne; Clascá, Francisco; Jabaudon, Denis

    2014-05-01

    Two main neuronal pathways connect facial whiskers to the somatosensory cortex in rodents: (i) the lemniscal pathway, which originates in the brainstem principal trigeminal nucleus and is relayed in the ventroposterior thalamic nucleus and (ii) the paralemniscal pathway, originating in the spinal trigeminal nucleus and relayed in the posterior thalamic nucleus. While lemniscal neurons are readily activated by whisker contacts, the contribution of paralemniscal neurons to perception is less clear. Here, we functionally investigated these pathways by manipulating input from the whisker pad in freely moving mice. We report that while lemniscal neurons readily respond to neonatal infraorbital nerve sectioning or whisker contacts in vivo, paralemniscal neurons do not detectably respond to these environmental changes. However, the paralemniscal pathway is specifically activated upon noxious stimulation of the whisker pad. These findings reveal a nociceptive function for paralemniscal neurons in vivo that may critically inform context-specific behaviour during environmental exploration.

  11. Novel strategies for ultrahigh specific activity targeted nanoparticles

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Dong

    2012-12-13

    We have developed novel strategies optimized for preparing high specific activity radiolabeled nanoparticles, targeting nuclear imaging of low abundance biomarkers. Several compounds have been labeled with F-18 and Cu-64 for radiolabeling of SCK-nanoparticles via Copper(I) catalyzed or copper-free alkyne-azide cyclolization. Novel strategies have been developed to achieve ultrahigh specific activity with administrable amount of dose for human study using copper-free chemistry. Ligands for carbonic anhydrase 12 (CA12), a low abundance extracellular biomarker for the responsiveness of breast cancer to endocrine therapie, have been labeled with F-18 and Cu-64, and one of them has been evaluated in animal models. The results of this project will lead to major improvements in the use of nanoparticles in nuclear imaging and will significantly advance their potential for detecting low abundance biomarkers of medical importance.

  12. Accelerator Production and Separations for High Specific Activity Rhenium-186

    Energy Technology Data Exchange (ETDEWEB)

    Jurisson, Silvia S. [Univ. of Missouri, Columbia, MO (United States); Wilbur, D. Scott [Univ. of Washington, Seattle, WA (United States)

    2016-04-01

    Tungsten and osmium targets were evaluated for the production of high specific activity rhenium-186. Rhenium-186 has potential applications in radiotherapy for the treatment of a variety of diseases, including targeting with monoclonal antibodies and peptides. Methods were evaluated using tungsten metal, tungsten dioxide, tungsten disulfide and osmium disulfide. Separation of the rhenium-186 produced and recycling of the enriched tungsten-186 and osmium-189 enriched targets were developed.

  13. Specific classification of financial analysis of enterprise activity

    Directory of Open Access Journals (Sweden)

    Synkevych Nadiia I.

    2014-01-01

    Full Text Available Despite the fact that one can find a big variety of classifications of types of financial analysis of enterprise activity, which differ with their approach to classification and a number of classification features and their content, in modern scientific literature, their complex comparison and analysis of existing classification have not been done. This explains urgency of this study. The article studies classification of types of financial analysis of scientists and presents own approach to this problem. By the results of analysis the article improves and builds up a specific classification of financial analysis of enterprise activity and offers classification by the following features: objects, subjects, goals of study, automation level, time period of the analytical base, scope of study, organisation system, classification features of the subject, spatial belonging, sufficiency, information sources, periodicity, criterial base, method of data selection for analysis and time direction. All types of financial analysis significantly differ with their inherent properties and parameters depending on the goals of financial analysis. The developed specific classification provides subjects of financial analysis of enterprise activity with a possibility to identify a specific type of financial analysis, which would correctly meet the set goals.

  14. Immunotherapy of BALB/c mice bearing Ehrlich ascites tumor with vitamin D-binding protein-derived macrophage activating factor.

    Science.gov (United States)

    Yamamoto, N; Naraparaju, V R

    1997-06-01

    Vitamin D3-binding protein (DBP; human DBP is known as Gc protein) is the precursor of macrophage activating factor (MAF). Treatment of mouse DBP with immobilized beta-galactosidase or treatment of human Gc protein with immobilized beta-galactosidase and sialidase generated a remarkably potent MAF, termed DBPMAF or GcMAF, respectively. The domain of Gc protein responsible for macrophage activation was cloned and enzymatically converted to the cloned MAF, designated CdMAF. In Ehrlich ascites tumor-bearing mice, tumor-specific serum alpha-N-acetylgalactosaminidase (NaGalase) activity increased linearly with time as the transplanted tumor cells grew in the peritoneal cavity. Therapeutic effects of DBPMAF, GcMAF, and CdMAF on mice bearing Ehrlich ascites tumor were assessed by survival time, the total tumor cell count in the peritoneal cavity, and serum NaGalase activity. Mice that received a single administration of DBPMAF or GcMAF (100 pg/mouse) on the same day after transplantation of tumor (1 x 10(5) cells) showed a mean survival time of 35 +/- 4 days, whereas tumor-bearing controls had a mean survival time of 16 +/- 2 days. When mice received the second DBPMAF or GcMAF administration at day 4, they survived more than 50 days. Mice that received two DBPMAF administrations, at days 4 and 8 after transplantation of 1 x 10(5) tumor cells, survived up to 32 +/- 4 days. At day 4 posttransplantation, the total tumor cell count in the peritoneal cavity was approximately 5 x 10(5) cells. Mice that received two DBPMAF administrations, at days 0 and 4 after transplantation of 5 x 10(5) tumor cells, also survived up to 32 +/- 4 days, while control mice that received the 5 x 10(5) ascites tumor cells only survived for 14 +/- 2 days. Four DBPMAF, GcMAF, or CdMAF administrations to mice transplanted with 5 x 10(5) Ehrlich ascites tumor cells with 4-day intervals showed an extended survival of at least 90 days and an insignificantly low serum NaGalase level between days 30 and 90.

  15. 特异性免疫治疗对慢性鼻窦炎伴变应性鼻炎患者鼻内镜手术效果的影响%Effect of specific immunotherapy on outcomes after endoscopic sinus surgery for chronic rhinosinusitis with allergic rhinitis

    Institute of Scientific and Technical Information of China (English)

    陈金湘; 赵青; 周宁霞

    2011-01-01

    目的 探讨特异性免疫治疗对慢性鼻窦炎(CRS)伴变应性鼻炎患者功能性内镜鼻窦手术(FESS)效果的影响.方法 将确诊为CRS伴常年性变应性鼻炎的57例患者按照尘螨过敏与否分成两组,尘螨过敏者为治疗Ⅰ组,FESS术后采用皮下免疫治疗;非尘螨过敏者为治疗Ⅱ组,单纯行FESS.分别对两组患者术前、术后6个月、术后1年的症状及体征进行评分并对比,采用鼻腔鼻窦结局测试-20 (SNOT-20)量表及Lund-Kennedy鼻内镜评分法.结果 两组患者术后6个月和1年的SNOT-20及Lund-Kennedy评分较术前均有明显改善(P<0.01),治疗Ⅰ组患者的疗效优于治疗Ⅱ组且组间差异有统计学意义(P<0.05).结论 特异性免疫治疗可改善CRS伴变应性鼻炎患者的手术效果.%Objective To investigate the effect of specific immunotherapy on outcomes after functional endoscopic sinus surgery (FESS) for chronic rhinosinusitis (CRS) with allergic rhinitis. Method Fifty-seven CRS patients accompanied with perennial allergic rhinitis were divided into two groups according to the results of allergen skin prick test. Those who were allergic to dust mites, the treatment group I, were treated with subcutaneous immunotherapy after FESS, others were treatment group II and treated with FESS merely. Before and 6, 12 months after FESS, the nasal symptoms and signs of all patients were evaluated by sino-nasal outcome test-20 (SNOT-20) and Lund-Kennedy endoscopic scores, and compared with each other. Results Compared to the scores before FESS, the SNOT-20 and Lund-Kennedy scores of two groups are significantly improved in 6 months and one year after FESS (P<0.01). Significantly better curative effects were obtained in the treatment group I when compared with the treatment group Ⅱ (F<0.05). Conclusion Specific immunotherapy may improve the surgical outcomes in CRS patients with allergic rhinitis.

  16. Immunotherapy Expands and Maintains the Function of High-Affinity Tumor-Infiltrating CD8 T Cells In Situ.

    Science.gov (United States)

    Moran, Amy E; Polesso, Fanny; Weinberg, Andrew D

    2016-09-15

    Cancer cells harbor high-affinity tumor-associated Ags capable of eliciting potent antitumor T cell responses, yet detecting these polyclonal T cells is challenging. Therefore, surrogate markers of T cell activation such as CD69, CD44, and programmed death-1 (PD-1) have been used. We report in this study that in mice, expression of activation markers including PD-1 is insufficient in the tumor microenvironment to identify tumor Ag-specific T cells. Using the Nur77GFP T cell affinity reporter mouse, we highlight that PD-1 expression can be induced independent of TCR ligation within the tumor. Given this, we characterized the utility of the Nur77GFP model system in elucidating mechanisms of action of immunotherapies independent of PD-1 expression. Coexpression of Nur77GFP and OX40 identifies a polyclonal population of high-affinity tumor-associated Ag-specific CD8(+) T cells, which produce more IFN-γ in situ than OX40 negative and doubles in quantity with anti-OX40 and anti-CTLA4 mAb therapy but not with anti-PD-1 or programmed death ligand-1. Moreover, expansion of these high-affinity CD8 T cells prolongs survival of tumor-bearing animals. Upon chronic stimulation in tumors and after adoptive cell therapy, CD8 TCR signaling and Nur77GFP induction is impaired, and tumors progress. However, this can be reversed and overall survival significantly enhanced after adoptive cell therapy with agonist OX40 immunotherapy. Therefore, we propose that OX40 agonist immunotherapy can maintain functional TCR signaling of chronically stimulated tumor-resident CD8 T cells, thereby increasing the frequency of cytotoxic, high-affinity, tumor-associated Ag-specific cells.

  17. How to design and evaluate randomized controlled trials in immunotherapy for allergic rhinitis: an ARIA-GA(2) LEN statement

    DEFF Research Database (Denmark)

    Bousquet, J; Schünemann, H J; Bousquet, P J;

    2011-01-01

    Specific immunotherapy (SIT) is one of the treatments for allergic rhinitis. However, for allergists, nonspecialists, regulators, payers, and patients, there remain gaps in understanding the evaluation of randomized controlled trials (RCTs). Although treating the same diseases, RCTs in SIT...

  18. 用抗独特型疫苗主动免疫治疗鼻咽癌病人的临床研究%A clinical trial of active immunotherapy with anti-idiotypic vaccine in nasopharyngeal carcinoma patients

    Institute of Scientific and Technical Information of China (English)

    李官成; 谢鹭; 周国华; 孙去病; 符红普; 周建华

    2002-01-01

    Objective To investigate the effect of active immunotherapy with anti-idiotypic vaccine in patients with nasopharyngeal carcinoma (NPC). Methods Anti-idiotypic antibodies (2H4/5D3) bearing the internal image of the NPC antigen were used in active immunotherapy in NPC patients receiving radiotherapy. Antibodies and cytokine levels in patient sera were determined using ELISA before and after active immunotherapy. IL-2 mRNA expression in the peripheral blood mononuclear cells (PBMC) was measured by in situ hybridization. Results Nineteen patients with NPC at stage Ⅳ were treated with alum-precipitated 2H4 or 5D3. Neither hypersensitivity nor adverse side effects were observed. The levels of anti-anti-idiotypic antibodies (Ab3) and anti-NPC antibodies (Ab1') were increased. Human anti-mouse antibodies (HAMA) were seen in 19 patients of the experimental group; the levels of Ab1' did not increse in the control group. Serum IL-2, IFN-γ and TNF-α levels were increased in most patients in the experimental group, while no differences were observed in Ab1' and cytokine levels between pre- and post-therapy in the control group. In addition, IL-2 mRNA expression in PBMCs from NPC patients was closely related to serum IL-2 (r=+0.8829) levels by in situ hybridization. Conclusions Anti-idiotype vaccine is safe for clinical active immunotherapy. Anti-idiotypic vaccine might be able to enhance humoral and/or cellular immunity in NPC patients receiving radiotherapy.%目的探讨抗独特型疫苗主动免疫治疗鼻咽癌病人的抗肿瘤效应.方法用两株具有鼻咽癌相关抗原内影像的抗独特型单克隆抗体2H4、5D3,经氢氧化铝凝胶沉淀法制备成抗独特型疫苗Alum-2H4、Alum-5D3,对19例晚期鼻咽癌放疗病人作主动免疫治疗,9例放疗加生理盐水注射为对照组.用ELISA检测治疗前后病人血清抗体和细胞因子水平.用原位Northern杂交检测外周血单个核细胞(PBMC)IL-2 mRNA的表达.结果接受Alum-2H4

  19. T Cell-Tumor Interaction Directs the Development of Immunotherapies in Head and Neck Cancer

    Directory of Open Access Journals (Sweden)

    A. E. Albers

    2010-01-01

    Full Text Available The competent immune system controls disease effectively due to induction, function, and regulation of effector lymphocytes. Immunosurveillance is exerted mostly by cytotoxic T-lymphocytes (CTLs while specific immune suppression is associated with tumor malignancy and progression. In squamous cell carcinoma of the head and neck, the presence, activity, but also suppression of tumor-specific CTL have been demonstrated. Functional CTL may exert a selection pressure on the tumor cells that consecutively escape by a combination of molecular and cellular evasion mechanisms. Certain of these mechanisms target antitumor effector cells directly or indirectly by affecting cells that regulate CTL function. This results in the dysfunction or apoptosis of lymphocytes and dysregulated lymphocyte homeostasis. Another important tumor-escape mechanism is to avoid recognition by dysregulation of antigen processing and presentation. Thus, both induction of functional CTL and susceptibility of the tumor and its microenvironment to become T cell targets should be considered in CTL-based immunotherapy.

  20. Cancer immunotherapy products: Regulatory aspects in the European Union

    OpenAIRE

    2012-01-01

    Active immunotherapy products (widely known as “cancer vaccines”) are products intended to stimulate an immune response to mediate tumor destruction or reduce the progression of disease in patients where cancer has been diagnosed. Some quality attributes of these products are very difficult to characterize or present a high variability (especially if they are for autologous use), further complicating the interpretation of some of the clinical data. Furthermore, questions arise in the evaluati...

  1. Assessing T-cell responses in anticancer immunotherapy

    Science.gov (United States)

    Escors, David; Liechtenstein, Therese; Perez-Janices, Noemi; Schwarze, Julia; Dufait, Ines; Goyvaerts, Cleo; Lanna, Alessio; Arce, Frederick; Blanco-Luquin, Idoia; Kochan, Grazyna; Guerrero-Setas, David; Breckpot, Karine

    2013-01-01

    Since dendritic cells operate as professional antigen-presenting cells (APCs) and hence are capable of jumpstarting the immune system, they have been exploited to develop a variety of immunotherapeutic regimens against cancer. In the few past years, myeloid-derived suppressor cells (MDSCs) have been shown to mediate robust immunosuppressive functions, thereby inhibiting tumor-targeting immune responses. Thus, we propose that the immunomodulatory activity of MDSCs should be carefully considered for the development of efficient anticancer immunotherapies. PMID:24244902

  2. Immunotherapies for Targeting Ancient Retrovirus during Breast Cancer

    Science.gov (United States)

    2014-03-01

    nature of virus activity in the cancer cell and its involvement in cancer prognosis. Melanoma forms 80% of all skin cancer and about 10% of all... CDK4 pathways in melanoma cells. Cancer investigation 28, 1031-1037 (2010). 7.Hahn, S., et al. Serological response to human endogenous retrovirus K...Award Number: W81XWH-11-1-0002 TITLE: Immunotherapies for Targeting Ancient Retrovirus during Breast Cancer

  3. Effects of surgery, immunization, and laser immunotherapy on a non-immunogenic metastic tumor model

    Science.gov (United States)

    Chen, Wei R.; Huang, Zheng; Andrienko, Kirill; Stefanov, Stefan; Wolf, Roman F.; Liu, Hong

    2006-08-01

    Traditional local cancer treatment modalities include surgery and radiation, which has the immediate tumor response due to tumor removal or radiation induced cell death. However, such therapeutic approaches usually do not result in eradiation of tumors, particularly when treating metastatic tumors. In fact, local treatment of primary tumors may stimulate the growth and spread of remote metastasis. Commonly used systemic therapies include chemotherapy and immunotherapy, which target the dividing cells or the immune systems. However, in addition to the severe side effects, chemotherapy often suppresses the immune systems, hence lessening the host's ability to fight the disease. Immunotherapy, on the other hand, aims at educating and stimulating immune systems using either general immune enhancements or antigen-oriented specific immune stimulation. However, so far, the traditional immunotherapy has yielded only limited success in treating cancer patients. A different approach is needed. To combine the advantages of both local therapies for acute and targeted treatment responses and the systemic therapies for stimulation of the immune systems, laser immunotherapy was proposed to use selective photothermal therapy as the local treatment modality and the adjuvant-assisted immunotherapy for systemic control. Laser immunotherapy has show positive results in treating metastatic tumors. In this study, we conducted a comparative study using surgery, freeze-thaw immunization and laser immunotherapy in the treatment of metastatic rat mammary tumors. Our results showed that removal of the primary tumors was unsuccessful at changing the course of tumor progression. The tumor cell lysate immunization delayed the emergence of metastases but did not provide immunity against the tumor challenge. Laser immunotherapy, on the other hand, resulted in regression and eradication.

  4. [Specific risks of physical activity in the elderly].

    Science.gov (United States)

    Paillard, T

    2015-01-01

    The aim of this paper is to present the specific risks of physical activity in elderly subjects. These risks mainly consist of the loss of physical integrity and the weakening of the capabilities of metabolic regulation. The risk of impairment of physical integrity (e.g. injury) related to regular physical activity is not overall greater in elderly subjects than in young subjects. The choice of a physical activity that is suited to the elderly subject's physical and cognitive abilities largely limits these risks. When physical activity is adapted to suit elderly subjects, the number of accidents in relation to the number of participants is actually very low. In fact, participation in a program of education for prevention related to physical activity reduces the risk of accidents and injuries (and, thus, falls) occurring thereafter. In the case of metabolic risks, isometric muscular contractions carried out under certain conditions (duration: > 6 seconds; intensity: > 50% of maximal voluntary contraction) are inappropriate. Physical activity carried out in extreme thermal atmospheres (0-5° 25-30°) should be avoided. Hydration is very important and liquids should be drunk well before any thirst sensation occurs.

  5. Toward immunotherapy with redirected T cells in a large animal model: ex vivo activation, expansion, and genetic modification of canine T cells.

    Science.gov (United States)

    Mata, Melinda; Vera, Juan F; Gerken, Claudia; Rooney, Cliona M; Miller, Tasha; Pfent, Catherine; Wang, Lisa L; Wilson-Robles, Heather M; Gottschalk, Stephen

    2014-10-01

    Adoptive transfer of T cells expressing chimeric antigen receptors (CARs) has shown promising antitumor activity in early phase clinical studies, especially for hematological malignancies. However, most preclinical models do not reliably mimic human disease. We reasoned that developing an adoptive T-cell therapy approach for spontaneous osteosarcoma (OS) occurring in dogs would more closely reproduce the condition in human cancer. To generate CAR-expressing canine T cells, we developed expansion and transduction protocols that allow for the generation of sufficient numbers of CAR-expressing canine T cells for future clinical studies in dogs within 2 weeks of ex vivo culture. To evaluate the functionality of CAR-expressing canine T cells, we targeted HER2(+) OS. We demonstrate that canine OS is positive for HER2, and that canine T cells expressing a HER2-specific CAR with human-derived transmembrane and CD28.ζ signaling domains recognize and kill HER2(+) canine OS cell lines in an antigen-dependent manner. To reduce the potential immunogenicity of the CAR, we evaluated a CAR with canine-derived transmembrane and signaling domains, and found no functional difference between human and canine CARs. Hence, we have successfully developed a strategy to generate CAR-expressing canine T cells for future preclinical studies in dogs. Testing T-cell therapies in an immunocompetent, outbred animal model may improve our ability to predict their safety and efficacy before conducting studies in humans.

  6. Novel Antibody-Based Proteins for Cancer Immunotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Fuenmayor, Jaheli; Montaño, Ramon F., E-mail: jfuenmay@ivic.gob.ve [Laboratorio de Patología Celular y Molecular, Centro de Medicina Experimental, Instituto Venezolano de Investigaciones Científicas. Caracas, 1020-A (Venezuela, Bolivarian Republic of)

    2011-08-19

    The relative success of monoclonal antibodies in cancer immunotherapy and the vast manipulation potential of recombinant antibody technology have encouraged the development of novel antibody-based antitumor proteins. Many insightful reagents have been produced, mainly guided by studies on the mechanisms of action associated with complete and durable remissions, results from experimental animal models, and our current knowledge of the human immune system. Strikingly, only a small percent of these new reagents has demonstrated clinical value. Tumor burden, immune evasion, physiological resemblance, and cell plasticity are among the challenges that cancer therapy faces, and a number of antibody-based proteins are already available to deal with many of them. Some of these novel reagents have been shown to specifically increase apoptosis/cell death of tumor cells, recruit and activate immune effectors, and reveal synergistic effects not previously envisioned. In this review, we look into different approaches that have been followed during the past few years to produce these biologics and analyze their relative success, mainly in terms of their clinical performance. The use of antibody-based antitumor proteins, in combination with standard or novel therapies, is showing significant improvements in objective responses, suggesting that these reagents will become important components of the antineoplastic protocols of the future.

  7. IgE-based immunotherapy of cancer: challenges and chances.

    Science.gov (United States)

    Singer, J; Jensen-Jarolim, E

    2014-02-01

    Passive immunotherapy with monoclonal antibodies is an indispensable cornerstone of clinical oncology. Notably, all FDA-approved antibodies comprise the IgG class, although numerous research articles proposed monoclonal antibodies of the IgM, IgG, IgA and IgE classes directed specifically against tumor-associated antigens. In particular, for the IgE isotype class, several recent studies could demonstrate high tumoricidic efficacy. Therefore, this review specifically highlights the latest developments toward IgE-based immunotherapy of cancer. Possible mechanisms and safety aspects of IgE-mediated tumor cell death are discussed with special focus on the attracted immune cells. An outlook is given on how especially comparative oncology could contribute to further developments. Humans and dogs have a highly comparable IgE biology, suggesting that translational AllergoOncology studies in patients with canine cancer could have predictive value for the potential of IgE-based anticancer immunotherapy in human clinical oncology.

  8. Semiallogenic fusions of MSI+ tumor cells and activated B cells induce MSI-specific T cell responses

    Directory of Open Access Journals (Sweden)

    Klier Ulrike

    2011-09-01

    Full Text Available Abstract Background Various strategies have been developed to transfer tumor-specific antigens into antigen presenting cells in order to induce cytotoxic T cell responses against tumor cells. One approach uses cellular vaccines based on fusions of autologous antigen presenting cells and allogeneic tumor cells. The fusion cells combine antigenicity of the tumor cell with optimal immunostimulatory capacity of the antigen presenting cells. Microsatellite instability caused by mutational inactivation of DNA mismatch repair genes results in translational frameshifts when affecting coding regions. It has been shown by us and others that these mutant proteins lead to the presentation of immunogenic frameshift peptides that are - in principle - recognized by a multiplicity of effector T cells. Methods We chose microsatellite instability-induced frameshift antigens as ideal to test for induction of tumor specific T cell responses by semiallogenic fusions of microsatellite instable carcinoma cells with CD40-activated B cells. Two fusion clones of HCT116 with activated B cells were selected for stimulation of T cells autologous to the B cell fusion partner. Outgrowing T cells were phenotyped and tested in functional assays. Results The fusion clones expressed frameshift antigens as well as high amounts of MHC and costimulatory molecules. Autologous T cells stimulated with these fusions were predominantly CD4+, activated, and reacted specifically against the fusion clones and also against the tumor cell fusion partner. Interestingly, a response toward 6 frameshift-derived peptides (of 14 tested could be observed. Conclusion Cellular fusions of MSI+ carcinoma cells and activated B cells combine the antigen-presenting capacity of the B cell with the antigenic repertoire of the carcinoma cell. They present frameshift-derived peptides and can induce specific and fully functional T cells recognizing not only fusion cells but also the carcinoma cells. These

  9. GTP-specific fab fragment-based GTPase activity assay.

    Science.gov (United States)

    Kopra, Kari; Rozwandowicz-Jansen, Anita; Syrjänpää, Markku; Blaževitš, Olga; Ligabue, Alessio; Veltel, Stefan; Lamminmäki, Urpo; Abankwa, Daniel; Härmä, Harri

    2015-03-17

    GTPases are central cellular signaling proteins, which cycle between a GDP-bound inactive and a GTP-bound active conformation in a controlled manner. Ras GTPases are frequently mutated in cancer and so far only few experimental inhibitors exist. The most common methods for monitoring GTP hydrolysis rely on luminescent GDP- or GTP-analogs. In this study, the first GTP-specific Fab fragment and its application are described. We selected Fab fragments using the phage display technology. Six Fab fragments were found against 2'/3'-GTP-biotin and 8-GTP-biotin. Selected antibody fragments allowed specific detection of endogenous, free GTP. The most potent Fab fragment (2A4(GTP)) showed over 100-fold GTP-specificity over GDP, ATP, or CTP and was used to develop a heterogeneous time-resolved luminescence based assay for the monitoring of GTP concentration. The method allows studying the GEF dependent H-Ras activation (GTP binding) and GAP-catalyzed H-Ras deactivation (GTP hydrolysis) at nanomolar protein concentrations.

  10. NK cell-based cancer immunotherapy: from basic biology to clinical application.

    Science.gov (United States)

    Li, Yang; Yin, Jie; Li, Ting; Huang, Shan; Yan, Han; Leavenworth, JianMei; Wang, Xi

    2015-12-01

    Natural killer (NK) cells, which recognize and kill target cells independent of antigen specificity and major histocompatibility complex (MHC) matching, play pivotal roles in immune defence against tumors. However, tumor cells often acquire the ability to escape NK cell-mediated immune surveillance. Thus, understanding mechanisms underlying regulation of NK cell phenotype and function within the tumor environment is instrumental for designing new approaches to improve the current cell-based immunotherapy. In this review, we elaborate the main biological features and molecular mechanisms of NK cells that pertain to regulation of NK cell-mediated anti-tumor activity. We further overview current clinical approaches regarding NK cell-based cancer therapy, including cytokine infusion, adoptive transfer of autologous or allogeneic NK cells, applications of chimeric antigen receptor (CAR)-expressing NK cells and adoptive transfer of memory-like NK cells. With these promising clinical outcomes and fuller understanding the basic questions raised in this review, we foresee that NK cell-based approaches may hold great potential for future cancer immunotherapy.

  11. Potential use of [gammadelta] T cell-based vaccines in cancer immunotherapy

    Directory of Open Access Journals (Sweden)

    Mohd Wajid A. Khan

    2014-10-01

    Full Text Available Immunotherapy is a fast advancing methodology involving one of two approaches: 1 compounds targeting immune checkpoints, and 2 cellular immunomodulators. The latter approach is still largely experimental and features in vitro generated, live immune effector cells or antigen-presenting cells (APC. [gammadelta] T cells are known for their efficient in vitro tumor killing activities. Consequently, many laboratories worldwide are currently testing the tumor killing function of [gammadelta] T cells in clinical trials. Reported benefits are modest; however, these studies have demonstrated that large [gammadelta] T cell infusions were well tolerated. Here, we discuss the potential of using human [gammadelta] T cells not as effector cells but as a novel cellular vaccine for treatment of cancer patients. Antigen-presenting [gammadelta] T cells do not require to home to tumor tissues but, instead, need to interact with endogenous, tumor-specific [alphabeta] T cells in secondary lymphoid tissues. Newly mobilised effector [alphabeta] T cells are then thought to overcome the immune blockade by creating proinflammatory conditions fit for effector T cell homing to and killing of tumor cells. Immunotherapy may include tumor antigen-loaded [gammadelta] T cells alone or in combination with immune checkpoint inhibitors.

  12. Role of IL-10 in Urinary Bladder Carcinoma and Bacillus Calmette-Guerin Immunotherapy

    Directory of Open Access Journals (Sweden)

    Yi Luo

    2012-01-01

    Full Text Available Problem statement: Bladder cancer is a common urologic cancer and intravesical Mycobacterium bovis Bacillus Calmette-Guerin (BCG is the mainstay in the treatment of superficial bladder cancer. However, the current BCG therapy is not desirable with respect to its efficacy and side effects. Interleukin (IL-10, a T helper type (Th 2 cytokine, plays an important regulatory role in bladder cancer immunosurveillance and BCG immunotherapy. Therefore, blocking IL-10 activity could be beneficial for bladder cancer patients undergoing BCG therapy. Approach: Treatment with intravesical BCG in combination with systemic IL-10 monoclonal antibody (mAb specific for IL-10 neutralization or IL-10 receptor (IL-10R blockage has been evaluated in preclinical bladder cancer models. Results: Addition of anti-IL-10 neutralizing mAb or anti-IL-10R1 mAb enhances BCG induction of Th1 immune responses and anti-bladder cancer immunity. Conclusion/Recommendations: BCG immunotherapy of bladder cancer can be enhanced by addition of IL-10 blocking mAb. Future studies should aim to explore the mechanisms underlying the induction of enhanced antitumor immunity by BCG combination therapy and develop therapeutic regimens for clinical evaluation of the safety and efficacy of BCG combination therapy.

  13. Cancer immunotherapy and immunological memory.

    Science.gov (United States)

    Murata, Kenji; Tsukahara, Tomohide; Torigoe, Toshihiko

    2016-01-01

      Human immunological memory is the key distinguishing hallmark of the adaptive immune system and plays an important role in the prevention of morbidity and the severity of infection. The differentiation system of T cell memory has been clarified using mouse models. However, the human T cell memory system has great diversity induced by natural antigens derived from many pathogens and tumor cells throughout life, and profoundly differs from the mouse memory system constructed using artificial antigens and transgenic T cells. We believe that only human studies can elucidate the human immune system. The importance of immunological memory in cancer immunotherapy has been pointed out, and the trafficking properties and long-lasting anti-tumor capacity of memory T cells play a crucial role in the control of malignant tumors. Adoptive cell transfer of less differentiated T cells has consistently demonstrated superior anti-tumor capacity relative to more differentiated T cells. Therefore, a human T cell population with the characteristics of stem cell memory is thought to be attractive for peptide vaccination and adoptive cell transfer. A novel human memory T cell population that we have identified is closer to the naive state than previous memory T cells in the T cell differentiation lineage, and has the characteristics of stem-like chemoresistance. Here we introduce this novel population and describe the fundamentals of immunological memory in cancer immunotherapy.

  14. Fundamental Activity Constraints Lead to Specific Interpretations of the Connectome

    Science.gov (United States)

    van Albada, Sacha J.; Diesmann, Markus; Helias, Moritz

    2017-01-01

    The continuous integration of experimental data into coherent models of the brain is an increasing challenge of modern neuroscience. Such models provide a bridge between structure and activity, and identify the mechanisms giving rise to experimental observations. Nevertheless, structurally realistic network models of spiking neurons are necessarily underconstrained even if experimental data on brain connectivity are incorporated to the best of our knowledge. Guided by physiological observations, any model must therefore explore the parameter ranges within the uncertainty of the data. Based on simulation results alone, however, the mechanisms underlying stable and physiologically realistic activity often remain obscure. We here employ a mean-field reduction of the dynamics, which allows us to include activity constraints into the process of model construction. We shape the phase space of a multi-scale network model of the vision-related areas of macaque cortex by systematically refining its connectivity. Fundamental constraints on the activity, i.e., prohibiting quiescence and requiring global stability, prove sufficient to obtain realistic layer- and area-specific activity. Only small adaptations of the structure are required, showing that the network operates close to an instability. The procedure identifies components of the network critical to its collective dynamics and creates hypotheses for structural data and future experiments. The method can be applied to networks involving any neuron model with a known gain function. PMID:28146554

  15. Practice induces function-specific changes in brain activity.

    Directory of Open Access Journals (Sweden)

    Tamar R van Raalten

    Full Text Available BACKGROUND: Practice can have a profound effect on performance and brain activity, especially if a task can be automated. Tasks that allow for automatization typically involve repeated encoding of information that is paired with a constant response. Much remains unknown about the effects of practice on encoding and response selection in an automated task. METHODOLOGY: To investigate function-specific effects of automatization we employed a variant of a Sternberg task with optimized separation of activity associated with encoding and response selection by means of m-sequences. This optimized randomized event-related design allows for model free measurement of BOLD signals over the course of practice. Brain activity was measured at six consecutive runs of practice and compared to brain activity in a novel task. PRINCIPAL FINDINGS: Prompt reductions were found in the entire cortical network involved in encoding after a single run of practice. Changes in the network associated with response selection were less robust and were present only after the third run of practice. CONCLUSIONS/SIGNIFICANCE: This study shows that automatization causes heterogeneous decreases in brain activity across functional regions that do not strictly track performance improvement. This suggests that cognitive performance is supported by a dynamic allocation of multiple resources in a distributed network. Our findings may bear importance in understanding the role of automatization in complex cognitive performance, as increased encoding efficiency in early stages of practice possibly increases the capacity to otherwise interfering information.

  16. Cancer immunotherapy with levamisole

    Directory of Open Access Journals (Sweden)

    Miwa,Hiroaki

    1978-07-01

    Full Text Available Levamisole, an agent acting upon depressed cellular immunity, enhancing and normalizing it and consequently showing antitumor activity in the cancer-bearing body, was administered to patients with gastrointestinal cancer at a daily dose of 150 mg for three consecutive days every other week, starting as a rule, three days before operation. The patients were evaluated for survival. Of the 143 patients (66 with curative resection, 40 with noncurative resection and 37 without resection who received levamisole therapy for one month or more, 57 survived postoperatively six months and of 44 treated 37 survived one year. In this study, 185 patients with gastrointestinal cancer were used for comparison purposes. The six-month survival rate was 100% (23/23 in the levamisole treated group and 95.3% (102/107 in the control group after curative resection (p greater than 0.5, 100% (23/23 and 90.5% (49/54 after noncurative resection (p less than 0.01, and 72.5% (8/11 and 33.3% (9/24, respectively, in non-resectable patients (p less than 0.01. The one-year survival rate was 100% (21/21 and 95.3% (102/107 after curative resection (p greater than 0.5, 77.8% (14/18 and 59.3% (32/54 after noncurative resection (0.05 less than p less than 0.1, and 40% (2/5 and 8.3% (2/24 in non-resectable patients (0.05 less than p than 0.1 in the levamisole group and in the control group, respectively. The difference in survival in survival rates between levamisole-treated and control groups was most prominent in the non-resectable patients followed by those undergoing noncurative resection and curative resection.

  17. Production of N-13 labeled compounds with high specific activity

    Energy Technology Data Exchange (ETDEWEB)

    Suzuki, Kazutoshi; Sasaki, Motoji; Yoshida, Yuichiro; Haradahira, Terushi; Inoue, Osamu [National Inst. of Radiological Sciences, Chiba (Japan)

    1997-03-01

    Nitrogen-13 was produced by irradiating ultra pure water saturated with a pure gas (N2, O2, He, H2) with 18 MeV protons. Ion species generated by irradiation were analyzed with radio ion chromatography systems. An automated equipment was developed to synthesize anhydrous (13N)NH3 as a synthetic precursor and (13N)p-nitrophenyl carbamate ((13N)NPC) as a model compound, using the (13N)NH3. The radiochemical yield and specific activity of (13N)NPC was high enough to carry out the receptor study with PET. (author)

  18. Exosomes as nanocarriers for immunotherapy of cancer and inflammatory diseases.

    Science.gov (United States)

    Tran, Thanh-Huyen; Mattheolabakis, George; Aldawsari, Hibah; Amiji, Mansoor

    2015-09-01

    Cell secreted exosomes (30-100nm vesicles) play a major role in intercellular communication due to their ability to transfer proteins and nucleic acids from one cell to another. Depending on the originating cell type and the cargo, exosomes can have immunosuppressive or immunostimulatory effects, which have potential application as immunotherapies for cancer and autoimmune diseases. Cellular components shed from tumor cells or antigen presenting cells (APCs), such as dendritic cells, macrophages and B cells, have been shown to be efficiently packaged in exosomes. In this review, we focus on the application of exosomes as nanocarriers and immunological agents for cancer and autoimmune immunotherapy. APC-derived exosomes demonstrate effective therapeutic efficacy for the treatment of cancer and experimental autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis. In addition to their intrinsic immunomodulating activity, exosomes have many advantages over conventional nanocarriers for drug and gene delivery.

  19. Aberrant expression and potency as a cancer immunotherapy target of alpha-methylacyl-coenzyme A racemase in prostate cancer

    Directory of Open Access Journals (Sweden)

    Masumori Naoya

    2009-12-01

    Full Text Available Abstract Alpha-methylacyl-CoA racemase (AMACR is an enzyme playing an important role in the beta-oxidation of branched-chain fatty acids and fatty acid derivatives. High expression levels of AMACR have been described in various cancers, including prostate cancer, colorectal cancer and kidney cancer. Because of its cancer-specific and frequent expression, AMACR could be an attractive target for cytotoxic T-lymphocyte (CTL-based immunotherapy for cancer. In the present study, we examined the induction of AMACR-specific CTLs from prostate cancer patients' peripheral blood mononuclear cells (PBMCs and determined HLA-A24-restricted CTL epitopes. RT-PCR and immunohistochemical analysis revealed that AMACR was strongly expressed in prostate cancer cell lines and tissues as compared with benign or normal prostate tissues. Four AMACR-derived peptides carrying the HLA-A24-binding motif were synthesized from the amino acid sequence of this protein and analyzed to determine their binding affinities to HLA-A24. By stimulating patient's PBMCs with the peptides, specific CTLs were successfully induced in 6 of 11 patients. The peptide-specific CTLs exerted significant cytotoxic activity against AMACR-expressing prostate cancer cells in the context of HLA-A24. Our study demonstrates that AMACR could become a target antigen for prostate cancer immunotherapy, and that the AMACR-derived peptides might be good peptide vaccine candidates for HLA-A24-positive AMACR-expressing cancer patients.

  20. Bioinformatics for cancer immunotherapy target discovery

    DEFF Research Database (Denmark)

    Olsen, Lars Rønn; Campos, Benito; Barnkob, Mike Stein

    2014-01-01

    The mechanisms of immune response to cancer have been studied extensively and great effort has been invested into harnessing the therapeutic potential of the immune system. Immunotherapies have seen significant advances in the past 20 years, but the full potential of protective and therapeutic...... cancer immunotherapies has yet to be fulfilled. The insufficient efficacy of existing treatments can be attributed to a number of biological and technical issues. In this review, we detail the current limitations of immunotherapy target selection and design, and review computational methods to streamline...

  1. Present and future perspectives on immunotherapy for advanced renal cell carcinoma: Going to the core or beating around the bush?

    Directory of Open Access Journals (Sweden)

    Hidenori Kawashima

    2015-03-01

    Full Text Available Metastatic lesions of renal cell carcinoma (RCC occasionally regress spontaneously after surgical removal of the primary tumor. Although this is an exceptionally rare occurrence, RCC has thus been postulated to be immunogenic. Immunotherapies, including cytokine therapy, peptide-based vaccines, and immune checkpoint inhibitors have therefore been used to treat patients with advanced, metastatic RCC. We review the history, trends, and recent progress in immunotherapy for advanced RCC and discuss future perspectives, with consideration of our experimental work on galectin 9 and PINCH as promising specific immunotherapy targets. 

  2. Immunotherapy of cancer employing adoptive T cell transfer

    Institute of Scientific and Technical Information of China (English)

    QIAOLI

    2005-01-01

    The current concept of“Adoptive T Cell Immunotherapy of Cancer”is quite different from how it was originally conceived.With the development of modern technology in molecular biology,cell biology,immunology and biochemistry during the last twenty years or so,adoptive immunotherapy has grown from its initial form of a simple“blood cell transfer”into its present process which involves host vauccination,effector cell activation/polarization and genetic modification.With the use of immune adjuvants and the identification/characterization of tumor-reactive T cell subsets,or in combination with other therapeutic strategies,adoptively transferred T cells have become much more potent inmediating tumor regression.In addition,studies on the trafficking of infused T cells,cell transfer performed in lymphopenic models,as well as the discovery of novel techniques in immune monitoring for the generation of effector cells in vitro and after cell transfer in vivo have provided useful tools to further improve the therapeutic efficacy of this approach.This article will review these related aspects of adoptive T cell immunotherapy of cancer with specific comments on certain critical areas in the application of this approach.With the rapidly evolving advances in this area,it is hoped that this cellular immunologic therapy as it was conceptualized in the past,can become more useful in the treatment of human cancer in the near future.

  3. Activities and specificities of homodimeric TALENs in Saccharomyces cerevisiae

    KAUST Repository

    Aouida, Mustapha

    2013-10-01

    The development of highly efficient genome engineering reagents is of paramount importance to launch the next wave of biotechnology. TAL effectors have been developed as an adaptable DNA binding scaffold that can be engineered to bind to any user-defined sequence. Thus, TAL-based DNA binding modules have been used to generate chimeric proteins for a variety of targeted genome modifications across eukaryotic species. For example, TAL effectors fused to the catalytic domain of FokI endonuclease (TALENs) were used to generate site-specific double strand breaks (DSBs), the repair of which can be harnessed to dictate user-desired, genome-editing outcomes. To cleave DNA, FokI endonuclease must dimerize which can be achieved using a pair of TALENs that bind to the DNA targeted in a tail-to-tail orientation with proper spacing allowing the dimer formation. Because TALENs binding to DNA are dependent on their repeat sequences and nucleotides binding specificities, homodimers and heterodimers binding can be formed. In the present study, we used several TALEN monomers with increased repeats binding degeneracy to allow homodimer formation at increased number of genomic loci. We assessed their binding specificities and genome modification activities. Our results indicate that homodimeric TALENs could be used to modify the yeast genome in a site-specific manner and their binding to the promoter regions might modulate the expression of target genes. Taken together, our data indicate that homodimeric TALENs could be used to achieve different engineering possibilities of biotechnological applications and that their transcriptional modulations need to be considered when analyzing their phenotypic effects. © 2013 Springer-Verlag.

  4. Bioreactor Transient Exposure Activates Specific Neurotrophic Pathway in Cortical Neurons

    Science.gov (United States)

    Zimmitti, V.; Benedetti, E.; Caracciolo, V.; Sebastiani, P.; Di Loreto, S.

    2010-02-01

    Altered gravity forces might influence neuroplasticity and can provoke changes in biochemical mechanisms. In this contest, neurotrophins have a pivotal role, particularly nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF). A suspension of dissociated cortical cells from rat embryos was exposed to 24 h of microgravity before plating in normal adherent culture system. Expression and transductional signalling pathways of NGF and BDNF were assessed at the end of maturational process (8-10 days in vitro). Rotating wall vessel bioreactor (RWV) pre-exposition did not induce changes in NGF expression and its high affinity receptor TrkA. On the contrary both BDNF expression and its high affinity receptor TrkB were strongly up-regulated, inducing Erk-5, but not Erk-1/2 activation and, in turn, MEF2C over-expression and activation. According to our previous and present results, we postulate that relatively short microgravitational stimuli, applied to neural cells during the developmental stage, exert a long time activation of specific neurotrophic pathways.

  5. DNA-inorganic hybrid nanovaccine for cancer immunotherapy

    Science.gov (United States)

    Zhu, Guizhi; Liu, Yijing; Yang, Xiangyu; Kim, Young-Hwa; Zhang, Huimin; Jia, Rui; Liao, Hsien-Shun; Jin, Albert; Lin, Jing; Aronova, Maria; Leapman, Richard; Nie, Zhihong; Niu, Gang; Chen, Xiaoyuan

    2016-03-01

    Cancer evolves to evade or compromise the surveillance of the immune system, and cancer immunotherapy aims to harness the immune system in order to inhibit cancer development. Unmethylated CpG dinucleotide-containing oligonucleotides (CpG), a class of potent adjuvants that activate the toll-like receptor 9 (TLR9) located in the endolysosome of many antigen-presenting cells (APCs), are promising for cancer immunotherapy. However, clinical application of synthetic CpG confronts many challenges such as suboptimal delivery into APCs, unfavorable pharmacokinetics caused by limited biostability and short in vivo half-life, and side effects associated with leaking of CpG into the systemic circulation. Here we present DNA-inorganic hybrid nanovaccines (hNVs) for efficient uptake into APCs, prolonged tumor retention, and potent immunostimulation and cancer immunotherapy. hNVs were self-assembled from concatemer CpG analogs and magnesium pyrophosphate (Mg2PPi). Mg2PPi renders hNVs resistant to nuclease degradation and thermal denaturation, both of which are demanding characteristics for effective vaccination and the storage and transportation of vaccines. Fluorophore-labeled hNVs were tracked to be efficiently internalized into the endolysosomes of APCs, where Mg2PPi was dissolved in an acidic environment and thus CpG analogs were exposed to hNVs. Internalized hNVs in APCs led to (1) elevated secretion of proinflammatory factors, and (2) elevated expression of co-stimulatory factors. Compared with molecular CpG, hNVs dramatically prolonged the tissue retention of CpG analogs and reduced splenomegaly, a common side effect of CpG. In a melanoma mouse model, two injections of hNVs significantly inhibited the tumor growth and outperformed the molecular CpG. These results suggest hNVs are promising for cancer immunotherapy.Cancer evolves to evade or compromise the surveillance of the immune system, and cancer immunotherapy aims to harness the immune system in order to inhibit

  6. 肺癌免疫治疗临床试验进展%Progress of immunotherapy trials in the treatment of lung cancer

    Institute of Scientific and Technical Information of China (English)

    刘皓; 高红军

    2015-01-01

    手术联合放化疗是肺癌常规治疗手段,但术后复发十分常见,患者死亡率高,生命质量较低。而术后免疫治疗可充分调动患者的机体防御机制,激活免疫细胞,杀灭残留癌细胞。目前关于肺癌免疫治疗的研究成果主要包括4大类:过继性免疫治疗、树突状细胞疫苗、非特异性抗原免疫治疗和抗原特异性疫苗。这些研究成果均表明肺癌术后免疫治疗干预可有效减少癌细胞残留,降低术后复发率,延长患者生存时间,显著改善预后,值得临床推广。%Surgery in combination with chemotherapy and radiotherapy is the standard of lung cancer treatment,but postoperative recurrence is very common which usually leads to higher mortality and lower life quality. Immunotherapy on post-operative patients fully mobilizes the body's defense mechanisms,activates the immune cells,and kills residual cancer cells. Current research on lung cancer immunotherapy mainly includes four categories:adoptive immunotherapy,dendritic cell vaccine,non-specific antigen immune therapy and anti-gen-specific vaccine. These studies show lung cancer immunotherapy intervention can effectively reduce postop-erative residual cancer cells,reduce postoperative recurrence rate,prolong survival,significantly improve the prognosis,and is worth spreading in clinical practice.

  7. Adoptive T cell therapy: Addressing challenges in cancer immunotherapy

    Directory of Open Access Journals (Sweden)

    Yee Cassian

    2005-04-01

    Full Text Available Abstract Adoptive T cell therapy involves the ex vivo selection and expansion of effector cells for the treatment of patients with cancer. In this review, the advantages and limitations of using antigen-specific T cells are discussed in counterpoint to vaccine strategies. Although vaccination strategies represent more readily available reagents, adoptive T cell therapy provides highly selected T cells of defined phenotype, specificity and function that may influence their biological behavior in vivo. Adoptive T cell therapy offers not only translational opportunities but also a means to address fundamental issues in the evolving field of cancer immunotherapy.

  8. Innovation in Bladder Cancer Immunotherapy.

    Science.gov (United States)

    Grossman, H Barton; Lamm, Donald L; Kamat, Ashish M; Keefe, Stephen; Taylor, John A; Ingersoll, Molly A

    2016-10-01

    Bladder cancer is understudied despite its high prevalence and its remarkable response to immunotherapy. Indeed, funding for studies to explore mechanisms of tumor immunity and novel new therapeutics is disproportionately lower for bladder cancer in comparison with malignancies of the breast, prostate, or lung. However, the recent successes of checkpoint blockade therapy suggest that new therapeutic strategies are on the horizon for bladder cancer. Here, we give a perspective into the evolution of bladder cancer therapy, focusing on strategies to treat high-risk nonmuscle invasive disease, followed by a discussion of recent advances in the treatment of muscle invasive bladder cancer and their potential applicability to lower stage disease. Finally, we explore immunotherapeutic strategies, which have been demonstrated to be successful in the treatment of other malignancies, for their potential to treat and cure patients with nonmuscle and muscle invasive bladder cancer.

  9. IMUNODIAGNOSTIC AND IMMUNOTHERAPY OF AUTISM

    Directory of Open Access Journals (Sweden)

    Vladimir TRAJKOVSKI

    2000-06-01

    Full Text Available Infantile autism is one of the most disabling illnesses of neurological, emotional and intellectual development. The cause of autism remains unknown. However, recent investigations suggest that this disorder shares several features of established autoimmune disorders.The aim of this article is to describe the news of imunodiagnostic and immunotherapy in autism. Interpretation of data is made by conceptual and methodological differences between studies. The autoimmune response is most likely directed against the brain myelin, perhaps secondary to a viral infection. The idea that autism is an autoimmune disorder is further strengthened by the fact that autistic patients respond well to treatment with immune modulating drugs. Immune interventions can produce immune modulation-state of suppression or stimulation. Immune therapy should always be done in consultation with physicians.

  10. Allergen immunotherapy for allergic rhinoconjunctivitis

    DEFF Research Database (Denmark)

    Dhami, Sangeeta; Nurmatov, Ulugbek; Roberts, Graham;

    2016-01-01

    BACKGROUND: The European Academy of Allergy and Clinical Immunology (EAACI) is in the process of developing the EAACI Guidelines for Allergen Immunotherapy (AIT) for the Management of Allergic Rhinoconjunctivitis. We seek to critically assess the effectiveness, cost-effectiveness and safety of AIT...... in the management of allergic rhinoconjunctivitis. METHODS: We will undertake a systematic review, which will involve searching international biomedical databases for published, in progress and unpublished evidence. Studies will be independently screened against pre-defined eligibility criteria and critically...... appraised using established instruments. Data will be descriptively and, if possible and appropriate, quantitatively synthesised. CONCLUSION: The findings from this review will be used to inform the development of recommendations for EAACI's Guidelines on AIT....

  11. Allergen immunotherapy for the prevention of allergy

    DEFF Research Database (Denmark)

    Kristiansen, Maria; Dhami, Sangeeta; Netuveli, Gopal

    2017-01-01

    Background: There is a need to establish the effectiveness, cost-effectiveness and safety of allergen immunotherapy (AIT) for the prevention of allergic disease. Methods:Two reviewers independently screened nine international biomedical databases. Studies were quantitatively synthesized using ran...

  12. Who Will Benefit from Cancer Immunotherapy?

    Science.gov (United States)

    Researchers have identified a “genetic signature” in the tumors of patients with advanced melanoma who responded to a form of immunotherapy called checkpoint blockade. The results could be the basis for a test that identifies likely responders.

  13. Increased antitumor activity of tumor-specific peptide modified thymopentin.

    Science.gov (United States)

    Lao, Xingzhen; Li, Bin; Liu, Meng; Chen, Jiao; Gao, Xiangdong; Zheng, Heng

    2014-12-01

    Thymopoietin pentapeptide (thymopentin, TP5), an immunomodulatory peptide, has been successfully used as an immune system enhancer for treating immune deficiency, cancer, and infectious diseases. However, poor penetration into tumors remains a key limitation to the efficacy and application of TP5. iRGD (CRGDK/RGPD/EC) has been introduced to certain anticancer agents, and increased specific tumor penetrability of drugs and cell internalization have been observed. In the present study, we fused this iRGD fragment with the C-terminal of TP5 to yield a new product, TP5-iRGD. Cell attachment assay showed that TP5-iRGD exhibits more extensive attachment to the melanoma cell line B16F10 than wild-type TP5. Tumor cell viability assay showed that iRGD conjugation with the TP5 C-terminus increases the basal antiproliferative activity of the pentapeptide against the melanoma cell line B16F10, the human lung cancer cell line H460, and the human breast cancer cell line MCF-7. Subsequent injections of TP5-iRGD inhibited in vivo melanoma progression more efficiently than the native TP5. Murine spleen lymphocyte proliferation assay also showed that TP5-iRGD and the parent pentapeptide feature nearly identical spleen lymphocyte proliferation activities. We built an integrin αvβ3 and TP5-iRGD computational binding model to investigate the mechanism by which TP5-iRGD promotes increased activity further. Conjugation with iRGD promotes binding to integrin αvβ3, thereby increasing the tumor-homing efficiency of the resultant peptide. These experimental and computational observations of increased TP5-iRGD activity help broaden the usage of TP5 and reflect the great application potential of the peptide as an anticancer agent.

  14. Human DJ-1-specific Transcriptional Activation of Tyrosine Hydroxylase Gene*

    Science.gov (United States)

    Ishikawa, Shizuma; Taira, Takahiro; Takahashi-Niki, Kazuko; Niki, Takeshi; Ariga, Hiroyoshi; Iguchi-Ariga, Sanae M. M.

    2010-01-01

    Loss-of-function mutation in the DJ-1 gene causes a subset of familial Parkinson disease. The mechanism underlying DJ-1-related selective vulnerability in the dopaminergic pathway is, however, not known. DJ-1 has multiple functions, including transcriptional regulation, and one of transcriptional target genes for DJ-1 is the tyrosine hydroxylase (TH) gene, the product of which is a key enzyme for dopamine biosynthesis. It has been reported that DJ-1 is a neuroprotective transcriptional co-activator that sequesters a transcriptional co-repressor polypyrimidine tract-binding protein-associated splicing factor (PSF) from the TH gene promoter. In this study, we found that knockdown of human DJ-1 by small interference RNA in human dopaminergic cell lines attenuated TH gene expression and 4-dihydroxy-l-phenylalanine production but that knockdown or knock-out of mouse DJ-1 in mouse cell lines or in mice did not affect such expression and TH activity. In reporter assays using the human TH gene promoter linked to the luciferase gene, stimulation of TH promoter activity was observed in human cells, but not mouse cells, that had been transfected with DJ-1. Although human DJ-1 and mouse DJ-1 were associated either with human or with mouse PSF, TH promoter activity inhibited by PSF was restored by human DJ-1 but not by mouse DJ-1. Chromatin immunoprecipitation assays revealed that the complex of PSF with DJ-1 bound to the human but not the mouse TH gene promoter. These results suggest a novel species-specific transcriptional regulation of the TH promoter by DJ-1 and one of the mechanisms for no reduction of TH in DJ-1-knock-out mice. PMID:20938049

  15. The effects of specific preconditioning activities on acute sprint performance.

    Science.gov (United States)

    Guggenheimer, Joshua D; Dickin, D Clark; Reyes, Gabriel F; Dolny, Dennis G

    2009-07-01

    Previous research suggests that specific preconditioning activities such as whole-body vibration (WBV) and resistance training may play an important role in ensuing dynamic activities. The purpose of this study was to examine the effects of 2 preconditioning activities, WBV and power cleans (PC), on acute sprint performance. Two studies were conducted in which 14 (WBV) and 9 (PC) male track and field athletes were subjects. The WBV treatment consisted of 4 bouts of 5 seconds of high-knee running on a vibrating platform at 0, 30, 40, or 50 Hz. The PC treatment consisted of 3 PC reps at 90% 1RM. In both cases, acute sprint performance was the dependent variable of interest. For WBV, split times were recorded at 10, 20, and 40 m. Reaction times (RXN) as well as 5-, 10-, and 40-m split times were recorded for the PC study. Results indicated no significant differences between treatment and nontreatment groups for both studies. However, significant correlations were present between RXN and 5-m splits (r = 0.65) and RXN and 10-m splits (r = 0.63), although they decreased as a function of sprint distance to r = 0.43 at 40 m. These results suggest little efficacy for the use of WBV and PC as a means of augmenting acute sprint performance. However, a trend within the 30-Hz protocol may suggest that WBV as part of a warm-up for sprinting activities greater than 40 m (i.e., 100 m) could potentially result in a decreased sprint time of nearly 1/10th of a second, which is worth future consideration.

  16. Immunotherapy in prostate cancer: review of the current evidence.

    Science.gov (United States)

    Fernández-García, E M; Vera-Badillo, F E; Perez-Valderrama, B; Matos-Pita, A S; Duran, I

    2015-05-01

    Prostate cancer is the most common male malignancy in the Western world. Once it metastasizes, it is incurable. The current gold standard for metastatic disease is the combined docetaxel/prednisone regimen. Prostate cancer shows several characteristics that make it a suitable candidate for immunotherapy, as recently exemplified by the approval of sipuleucel-T, the first vaccine to treat any malignancy. Here, we review different tumor-associated antigen immunotherapy strategies currently being investigated, from a humanized radiolabeled monoclonal antibody (J-591) that targets radiation into tumor cells, moving on to vaccines and through to immunomodulator agents such as anti-CPLA-4 and anti-PD-1 monoclonal antibodies that activate T-cell responses via immune checkpoint inhibition. We explore different opinions on the best approach to integrate immunotherapy into existing standard therapies, such as androgen-deprivation therapy, radiotherapy or chemotherapy, and review different combination sequences, patient types and time points during the course of the disease to achieve a lasting immune response. We present data from recent phase III clinical trials that call for a change in trial endpoint design with immunotherapy agents, from the traditional tumor progression to overall survival and how such trials should include immune response measurements as secondary or intermediate endpoints to help identify patient clinical benefit in the earlier phases of treatment. Finally, we join in the recent questioning on the validity of RECIST criteria to measure response to immunotherapeutic agents, as initial increases in the size of tumors/lymph nodes, which are part of a normal immune response, could be categorized as disease progression under RECIST.

  17. VRP immunotherapy targeting neu: treatment efficacy and evidence for immunoediting in a stringent rat mammary tumor model.

    Science.gov (United States)

    Laust, Amanda K; Sur, Brandon W; Wang, Kehui; Hubby, Bolyn; Smith, Jonathan F; Nelson, Edward L

    2007-12-01

    The ability to overcome intrinsic tolerance to a strict "self" tumor-associated antigen (TAA) and successfully treat pre-existing tumor is the most stringent test for anti-tumor immunotherapeutic strategies. Although this capacity has been demonstrated in various models using complicated strategies that may not be readily translated into the clinical arena, straightforward antigen-specific immunotherapeutic strategies in the most stringent models of common epithelial cancers have largely failed to meet this standard. We employed an immunotherapeutic strategy using an alphavirus-based, virus-like replicon particle (VRP), which has in vivo tropism for dendritic cells, to elicit immune responses to the non-mutated TAA rat neu in an aggressive rat mammary tumor model. Using this VRP-based immunotherapeutic strategy targeting a single TAA, we generated effective anti-tumor immunity in the setting of pre-existing tumor resulting in the cure of 36% of rats over multiple experiments, P = 0.002. We also observed down-regulation of rat neu expression in tumors that showed initial responses followed by tumor escape with resumption of rapid tumor growth. These responses were accompanied by significant anti-tumor proliferative responses and CD8+ cellular tumor infiltrates, all of which were restricted to animals receiving the anti-neu immunotherapy. Together these data, obtained in a stringent "self" TAA model, indicate that the VRP-based antigen-specific immunotherapy elicits sufficiently potent immune responses to exert immunologic pressure, selection, and editing of the growing tumors, thus supporting the activity of this straightforward immunotherapy and suggesting that it is a promising platform upon which to build even more potent strategies.

  18. Immunotherapy for food allergies in children.

    Science.gov (United States)

    Martinolli, Francesco; Carraro, Silvia; Berardi, Mariangela; Ferraro, Valentina; Baraldi, Eugenio; Zanconato, Stefania

    2014-01-01

    Food allergy is an increasingly prevalent problem all over the world and especially in westernized countries, and there is an unmet medical need for an effective form of therapy. During childhood natural tolerance development is frequent, but some children with cow's milk or hen's egg allergy and the majority of children with peanut allergy will remain allergic until adulthood, limiting not only the diet of patients but also their quality of life. Within the last several years, the usefulness of immunotherapy for food allergies has been investigated in food allergic patients. Several food immunotherapies are being developed; these involve oral, sublingual, epicutaneous, or subcutaneous administration of small amounts of native or modified allergens to induce immune tolerance. The approach generally follows the same principles as immunotherapy of other allergic disorders and involves administering small increasing doses of food during an induction phase followed by a maintenance phase with regular intake of a maximum tolerated amount of food. Oral immunotherapy seems to be a promising approach for food allergic patients based on results from small uncontrolled and controlled studies. Diet containing heated milk and egg may represent an alternative approach to oral immunomodulation for cow's milk and egg allergic subjects. However, oral food immunotherapy remains an investigational treatment to be further studied before advancing into clinical practice. Additional bigger, multicentric and hopefully randomized-controlled studies must answer multiple questions including optimal dose, ideal duration of immunotherapy, degree of protection, efficacy for different ages, severity and type of food allergy responsive to treatment.

  19. Activities-specific balance confidence in people with multiple sclerosis.

    Science.gov (United States)

    Nilsagård, Ylva; Carling, Anna; Forsberg, Anette

    2012-01-01

    Objective. To evaluate the validity of the Activities-specific Balance Confidence scale (ABC) in people with multiple sclerosis (PwMS). Design. A multicentre, cross-sectional study. Setting. Six rural and urban Swedish sites, including specialized units at hospitals and primary care centers. Participants. A sample of 84 PwMS with subjective gait and balance impairment but still able to walk 100 m (comparable with EDSS 1-6). Outcome Measures. Timed Up and Go, Timed Up and Go(cog), 25-foot Timed Walk Test, Four Square Step Test, Dynamic Gait Index, Chair Stand Test, 12-item MS Walking Scale, self-reported falls, and use of assistive walking device were used for validation. Results. The concurrent convergent validity was moderate to good (0.50 to -0.75) with the highest correlation found for the 12-item MS Walking Scale. The ABC discriminated between multiple fallers and nonfallers but not between men and women. Ecological validity is suggested since ABC discriminated between users of assistive walking device and nonusers. The internal consistency was high at α = 0.95, and interitem correlations were between 0.30 and 0.83. Conclusion. This study supports the validity of the ABC for persons with mild-to-moderate MS. The participants lacked balance confidence in many everyday activities, likely restricting their participation in society.

  20. Effective Delivery of Antigen-Encapsulin Nanoparticle Fusions to Dendritic Cells Leads to Antigen-Specific Cytotoxic T Cell Activation and Tumor Rejection.

    Science.gov (United States)

    Choi, Bongseo; Moon, Hyojin; Hong, Sung Joon; Shin, Changsik; Do, Yoonkyung; Ryu, Seongho; Kang, Sebyung

    2016-08-23

    In cancer immunotherapy, robust and efficient activation of cytotoxic CD8(+) T cell immune responses is a promising, but challenging task. Dendritic cells (DCs) are well-known professional antigen presenting cells that initiate and regulate antigen-specific cytotoxic CD8(+) T cells that kill their target cells directly as well as secrete IFN-γ, a cytokine critical in tumor rejection. Here, we employed recently established protein cage nanoparticles, encapsulin (Encap), as antigenic peptide nanocarriers by genetically incorporating the OT-1 peptide of ovalbumin (OVA) protein to the three different positions of the Encap subunit. With them, we evaluated their efficacy in activating DC-mediated antigen-specific T cell cytotoxicity and consequent melanoma tumor rejection in vivo. DCs efficiently engulfed Encap and its variants (OT-1-Encaps), which carry antigenic peptides at different positions, and properly processed them within phagosomes. Delivered OT-1 peptides were effectively presented by DCs to naïve CD8(+) T cells successfully, resulting in the proliferation of antigen-specific cytotoxic CD8(+) T cells. OT-1-Encap vaccinations in B16-OVA melanoma tumor bearing mice effectively activated OT-1 peptide specific cytotoxic CD8(+) T cells before or even after tumor generation, resulting in significant suppression of tumor growth in prophylactic as well as therapeutic treatments. A large number of cytotoxic CD8(+) T cells that actively produce both intracellular and secretory IFN-γ were observed in tumor-infiltrating lymphocytes collected from B16-OVA tumor masses originally vaccinated with OT-1-Encap-C upon tumor challenges. The approaches we describe herein may provide opportunities to develop epitope-dependent vaccination systems that stimulate and/or modulate efficient and epitope-specific cytotoxic T cell immune responses in nonpathogenic diseases.

  1. The use of growth factors to modulate the activities of antigen–specific CD8+ T cells in vitro

    Science.gov (United States)

    Alenzi, FQ; Alenazi, FA; Al-Kaabi, Y; Salem, ML

    2011-01-01

    survival of antigen–specific T cells can be differently modulated by immunomodulatory factors, where, interleukin–12 and IGF–1 induced the favorable effect. These results have a significant implication for T cell adoptive immunotherapy in different settings. PMID:22514573

  2. Immunotherapy in high-risk chemotherapy-resistant patients with metastatic solid tumors and hematological malignancies using intentionally mismatched donor lymphocytes activated with rIL-2: a phase I study.

    Science.gov (United States)

    Slavin, Shimon; Ackerstein, Aliza; Or, Reuven; Shapira, Michael Y; Gesundheit, Benjamin; Askenasy, Nadir; Morecki, Shoshana

    2010-10-01

    The feasibility and safety of immunotherapy mediated by intentionally mismatched rIL-2 activated killer lymphocytes (IMAK) with no prior stem cell engraftment was investigated in patients with advanced chemotherapy-resistant hematological malignancies and metastatic solid tumors. Our goals were to maximize anti-cancer activity by using intentionally mismatched donor lymphocytes; amplify killing of target cancer cells by rIL-2 activation of killer cells in vitro and in vivo, and avoid the risk of graft-versus-host disease (GVHD) by anticipated rejection of alloreactive donor lymphocytes. Conditioning consisted of 5 days of fludarabine 25 mg/m(2) or a single dose of cyclophosphamide 1,000 mg/m(2), 2 subcutaneous injections of alpha interferon (IFN) 3 x 10(6) and COX2 inhibitors, followed by administration of IMAK (65 +/- 5 CD3(+)CD56(-); 17 +/- 5 CD3(-)CD56(+)) in conjunction with low dose subcutaneous rIL-2 (6 x 10(6) IU/m(2)/day) for 5 days for continuous activation of alloreactive donor lymphocytes prior to their anticipated rejection. Here, we present our phase 1 clinical study data in a cohort of 40 high-risk patients with metastatic solid tumors and hematological malignancies. Treatment was accompanied by some malaise and occasional self-limited fever but otherwise well tolerated on an outpatient basis. Transient engraftment of donor cells was documented in two patients and only one developed self-limited grade 1 GVHD. Among patients with chemotherapy-resistant disease, long-term progression-free survival was recorded in 5 of 21 evaluable patients with metastatic solid tumors and in four of five patients with hematological malignancies. We conclude that the proposed procedure is feasible, safe, and potentially effective, with some otherwise resistant cancer patients long-term disease-free, thus justifying larger Phase II studies in patients with hematological malignancies and metastatic solid tumors, preferably at a stage of minimal residual disease with the

  3. Immunological comparison of allergen immunotherapy tablet treatment and subcutaneous immunotherapy against grass allergy

    DEFF Research Database (Denmark)

    Aasbjerg, K; Backer, V; Lund, G;

    2014-01-01

    BACKGROUND: IgE-mediated allergic rhinitis to grass pollen can successfully be treated with either allergen immunotherapy tablets (SLIT tablet) or SQ-standardized subcutaneous immunotherapy (SCIT). The efficacy of these two treatment modalities for grass allergy is comparable, but the immunological...

  4. Enhancing the Efficacy of Prostate Cancer Immunotherapy by Manipulating T-Cell Receptor Signaling in Order to Alter Peripheral Regulatory T-Cell Activity

    Science.gov (United States)

    2011-07-01

    Splenocytes were treated for twenty four hours with mPSCA83-91 and IL-2, with Brefeldin-A being added in the last six hours in order to arrest the Golgi ... apparatus of the cells, thus allowing detectable levels of IFNγ to build up in the cytoplasm of activated T cells. Splenocytes were washed and

  5. Cancer immunotherapy out of the gate: the 22nd annual Cancer Research Institute International Immunotherapy Symposium.

    Science.gov (United States)

    Tontonoz, Matthew; Gee, Connie E

    2015-05-01

    The 22nd annual Cancer Research Institute (CRI) International Immunotherapy Symposium was held from October 5-8, 2014, in New York City. Titled "Cancer Immunotherapy: Out of the Gate," the symposium began with a Cancer Immunotherapy Consortium satellite meeting focused on issues in immunotherapy drug development, followed by five speaker sessions and a poster session devoted to basic and clinical cancer immunology research. The second annual William B. Coley lecture was delivered by Lieping Chen, one of the four recipients of the 2014 William B. Coley Award for Distinguished Research in Tumor Immunology; the other three recipients were Gordon Freeman, Tasuku Honjo, and Arlene Sharpe. Prominent themes of the conference were the use of genomic technologies to identify neoantigens and the emergence of new immune modulatory molecules, beyond CTLA-4 and PD-1/PD-L1, as new therapeutic targets for immunotherapy.

  6. Is active participation in specific sport activities linked with back pain?

    DEFF Research Database (Denmark)

    Mogensen, A.M.; Gausel, AM; Wedderkopp, Niels

    2007-01-01

    specific kinds of sports and self-reported back problems. Back pain is a common complaint in young people and physical inactivity is generally thought to contribute to this. However, some specific sport activities may be detrimental or beneficial to the spine. Information was collected through a semi......-structured interview, a physical examination, and a questionnaire. Associations for back pain, low back pain, mid back pain and neck pain in the preceding month were investigated in relation to specific sports. Associations were controlled for body mass index, puberty stage and sex. There was no association between...

  7. Prussian blue nanoparticle-based photothermal therapy combined with checkpoint inhibition for photothermal immunotherapy of neuroblastoma.

    Science.gov (United States)

    Cano-Mejia, Juliana; Burga, Rachel A; Sweeney, Elizabeth E; Fisher, John P; Bollard, Catherine M; Sandler, Anthony D; Cruz, Conrad Russell Y; Fernandes, Rohan

    2017-02-01

    We describe "photothermal immunotherapy," which combines Prussian blue nanoparticle (PBNP)-based photothermal therapy (PTT) with anti-CTLA-4 checkpoint inhibition for treating neuroblastoma, a common, hard-to-treat pediatric cancer. PBNPs exhibit pH-dependent stability, which makes them suitable for intratumorally-administered PTT. PBNP-based PTT is able to lower tumor burden and prime an immune response, specifically an increased infiltration of lymphocytes and T cells to the tumor area, which is complemented by the antitumor effects of anti-CTLA-4 immunotherapy, providing a more durable treatment against neuroblastoma in an animal model. We observe 55.5% survival in photothermal immunotherapy-treated mice at 100days compared to 12.5%, 0%, 0%, and 0% survival in mice receiving: anti-CTLA-4 alone, PBNPs alone, PTT alone, and no treatment, respectively. Additionally, long-term surviving, photothermal immunotherapy-treated mice exhibit protection against neuroblastoma rechallenge, suggesting the development of immunity against these tumors. Our findings suggest the potential of photothermal immunotherapy in improving treatments for neuroblastoma.

  8. T细胞性急性淋巴细胞白血病的特异性免疫治疗及靶向基因治疗研究进展%Research Progress of Specific Immunotherapy and Targeted Gene Therapy on T-cell Acute Lymphoblastic Leukemia

    Institute of Scientific and Technical Information of China (English)

    迟昨非; 吴斌; 杨威

    2015-01-01

    T细胞性急性淋巴细胞白血病( T-ALL)预后差,易早期复发,寻找安全有效的治疗手段成为临床研究热点。特异性免疫治疗及靶向基因治疗克服了传统化疗药物的非靶向性,为解决化疗对正常细胞和机体损伤较大的问题提供了可能。本文对Campath-1H、Dachzumab、抗原特异性细胞毒性 T细胞( CTL)等特异性免疫治疗及阻断Lmo2基因、FMS样酪氨酸激酶-3(FLT3)、Bcl-2相互作用的细胞凋亡调节因子(Bim)和Notch1等靶向基因治疗T-ALL进行综述,阐述其抗T-ALL细胞的作用机制和相关临床试验,为T-ALL的治疗提供参考和新的研究思路。%T-cell acute lymphoblastic leukemia( T-ALL)has poor prognosis and early relapse,which makes it a research hotspot to find safe and effective therapies. Specific immunotherapy and targeted gene therapy have the superiority of killing T-ALL cells without injuring normal cells and body compared with the traditional chemotherapy drugs. The article made a review of specific immunotherapy,such as Campath-1H,Dachzumab and CTL,and targeted gene therapy,such as blocking Lmo2,FLT3,Bim and Notch1 on T-ALL and illustrated the mechanism and relevant clinical trials,in order to provide a reference for the treatment of T-ALL and new thoughts for relevant research.

  9. Immunotherapy of acute leukemia by chimeric antigen receptor-modified lymphocytes using an improved Sleeping Beauty transposon platform.

    Science.gov (United States)

    Magnani, Chiara F; Turazzi, Nice; Benedicenti, Fabrizio; Calabria, Andrea; Tenderini, Erika; Tettamanti, Sarah; Giordano Attianese, Greta M P; Cooper, Laurence J N; Aiuti, Alessandro; Montini, Eugenio; Biondi, Andrea; Biagi, Ettore

    2016-08-09

    Chimeric antigen receptor (CAR)-modified T-cell adoptive immunotherapy is a remarkable therapeutic option proven effective in the treatment of hematological malignancies. In order to optimize cell manufacturing, we sought to develop a novel clinical-grade protocol to obtain CAR-modified cytokine-induced killer cells (CIKs) using the Sleeping Beauty (SB) transposon system. Administration of irradiated PBMCs overcame cell death of stimulating cells induced by non-viral transfection, enabling robust gene transfer together with efficient T-cell expansion. Upon single stimulation, we reached an average of 60% expression of CD123- and CD19- specific 3rd generation CARs (CD28/OX40/TCRzeta). Furthermore, modified cells displayed persistence of cell subsets with memory phenotype, specific and effective lytic activity against leukemic cell lines and primary blasts, cytokine secretion, and proliferation. Adoptive transfer of CD123.CAR or CD19.CAR lymphocytes led to a significant anti-tumor response against acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL) disseminated diseases in NSG mice. Notably, we found no evidence of integration enrichment near cancer genes and transposase expression at the end of the differentiation. Taken all together, our findings describe a novel donor-derived non-viral CAR approach that may widen the repertoire of available methods for T cell-based immunotherapy.

  10. Development of sipuleucel-T: autologous cellular immunotherapy for the treatment of metastatic castrate resistant prostate cancer.

    Science.gov (United States)

    Sims, Robert B

    2012-06-19

    Sipuleucel-T, the first autologous cellular immunotherapy approved by the United States Food and Drug Administration, is designed to stimulate an immune response to prostate cancer. Sipuleucel-T is manufactured by culturing a patient's peripheral blood mononuclear cells, including autologous antigen presenting cells (APCs), with a recombinant protein comprising a tumor-associated antigen (prostatic acid phosphatase [PAP]) and granulocyte colony-macrophage stimulating factor (GM-CSF). A full course of treatment comprises 3 infusions of sipuleucel-T, given at approximately 2-week intervals. The pattern of APC activation is consistent with priming by the first infusion, and boosting by the second and third infusions. Preclinical and clinical studies have demonstrated evidence of a robust antigen-specific immune response that includes a progressive and persistent increase in antigen-specific cellular and humoral immune responses. Treatment with sipuleucel-T has demonstrated a survival benefit in Phase 3 studies of subjects with metastatic castrate resistant (hormone refractory) prostate cancer (mCRPC). Adverse events with sipuleucel-T were generally mild to moderate and resolved within 2 days. Serious adverse events, autoimmune events, and cerebrovascular events occurred at a similar rate to control subjects. As the first autologous cellular immunotherapy to demonstrate an improvement in overall survival in asymptomatic or minimally symptomatic mCRPC patients, sipuleucel-T represents a new treatment paradigm in oncology.

  11. Sarcoma Immunotherapy: Past Approaches and Future Directions

    Directory of Open Access Journals (Sweden)

    S. P. D'Angelo

    2014-01-01

    Full Text Available Sarcomas are heterogeneous malignant tumors of mesenchymal origin characterized by more than 100 distinct subtypes. Unfortunately, 25–50% of patients treated with initial curative intent will develop metastatic disease. In the metastatic setting, chemotherapy rarely leads to complete and durable responses; therefore, there is a dire need for more effective therapies. Exploring immunotherapeutic strategies may be warranted. In the past, agents that stimulate the immune system such as interferon and interleukin-2 have been explored and there has been evidence of some clinical activity in selected patients. In addition, many cancer vaccines have been explored with suggestion of benefit in some patients. Building on the advancements made in other solid tumors as well as a better understanding of cancer immunology provides hope for the development of new and exciting therapies in the treatment of sarcoma. There remains promise with immunologic checkpoint blockade antibodies. Further, building on the success of autologous cell transfer in hematologic malignancies, designing chimeric antigen receptors that target antigens that are over-expressed in sarcoma provides a great deal of optimism. Exploring these avenues has the potential to make immunotherapy a real therapeutic option in this orphan disease.

  12. Immunotherapy applications of carbon nanotubes: from design to safe applications.

    Science.gov (United States)

    Fadel, Tarek R; Fahmy, Tarek M

    2014-04-01

    Carbon nanotubes (CNTs) have the potential to overcome significant challenges related to vaccine development and immunotherapy. Central to these applications is an improved understanding of CNT interactions with the immune system. Unique properties such as high aspect ratio, flexible surface chemistry, and control over structure and morphology may allow for enhanced target specificity and transport of antigens across cell membranes. Although recent work has demonstrated the potential of CNTs to amplify the immune response as adjuvants, other results have also linked their proinflammatory properties to harmful health effects. Here, we review the recent advances of CNT-based immunological research, focusing on current understandings of therapeutic efficacy and mechanisms of immunotoxicology.

  13. The journey from discoveries in fundamental immunology to cancer immunotherapy.

    Science.gov (United States)

    Miller, Jacques F A P; Sadelain, Michel

    2015-04-13

    Recent advances in cancer immunotherapy have directly built on 50 years of fundamental and technological advances that made checkpoint blockade and T cell engineering possible. In this review, we intend to show that research, not specifically designed to bring relief or cure to any particular disease, can, when creatively exploited, lead to spectacular results in the management of cancer. The discovery of thymus immune function, T cells, and immune surveillance bore the seeds for today's targeted immune interventions and chimeric antigen receptors.

  14. Effect of house dust mite immunotherapy on interleukin-10-secreting regulatory T cells in asthmatic children

    Institute of Scientific and Technical Information of China (English)

    WANG Wei; XIANG Li; LIU Yong-ge; WANG Yong-hong; SHEN Kun-ling

    2010-01-01

    Background Subcutaneous specific immunotherapy has been demonstrated to be capable of inducing T-cell regulatory response.Interleukin-10 (IL-10) plays a crucial role in inducing allergen-specific tolerance.However the reports of the changes of IL-10 in house dust mite (HDM)-specific immunotherapy were varied.The aim of this study was to evaluate the function of IL-10-secreting regulatory T cells in asthma children successfully treated with HDM immunotherapy.Methods Peripheral blood mononuclear cells (PBMCs) were isolated from 27 patients following 1.5--2 years of HDM-specific immunotherapy (SIT, SIT group) and from 27 matched treated asthmatic children allergic to HDM (asthmagroup).After 48 hours of in vitro stimulation with HDM extracts, IL-10-secreting regulatory T cells were measured by four colour flow cytometry.Sera were tested for allergen-specific IgG4 and IgE using the Immuno CAP 100 assay.Results PBMCs from children undergoing immunotherapy following HDM extracts stimuli produced significantly more IL-10 compared with the asthma group.The frequency of iTreg cells and aTreg cells increased in SIT group after HDM stimulation, while it was not affected in the asthma group.Among the iTreg cells and aTreg cells, the frequency of CD4+CD25-Foxp3-IL-10+ Treg cells increased the most which was 2 times higher than that in unstimulated cultures in SIT group.The levels of HDM-specific IgG4 of SIT group was significiently higher compared with asthma group, but there was no correlation of the levels of HDM-specific IgG4 and IL-10 secreting Treg cells.Conclusions HDM-specific immunotherapy can successfully upregulate the frequency of IL-10-secreting Treg cells.CD4+CD25-Foxp3-IL-10+ Treg cells may play a key role in inducing the immune tolerance in HDM-specific immunotherapy.

  15. Research on Immunotherapy: Using the Immune System to Treat Cancer

    Science.gov (United States)

    ... cells that suppress immune responses. These advances in cancer immunotherapy are the result of long-term investments in ... Engineering Patients’ Immune Cells to Treat Their Cancers Cancer immunotherapy in children: How does it differ from approaches ...

  16. Sublingual immunotherapy: World Allergy Organization position paper 2013 update

    NARCIS (Netherlands)

    G.W. Canonica (Giorgio Walter); L. Cox (Linda); R. Pawankar (Ruby); C.E. Baena-Cagnani (Carlos); M.S. Blaiss (Michael); S. Bonini (Sergio); J. Bousquet (Jean); M. Calderon (Moises); E. Compalati (Enrico); S.R. Durham (Stephen); R. Gerth van Wijk (Roy); D. Larenas-Linnemann (Désirée); H. Nelson (Harold); G. Passalacqua (Giovanni); O. Pfaar (Oliver); K. Rosario (Karyna); D. Ryan (Dermot); L. Rosenwasser (Lanny); P. Schmid-Grendelmeier (Peter); G.E. Senna (Gianenrico); E. Valovirta (Erkka); H.P. van Bever (Hugo); P. Vichyanond (Pakit); U. Wahn (Ulrich); O.M. Yusuf (Osman)

    2014-01-01

    textabstractWe have prepared this document, "Sublingual Immunotherapy: World Allergy Organization Position Paper 2013 Update", according to the evidence-based criteria, revising and updating chapters of the originally published paper, "Sublingual Immunotherapy: World Allergy Organization Position Pa

  17. Increased parasellar activity on gallium SPECT is not specific for active cluster headache

    Energy Technology Data Exchange (ETDEWEB)

    Sianard-Gainko, J.; Milet, J.; Ghuysen, V.; Schoenen, J. (Univ. Departments of Neurology and Nuclear Medicine, Liege (Belgium))

    1994-04-01

    The authors have performed gallium SPECT head scans in 30 successive cluster headache (CH) patients and in 7 migraineurs without aura. Parasellar hyperactivity was judged as present in 81% of chronic CH patients. 54% of episodic CH patients in an active period, 56% of episodic CH patients in remission and 71% of migraineurs. No significant correlations were found between the SPECT images and the duration of the disease, of cluster periods or of remissions. Increased parasellar activity on gallium SPECT is thus not specific for CH, nor for the active period of episodic CH. The method lacks reliability for investigation of putative cavernous sinus inflammation. 4 refs., 1 tab.

  18. Use of new technology to improve utilization and adherence to immunotherapy.

    Science.gov (United States)

    Joshi, Smita; Dimov, Ves

    2014-01-01

    Technology and social media have dramatically altered the landscape in which we practice medicine. Clinicians have increasingly turned to technology and the internet to enhance patient care. Allergists have used these modalities to improve utilization and adherence to immunotherapy. Electronic medical records (EMRs) are being widely adopted by allergy practices and some offer allergy/immunology specific modules that aid in daily workflow. The development of specialized devices that reduce pain associated with immunotherapy administration may improve compliance with immunotherapy. Social media and other forms of electronic communication such as e-mail, Facebook, Twitter, short message service (SMS), and YouTube give clinicians multiple avenues to disseminate information and reach their patients, possibly improving patient adherence to therapy. Finally, tablet computers, online networks, and electronic surveys provide additional ways to connect patients and physicians.

  19. The number of FceRI receptors on basophils decreases during subcutaneous immunotherapy

    DEFF Research Database (Denmark)

    Schmid, J. M.; Dahl, R.; Hoffmann, H. J.

    2015-01-01

    Background: Allergen specific immunotherapy is the only disease modifying treatment of allergic diseases. It induces complex cellular and humoral changes leading to an inhibition of type-1 allergic reactions. Method: Twenty four young grass pollen allergic adults suffering from seasonal rhino-con...

  20. The use of bispecific antibodies in tumor cell and tumor vasculature directed immunotherapy

    NARCIS (Netherlands)

    Molema, G; Kroesen, BJ; Helfrich, W; Meijer, DKF; de Leij, LFMH

    2000-01-01

    To overcome dose limiting toxicities and to increase efficacy of immunotherapy of cancer, a number of strategies are under development for selectively redirecting effector cells/molecules towards tumor cells. Many of these strategies exploit the specificity of tumor associated antigen recognition by

  1. Focal radiation therapy combined with 4-1BB activation and CTLA-4 blockade yields long-term survival and a protective antigen-specific memory response in a murine glioma model.

    Directory of Open Access Journals (Sweden)

    Zineb Belcaid

    Full Text Available BACKGROUND: Glioblastoma (GBM is the most common malignant brain tumor in adults and is associated with a poor prognosis. Cytotoxic T lymphocyte antigen -4 (CTLA-4 blocking antibodies have demonstrated an ability to generate robust antitumor immune responses against a variety of solid tumors. 4-1BB (CD137 is expressed by activated T lymphocytes and served as a co-stimulatory signal, which promotes cytotoxic function. Here, we evaluate a combination immunotherapy regimen involving 4-1BB activation, CTLA-4 blockade, and focal radiation therapy in an immune-competent intracranial GBM model. METHODS: GL261-luciferace cells were stereotactically implanted in the striatum of C57BL/6 mice. Mice were treated with a triple therapy regimen consisted of 4-1BB agonist antibodies, CTLA-4 blocking antibodies, and focal radiation therapy using a small animal radiation research platform and mice were followed for survival. Numbers of brain-infiltrating lymphocytes were analyzed by FACS analysis. CD4 or CD8 depleting antibodies were administered to determine the relative contribution of T helper and cytotoxic T cells in this regimen. To evaluate the ability of this immunotherapy to generate an antigen-specific memory response, long-term survivors were re-challenged with GL261 glioma en B16 melanoma flank tumors. RESULTS: Mice treated with triple therapy had increased survival compared to mice treated with focal radiation therapy and immunotherapy with 4-1BB activation and CTLA-4 blockade. Animals treated with triple therapy exhibited at least 50% long-term tumor free survival. Treatment with triple therapy resulted in a higher density of CD4+ and CD8+ tumor infiltrating lymphocytes. Mechanistically, depletion of CD4+ T cells abrogated the antitumor efficacy of triple therapy, while depletion of CD8+ T cells had no effect on the treatment response. CONCLUSION: Combination therapy with 4-1BB activation and CTLA-4 blockade in the setting of focal radiation therapy

  2. CD70: An emerging target in cancer immunotherapy.

    Science.gov (United States)

    Jacobs, J; Deschoolmeester, V; Zwaenepoel, K; Rolfo, C; Silence, K; Rottey, S; Lardon, F; Smits, E; Pauwels, P

    2015-11-01

    Over the last decades, advances in the knowledge of immunology have led to the identification of immune checkpoints, reinvigorating cancer immunotherapy. Although normally restricted to activated T and B cells, constitutive expression of CD70 in tumor cells has been described. Moreover, CD70 is implicated in tumor cell and regulatory T cell survival through interaction with its ligand, CD27. In this review, we summarize the targetable expression patterns of CD70 in a wide range of malignancies and the promising mechanism of anti-CD70 therapy in stimulating the anti-tumor immune response. In addition, we will discuss clinical data and future combination strategies.

  3. Immunotherapy in prostate cancer: challenges and opportunities.

    Science.gov (United States)

    Noguchi, Masanori; Koga, Noriko; Moriya, Fukuko; Itoh, Kyogo

    2016-01-01

    Although treatment options for castration-resistant prostate cancer (CRPC) have increased over the last decade, there remains a need for strategies that can provide durable disease control and long-term benefit. Recently, immunotherapy has emerged as a viable and attractive strategy for the treatment of CRPC. To date, there are multiple strategies to target the immune system, and several approaches including therapeutic cancer vaccines and immune checkpoint inhibitors have been most successful in clinical trials. With regard to this, we report the results of the most recent clinical trials investigating immunotherapy in CRPC and discuss the future development of immunotherapy for CRPC, as well as the potential importance of biomarkers in the future progress of this field.

  4. Defining the critical hurdles in cancer immunotherapy

    DEFF Research Database (Denmark)

    Fox, Bernard A; Schendel, Dolores J; Butterfield, Lisa H

    2011-01-01

    Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move...... immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation...... companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed...

  5. Immunotherapy: Shifting the Balance of Cell-Mediated Immunity and Suppression in Human Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Tucker, Jo A.; Jochems, Caroline [Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (United States); Gulley, James L. [Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (United States); Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (United States); Schlom, Jeffrey, E-mail: js141c@nih.gov; Tsang, Kwong Y. [Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (United States)

    2012-12-11

    Active immunotherapy is dependent on the ability of the immune system to recognize and respond to tumors. Despite overwhelming evidence to support a cell-mediated immune response to prostate cancer, it is insufficient to eradicate the disease. This is likely due to a high level of suppression at the tumor site from a variety of sources, including immunosuppressive cells. Immune cells entering the tumor microenvironment may be inhibited directly by the tumor, stromal cells or other immune cells that have been induced to adopt a suppressive phenotype. The resurgence of interest in immunotherapy following the approval of sipuleucel-T and ipilimumab by the Food and Drug Administration has brought about new strategies for overcoming tumor-mediated suppression and bolstering anti-tumor responses. Improved understanding of the immune response to prostate cancer can lead to new combination therapies, such as the use of vaccine with small molecule and checkpoint inhibitors or other immunotherapies.

  6. Immunotherapy: Shifting the Balance of Cell-Mediated Immunity and Suppression in Human Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Jeffrey Schlom

    2012-12-01

    Full Text Available Active immunotherapy is dependent on the ability of the immune system to recognize and respond to tumors. Despite overwhelming evidence to support a cell-mediated immune response to prostate cancer, it is insufficient to eradicate the disease. This is likely due to a high level of suppression at the tumor site from a variety of sources, including immunosuppressive cells. Immune cells entering the tumor microenvironment may be inhibited directly by the tumor, stromal cells or other immune cells that have been induced to adopt a suppressive phenotype. The resurgence of interest in immunotherapy following the approval of sipuleucel-T and ipilimumab by the Food and Drug Administration has brought about new strategies for overcoming tumor-mediated suppression and bolstering anti-tumor responses. Improved understanding of the immune response to prostate cancer can lead to new combination therapies, such as the use of vaccine with small molecule and checkpoint inhibitors or other immunotherapies.

  7. Targeted immunotherapy of cancer with CAR T cells: achievements and challenges.

    Science.gov (United States)

    Lipowska-Bhalla, Grazyna; Gilham, David E; Hawkins, Robert E; Rothwell, Dominic G

    2012-07-01

    The adoptive transfer of chimeric antigen receptor (CAR)-expressing T cells is a relatively new but promising approach in the field of cancer immunotherapy. This therapeutic strategy is based on the genetic reprogramming of T cells with an artificial immune receptor that redirects them against targets on malignant cells and enables their destruction by exerting T cell effector functions. There has been an explosion of interest in the use of CAR T cells as an immunotherapy for cancer. In the pre-clinical setting, there has been a considerable focus upon optimizing the structural and signaling potency of the CAR while advances in bio-processing technology now mean that the clinical testing of these gene-modified T cells has become a reality. This review will summarize the concept of CAR-based immunotherapy and recent clinical trial activity and will further discuss some of the likely future challenges facing CAR-modified T cell therapies.

  8. In vitro methods for generating CD8+ T-cell clones for immunotherapy from the naïve repertoire.

    Science.gov (United States)

    Ho, William Y; Nguyen, Hieu N; Wolfl, Matthias; Kuball, Juergen; Greenberg, Philip D

    2006-03-20

    . Using these techniques, high-avidity CTL clones specific for an A()0201-restricted epitope of WT1 have been generated from nearly all normal A2(+) donors tested. Such clones have been demonstrated to be capable of recognizing and lysing leukemic cells, and will soon be tested for therapeutic activity in clinical trials of adoptive immunotherapy in patients with relapsed leukemia after transplantation.

  9. 癌症的免疫治疗和细胞治疗%Immunotherapy and cell therapy for cancer

    Institute of Scientific and Technical Information of China (English)

    Jeremy COPP; 谢伟东; 张朝杰; Jon BERGLIN

    2016-01-01

    最近,癌症免疫治疗作为可行性的新治疗法而得到广泛青睐。免疫治疗主要分为2种类型,即被动免疫治疗和主动免疫治疗。被动免疫治疗包括单克隆抗体和(或)抗体-药物偶联物治疗;主动免疫治疗包括癌症疫苗和嵌合抗原受体T细胞(CAR-T)治疗。癌症疫苗是利用患者自身的细胞作为抗原递呈细胞,识别特异性的肿瘤抗原。CAR-T治疗是利用遗传工程改造的患者的T细胞,通过嵌合抗原受体识别肿瘤抗原。最近一些成功的案例,包括美国FDA批准的癌症免疫疗法,让各大制药公司对癌症免疫治疗研究报以强烈兴趣,如使用抗免疫检查点抑制剂单克隆抗体治疗肿瘤和针对前列腺癌的Provenge癌症疫苗,以及治疗复发或难治性急性淋巴细胞白血病的具有突破性的CAR-T免疫治疗。本综述讨论了目前肿瘤免疫学领域的最新进展以及未来的发展方向。%Cancer immunotherapies are recently gaining attention as viable therapeutic options. There are two types of immunotherapy:passive and active. The passive immunotherapies include several treatments such as monoclonal antibodies,either alone or as antibody-drug conjugates. The active immunotherapies include cancer vaccines which utilize the patient′s own cells as antigen presenting cells and target specific cancer antigens,and chimeric antigen receptor T-cell(CAR-T)therapy which engineers a patient′s T-cells to recognize cancer antigens through chimeric antigen receptors. Recent successes include the US FDA approval of a number of cancer immunotherapies such as treatments utilizing monoclonal antibodies against immune checkpoint inhibitors,the Provenge cancer vaccine that targets prostrate cancer,and a CAR-T against relapsed/refractory acute lymphoblastic leukemia that was designated with breakthrough drug status,all of which has had drug companies investigating cancer immunotherapies with intense

  10. Non-stiff anti-amphiphysin syndrome: clinical manifestations and outcome after immunotherapy.

    Science.gov (United States)

    Moon, Jangsup; Lee, Soon-Tae; Shin, Jung-Won; Byun, Jung-Ick; Lim, Jung-Ah; Shin, Yong-Won; Kim, Tae-Joon; Lee, Keon-Joo; Park, Kyung-Il; Jung, Keun-Hwa; Jung, Ki-Young; Lee, Sang Kun; Chu, Kon

    2014-09-15

    Amphiphysin antibody causes paraneoplastic stiff-person syndrome and can also result in a variety of neurological manifestations. Here, we investigated the clinical spectrum of 20 patients with non-stiff anti-amphiphysin syndrome and their responses to immunotherapy. The most common neurological manifestation was limbic encephalitis (n=10), followed by dysautonomia (n=9), and cerebellar dysfunction (n=6). Cancer was detected in only seven patients. Intravenous immunoglobulin or steroid treatment was effective in most patients, but three improved only after rituximab treatment. Our study suggests that anti-amphiphysin syndrome can manifest as non-stiff encephalomyelitis and is only partially associated with cancer. Active immunotherapy, including rituximab, would be beneficial.

  11. Targeting the MHC Class II antigen presentation pathway in cancer immunotherapy.

    Science.gov (United States)

    Thibodeau, Jacques; Bourgeois-Daigneault, Marie-Claude; Lapointe, Réjean

    2012-09-01

    The success of immunotherapy relies on the participation of all arms of the immune system and the role of CD4+ T lymphocytes in preventing tumor growth is now well established. Understanding how tumors evade immune responses holds the key to the development of cancer immunotherapies. In this review, we discuss how MHC Class II expression varies in cancer cells and how this influences antitumor immune responses. We also discuss the means that are currently available for harnessing the MHC Class II antigen presentation pathway for the development of efficient vaccines to activate the immune system against cancer.

  12. Comparison of clinical grade type 1 polarized and standard matured dendritic cells for cancer immunotherapy

    DEFF Research Database (Denmark)

    Hansen, Morten; Hjortø, Gertrud Malene; Donia, Marco

    2013-01-01

    Monocyte-derived dendritic cells (DCs) used for immunotherapy e.g. against cancer are commonly matured by pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and prostaglandin E2 although the absence of Toll-like receptor mediated activation prevents secretion of IL-12 from DCs and subsequent efficient......DCs and strikingly had the highest expression of the inhibitory molecules PD-L1 and CD25. Thus, further studies with type 1 polarized DCs are warranted for use in immunotherapy, but when combined with PGE2 as in mpDCs, they seems to be less optimal for maturation of DCs....

  13. Toward Maximizing Immunotherapy in Metastatic Castration Resistant Prostate Cancer – Rationale for Combinatorial Approaches Using Chemotherapy

    Directory of Open Access Journals (Sweden)

    Susan F Slovin

    2012-05-01

    Full Text Available Prostate cancer is particularly suited for active immunotherapy because of the expression of a distinctive number of antigens which are overexpressed on prostate cancer cells and cell lines. There is evidence in this disease that tumors promote immune tolerance starting early in the disease course. As such, chemotherapy, by suppressing tumors and activating immune system homeostatic mechanisms, may help overcome this tumor-induced immune tolerance. Sipuleucel-T which has recently been approved in the US, is an autologous cellule product immunotherapy that induces immune activity likely through activation of dendritic cells. This was associated with a survival benefit in the absence of significant toxicity. However, a post hoc analysis of phase III trial participants found a substantial survival benefit to receiving docetaxel some months after sipuleucel-T. However, another phase III immunotherapy trial combining a prostate cancer therapeutic vaccine G-VAX plus docetaxel versus standard docetaxel therapy in advanced prostate cancer, observed a lower overall survival with the vaccine regimen. These trials highlight major unresolved questions concerning the optimum choice, dosing, and timing of chemotherapy relative to active immunotherapy and the overall merits of considering this approach. The ideal treatment approach remains unclear; advances in biomarker validation and trial design may likely improve our ability to assess biologic benefit irrespective of the development of true anti-tumor immunity.

  14. Synthesis of a high specific activity methyl sulfone tritium isotopologue of fevipiprant (NVP-QAW039).

    Science.gov (United States)

    Luu, Van T; Goujon, Jean-Yves; Meisterhans, Christian; Frommherz, Matthias; Bauer, Carsten

    2015-05-15

    The synthesis of a triple tritiated isotopologue of the CRTh2 antagonist NVP-QAW039 (fevipiprant) with a specific activity >3 TBq/mmol is described. Key to the high specific activity is the methylation of a bench-stable dimeric disulfide precursor that is in situ reduced to the corresponding thiol monomer and methylated with [(3)H3]MeONos having per se a high specific activity. The high specific activity of the tritiated active pharmaceutical ingredient obtained by a build-up approach is discussed in the light of the specific activity usually to be expected if hydrogen tritium exchange methods were applied.

  15. Specific Energy Characteristics of Nanoporous Carbon Activated by Orthophosphoric Acid

    Directory of Open Access Journals (Sweden)

    B.I. Rachiy

    2015-12-01

    Full Text Available This paper investigated the effect of the amount of phosphoric acid on the structure nanoporous carbon materials (NCM obtained from raw materials of plant origin. The results voltammetry defined specific capacitance characteristics of NCM and conditions its synthesis with optimal energy parameters established. It is shown that reducing the number of lignin-cellulose materials in precursor volume due to carbonization leads to a decline in specific capacity of NCM approximately 6-20 %.

  16. Targeting the undruggable: immunotherapy meets personalized oncology in the genomic era.

    Science.gov (United States)

    Martin, S D; Coukos, G; Holt, R A; Nelson, B H

    2015-12-01

    Owing to recent advances in genomic technologies, personalized oncology is poised to fundamentally alter cancer therapy. In this paradigm, the mutational and transcriptional profiles of tumors are assessed, and personalized treatments are designed based on the specific molecular abnormalities relevant to each patient's cancer. To date, such approaches have yielded impressive clinical responses in some patients. However, a major limitation of this strategy has also been revealed: the vast majority of tumor mutations are not targetable by current pharmacological approaches. Immunotherapy offers a promising alternative to exploit tumor mutations as targets for clinical intervention. Mutated proteins can give rise to novel antigens (called neoantigens) that are recognized with high specificity by patient T cells. Indeed, neoantigen-specific T cells have been shown to underlie clinical responses to many standard treatments and immunotherapeutic interventions. Moreover, studies in mouse models targeting neoantigens, and early results from clinical trials, have established proof of concept for personalized immunotherapies targeting next-generation sequencing identified neoantigens. Here, we review basic immunological principles related to T-cell recognition of neoantigens, and we examine recent studies that use genomic data to design personalized immunotherapies. We discuss the opportunities and challenges that lie ahead on the road to improving patient outcomes by incorporating immunotherapy into the paradigm of personalized oncology.

  17. 舌下含服粉尘螨滴剂对小儿过敏性鼻炎伴腺样体肥大的疗效%Specific Sublingual Immunotherapy with Dermatophagoides Farinae Drops for Allergic Rhinitis Complicated by Adenoid Hypertrophy in Children

    Institute of Scientific and Technical Information of China (English)

    吕显林; 岳耀光; 张永强; 朱绪亮; 张俊; 郭军; 黄丽芳; 梁仕才

    2015-01-01

    ABSTRACT:Objective To investigate the curative effects of specific sublingual immunotherapy with Dermatophagoides farinae drops on allergic rhinitis complicated by adenoid hypertrophy in children.Methods Ninety children with allergic rhinitis and adenoid hypertrophy randomly re-ceived sublingual immunotherapy with Dermatophagoides farinae drops(group A,n=30),conven-tional treatment with anti-allergic drugs(group B,n=30),or their combination(group C,n=30). Nasal symptoms(nasal congestion,nasal itching,sneezing,runny nose,etc.)and snoring symp-toms(labored breathing,waking up repeatedly,snoring,mouth breathing,etc.)were evaluated u-sing the visual analogue scale(VAS)before and after treatment for 6 months.The maximum thickness of adenoid/anterior-posterior diameter of nasopharyngeal air space (A/N)ratio was measured by X-ray absorptiometry and computed tomography.Results Before treatment,there were no significant differences among the three groups in VAS scores of nasal symptoms and sno-ring symptoms,as well as in A/N ratio(P >0.05).After treatment for 6 months,VAS scores of nasal symptoms and snoring symptoms and A/N ratio obviously reduced in all the three groups (P 0.05).Compared with group B,VAS scores of snoring symp-toms and A/N ratio increased in group A but decreased in group C(P <0.05).Conclusion There is a close relationship between allergic rhinitis and adenoid hypertrophy in children.Specific sub-lingual immunotherapy not only improves nasal allergic symptoms,but also relieves snoring symptoms through reducing adenoid volume.Therefore,specific sublingual immunotherapy pro-vides a new method for non-surgical treatment of allergic rhinitis complicated by adenoid hyper-trophy.%目的:探讨儿童过敏性鼻炎伴腺样体肥大患儿采用舌下含服粉尘螨滴剂治疗的疗效。方法将90例过敏性鼻炎合并腺样体肥大的患儿按随机数字表法分为 A、B、C 3组,每组30例。A 组给予舌下含服粉尘螨滴剂治疗;B 组

  18. Cancer immunotherapy: nanodelivery approaches for immune cell targeting and tracking

    Science.gov (United States)

    Conniot, João; Silva, Joana; Fernandes, Joana; Silva, Liana; Gaspar, Rogério; Brocchini, Steve; Florindo, Helena; Barata, Teresa

    2014-11-01

    Cancer is one of the most common diseases afflicting people globally. New therapeutic approaches are needed due to the complexity of cancer as a disease. Many current treatments are very toxic and have modest efficacy at best. Increased understanding of tumor biology and immunology has allowed the development of specific immunotherapies with minimal toxicity. It is important to highlight the performance of monoclonal antibodies, immune adjuvants, vaccines and cell-based treatments. Although these approaches have shown varying degrees of clinical efficacy, they illustrate the potential to develop new strategies. Targeted immunotherapy is being explored to overcome the heterogeneity of malignant cells and the immune suppression induced by both the tumor and its microenvironment. Nanodelivery strategies seek to minimize systemic exposure to target therapy to malignant tissue and cells. Intracellular penetration has been examined through the use of functionalized particulates. These nano-particulate associated medicines are being developed for use in imaging, diagnostics and cancer targeting. Although nano-particulates are inherently complex medicines, the ability to confer, at least in principle, different types of functionality allows for the plausible consideration these nanodelivery strategies can be exploited for use as combination medicines. The development of targeted nanodelivery systems in which therapeutic and imaging agents are merged into a single platform is an attractive strategy. Currently, several nanoplatform-based formulations, such as polymeric nanoparticles, micelles, liposomes and dendrimers are in preclinical and clinical stages of development. Herein, nanodelivery strategies presently investigated for cancer immunotherapy, cancer targeting mechanisms and nanocarrier functionalization methods will be described. We also intend to discuss the emerging nano-based approaches suitable to be used as imaging techniques and as cancer treatment options.

  19. Subcutaneous Immunotherapy Improves the Symptomatology of Allergic Rhinitis

    Directory of Open Access Journals (Sweden)

    Lourenço, Edmir Américo

    2015-10-01

    Full Text Available Introduction The relevance of allergic rhinitis is unquestionable. This condition affects people's quality of life and its incidence has increased over the last years. Objective Thus, this study aims to analyze the effectiveness of subcutaneous injectable immunotherapy in cases of nasal itching, sneeze, rhinorrhea and nasal congestion in allergic rhinitis patients. Methods In the present study, the same researcher analyzed the records of 281 patients. Furthermore, the researchers identified allergens through puncture cutaneous tests using standardized extracts containing acari, fungi, pet hair, flower pollen, and feathers. Then, the patients underwent treatment with subcutaneous specific immunotherapy, using four vaccine vials for desensitization, associated with environmental hygiene. The authors analyzed conditions of nasal itching, sneeze, rhinorrhea, and nasal congestion throughout the treatment, and assigned them with a score ranging from zero (0, meaning absence of these symptoms to three (3, for severe cases. The symptoms were statistically compared in the beginning, during, and after treatment. Results In this study, authors analyzed the cases distribution according to age and the evolution of symptomatology according to the scores, comparing all phases of treatment. The average score for the entire population studied was 2.08 before treatment and 0.44 at the end. These results represent an overall improvement of ∼79% in symptomatology of allergic rhinitis in the studied population. Conclusion The subcutaneous immunotherapy as treatment of allergic rhinitis led to a reduction in all symptoms studied, improving the quality of life of patients, proving itself as an important therapeutic tool for these pathological conditions.

  20. Recombinant DNA technology for melanoma immunotherapy: anti-Id DNA vaccines targeting high molecular weight melanoma-associated antigen.

    Science.gov (United States)

    Barucca, A; Capitani, M; Cesca, M; Tomassoni, D; Kazmi, U; Concetti, F; Vincenzetti, L; Concetti, A; Venanzi, F M

    2014-11-01

    Anti-idiotypic MK2-23 monoclonal antibody (anti-Id MK2-23 mAb), which mimics the high molecular weight melanoma-associated antigen (HMW-MAA), has been used to implement active immunotherapy against melanoma. However, due to safety and standardization issues, this approach never entered extensive clinical trials. In the present study, we investigated the usage of DNA vaccines as an alternative to MK2-23 mAb immunization. MK2-23 DNA plasmids coding for single chain (scFv) MK2-23 antibody were constructed via the insertion of variable heavy (V H) and light (V L) chains of MK2-23 into the pVAC-1mcs plasmids. Two alternative MK2-23 plasmids format V H/V L, and V L/V H were assembled. We demonstrate that both polypeptides expressed by scFv plasmids in vitro retained the ability to mimic HMW-MAA antigen, and to elicit specific anti-HMW-MAA humoral and cellular immunoresponses in immunized mice. Notably, MK2-23 scFv DNA vaccines impaired the onset and growth of transplantable B16 melanoma cells not engineered to express HMW-MAA. This pilot study suggests that optimized MK2-23 scFv DNA vaccines could potentially provide a safer and cost-effective alternative to anti-Id antibody immunization, for melanoma immunotherapy.

  1. Gene program-specific regulation of PGC-1{alpha} activity

    DEFF Research Database (Denmark)

    Schmidt, Søren F; Mandrup, Susanne

    2011-01-01

    Peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1 α (PGC-1α) activation coordinates induction of the hepatic fasting response through coactivation of numerous transcription factors and gene programs. In the June 15, 2011, issue of Genes & Development, Lustig and colleagues (pp...

  2. Can immunotherapy be useful as a “functional cure” for infection with Human Immunodeficiency Virus-1?

    Directory of Open Access Journals (Sweden)

    Vanham Guido

    2012-09-01

    Full Text Available Abstract Immunotherapy aims to assist the natural immune system in achieving control over viral infection. Various immunotherapy formats have been evaluated in either therapy-naive or therapy-experienced HIV-infected patients over the last 20 years. These formats included non-antigen specific strategies such as cytokines that stimulate immunity or suppress the viral replication, as well as antibodies that block negative regulatory pathways. A number of HIV-specific therapeutic vaccinations have also been proposed, using in vivo injection of inactivated virus, plasmid DNA encoding HIV antigens, or recombinant viral vectors containing HIV genes. A specific format of therapeutic vaccines consists of ex vivo loading of autologous dendritic cells with one of the above mentioned antigenic formats or mRNA encoding HIV antigens. This review provides an extensive overview of the background and rationale of these different therapeutic attempts and discusses the results of trials in the SIV macaque model and in patients. To date success has been limited, which could be explained by insufficient quality or strength of the induced immune responses, incomplete coverage of HIV variability and/or inappropriate immune activation, with ensuing increased susceptibility of target cells. Future attempts at therapeutic vaccination should ideally be performed under the protection of highly active antiretroviral drugs in patients with a recovered immune system. Risks for immune escape should be limited by a better coverage of the HIV variability, using either conserved or mosaic sequences. Appropriate molecular adjuvants should be included to enhance the quality and strength of the responses, without inducing inappropriate immune activation. Finally, to achieve a long-lasting effect on viral control (i.e. a “functional cure” it is likely that these immune interventions should be combined with anti-latency drugs and/or gene therapy.

  3. Enhancement and abrogation : modifications of host immune status influence IL-2 and LAK cell immunotherapy

    NARCIS (Netherlands)

    E.P. Steller (Erick)

    1988-01-01

    textabstractThis thesis will discuss the role immune cells and the host immune system can play in enhancement and abrogation of this novel immunotherapy with interleukin 2 and lymphokine-activated killer cells. Chapter 3 and 4 will discuss the scoring methods in this intraperitoneal cancer and immun

  4. Intracranial administration of deglycosylated C-terminal-specific anti-Aβ antibody efficiently clears amyloid plaques without activating microglia in amyloid-depositing transgenic mice

    Directory of Open Access Journals (Sweden)

    Gordon Marcia N

    2006-05-01

    Full Text Available Abstract Background Antibodies against the Aß peptide clear Aß deposits when injected intracranially. Deglycosylated antibodies have reduced effector functions compared to their intact counterparts, potentially avoiding immune activation. Methods Deglycosylated or intact C-terminal specific high affinity anti-Aβ antibody (2H6 were intracranially injected into the right frontal cortex and hippocampus of amyloid precursor protein (APP transgenic mice. The untreated left hemisphere was used to normalize for the extent of amyloid deposition present in each mouse. Control transgenic mice were injected with an antibody against a drosophila-specific protein (amnesiac. Tissues were examined for brain amyloid deposition and microglial responses 3 days after the injection. Results The deglycosylated 2H6 antibody had lower affinity for several murine Fcγ receptors and human complement than intact 2H6 without a change in affinity for Aß. Immunohistochemistry for Aβ and thioflavine-S staining revealed that both diffuse and compact deposits were reduced by both antibodies. In animals treated with the intact 2H6 antibody, a significant increase in Fcγ-receptor II/III immunostaining was observed compared to animals treated with the control IgG antibody. No increase in Fcγ-receptor II/III was found with the deglycosylated 2H6 antibody. Immunostaining for the microglial activation marker CD45 demonstrated a similar trend. Conclusion These findings suggest that the deglycosylated 2H6 is capable of removing both compact and diffuse plaques without activating microglia. Thus, antibodies with reduced effector functions may clear amyloid without concomitant immune activation when tested as immunotherapy for Alzheimer's disease.

  5. Specification of High Activity Gamma-Ray Sources.

    Science.gov (United States)

    International Commission on Radiation Units and Measurements, Washington, DC.

    The report is concerned with making recommendations for the specifications of gamma ray sources, which relate to the quantity of radioactive material and the radiation emitted. Primary consideration is given to sources in teletherapy and to a lesser extent those used in industrial radiography and in irradiation units used in industry and research.…

  6. Immunotherapy for the treatment of breast cancer: checkpoint blockade, cancer vaccines, and future directions in combination immunotherapy.

    Science.gov (United States)

    McArthur, Heather L; Page, David B

    2016-11-01

    Immunotherapy encompasses both vaccines that direct immune responses to tumor-associated antigens, and checkpoint blocking antibodies that inhibit immune system suppression by targeting key pathways mediated by cytotoxic T-lymphocyte-associated antigen 4, programmed death 1 (PD-1), and programmed death ligand 1 (PD-L1). Both of these approaches currently are being explored as potential strategies for the treatment of breast cancer. Recent studies suggest that immunotherapy is poised to change the therapeutic landscape for some breast cancers. Specifically, overall response rates of 19% with PD-1/PD-L1-directed antibodies have been reported in 2 small studies of women with PD-L1-positive, heavily pretreated advanced triple-negative breast cancer. In combination with nab-paclitaxel, confirmed response rates were 46% in a PD-L1-unselected population in the first-line metastatic triple-negative breast cancer setting. Checkpoint-blocking antibodies also have been evaluated in small studies of women with hormone receptor-positive metastatic breast cancer, and in women whose breast cancers lack PD-L1 expression, with more modest response rates. It has been hypothesized that some breast cancers are not inherently recognized by the immune system; however, preclinical and preliminary clinical data suggest that inherently modest immunogenicity may be overcome with novel vaccination strategies, as well as strategies that combine immune checkpoint blockade with methods of optimizing antigen presentation, such as tumor ablation, radiation, chemotherapy, or other approaches. If ongoing registrational trials support the use of immunotherapy, it could revolutionize the care of early-stage and metastatic breast cancer, and ideally improve cure rates.

  7. Mutation specific functions of EGFR result in a mutation-specific downstream pathway activation

    NARCIS (Netherlands)

    L. Eraslan-Erdem (Lale); Y. Gao; N.K. Kloosterhof (Nanne); Y. Atlasi (Yaser); J.A.A. Demmers (Jeroen); A. Sacchetti (Andrea); J.M. Kros (Johan); P.A.E. Sillevis Smitt (Peter); J.G.J.V. Aerts (Joachim); P.J. French (Pim)

    2015-01-01

    markdownabstractBackground: Epidermal growth factor receptor (EGFR) is frequently mutated in various types of cancer. Although all oncogenic mutations are considered activating, different tumour types have different mutation spectra. It is possible that functional differences underlie this tumour-ty

  8. Proceedings of the 2016 China Cancer Immunotherapy Workshop

    Directory of Open Access Journals (Sweden)

    Bin Xue

    2016-10-01

    Full Text Available Table of contents A1 Proceedings of 2016 China Cancer Immunotherapy Workshop, Beijing, China Bin Xue, Jiaqi Xu, Wenru Song, Zhimin Yang, Ke Liu, Zihai Li A2 Set the stage: fundamental immunology in forty minutes Zihai Li A3 What have we learnt from the anti-PD-1/PD-L1 therapy of advanced human cancer? Lieping Chen A4 Immune checkpoint inhibitors in lung cancer Edward B. Garon A5 Mechanisms of response and resistance to checkpoint inhibitors in melanoma Siwen Hu-Lieskovan A6 Checkpoint inhibitor immunotherapy in lymphoid malignancies Wei Ding A7 Translational research to improve the efficacy of immunotherapy in genitourinary malignancies Chong-Xian Pan A8 Immune checkpoint inhibitors in gastrointestinal malignancies Weijing Sun A9 What’s next beyond PD-1/PDL1? Yong-Jun Liu A10 Cancer vaccines: new insights into the oldest immunotherapy strategy Lei Zheng A11 Bispecific antibodies for cancer immunotherapy Delong Liu A12 Updates on CAR-T immunotherapy Michel Sadelain A13 Adoptive T cell therapy: personalizing cancer treatment Cassian Yee A14 Immune targets and neoantigens for cancer immunotherapy Rongfu Wang A15 Phase I/IIa trial of chimeric antigen receptor modified T cells against CD133 in patients with advanced and metastatic solid tumors Meixia Chen, Yao Wang, Zhiqiang Wu, Hanren Dai, Can Luo, Yang Liu, Chuan Tong, Yelei Guo, Qingming Yang, Weidong Han A16 Cancer immunotherapy biomarkers: progress and issues Lisa H. Butterfield A17 Shaping of immunotherapy response by cancer genomes Timothy A. Chan A18 Unique development consideration for cancer immunotherapy Wenru Song A19 Immunotherapy combination Ruirong Yuan A20 Immunotherapy combination with radiotherapy Bo Lu A21 Cancer immunotherapy: past, present and future Ke Liu A22 Breakthrough therapy designation drug development and approval Max Ning A23 Current European regulation of innovative oncology medicines: opportunities for immunotherapy Harald Enzmann, Heinz Zwierzina

  9. Adapting conventional cancer treatment for immunotherapy.

    Science.gov (United States)

    Qiao, Jian; Liu, Zhida; Fu, Yang-Xin

    2016-05-01

    The efficacy of directly killing tumors by conventional cancer therapies, such as chemotherapy and radiotherapy, has been for several decades well established. But, a suppressed immune response might become a lethal side effect after repeated cycles of intensive treatment. Recently, achievements in immune checkpoint inhibitors and adoptive T cell-mediated immunotherapies have resulted in changes in frontline management of advanced cancer diseases. However, accumulated evidence indicates that immunotherapeutic and conventional strategies alone are often ineffective to eradicate big tumors or metastasis. To improve the outcomes of treatment for advanced cancer diseases, the combination of conventional cancer treatment with various immunotherapeutic approaches has been attempted and has shown potential synergistic effects. Recent studies have unexpectedly demonstrated that some strategies of conventional cancer treatment can regulate the immune response positively, thus the understanding of how to adapt conventional treatment for immunotherapy is crucial to the design of effective combination therapy of conventional treatment with immunotherapy. Here, we review both experimental and clinical studies on the therapeutic effect and its mechanisms of combining conventional therapy with immunotherapy in treatment of cancer.

  10. Improved endpoints for cancer immunotherapy trials

    NARCIS (Netherlands)

    A. Hoos (Axel); A.M.M. Eggermont (Alexander); S. Janetzki (Sylvia); F.S. Hodi (Stephen); R. Ibrahim (Ramy); A. Anderson (Aparna); R. Humphrey (Rachel); B. Blumenstein (Brent); L. Old (Lloyd); J. Wolchok (Jedd)

    2010-01-01

    textabstractUnlike chemotherapy, which acts directly on the tumor, cancer immunotherapies exert their effects on the immune system and demonstrate new kinetics that involve building a cellular immune response, followed by changes in tumor burden or patient survival. Thus, adequate design and evaluat

  11. Sublingual Immunotherapy for Allergic Fungal Sinusitis.

    Science.gov (United States)

    Melzer, Jonathan M; Driskill, Brent R; Clenney, Timothy L; Gessler, Eric M

    2015-10-01

    Allergic fungal sinusitis (AFS) is a condition that has an allergic basis caused by exposure to fungi in the sinonasal tract leading to chronic inflammation. Despite standard treatment modalities, which typically include surgery and medical management of allergies, patients still have a high rate of recurrence. Subcutaneous immunotherapy (SCIT) has been used as adjuvant treatment for AFS. Evidence exists to support the use of sublingual immunotherapy (SLIT) as a safe and efficacious method of treating allergies, but no studies have assessed the utility of SLIT in the management of allergic fungal sinusitis. A record review of cases of AFS that are currently or previously treated with sublingual immunotherapy from 2007 to 2011 was performed. Parameters of interest included serum IgE levels, changes in symptoms, Lund-McKay scores, decreased sensitization to fungal allergens associated with AFS, and serum IgE levels. Ten patients with diagnosed AFS were treated with SLIT. No adverse effects related to the use of SLIT therapy were identified. Decreases in subjective complaints, exam findings, Lund-McKay scores, and serum IgE levels were observed. Thus, sublingual immunotherapy appears to be a safe adjunct to the management of AFS that may improve patient outcomes.

  12. Cancer immunotherapy : insights from transgenic animal models

    NARCIS (Netherlands)

    McLaughlin, PMJ; Kroesen, BJ; Harmsen, MC; de Leij, LFMH

    2001-01-01

    A wide range of strategies in cancer immunotherapy has been developed in the last decade, some of which are currently being used in clinical settings. The development of these immunotherapeutical strategies has been facilitated by the generation of relevant transgenic animal models. Since the differ

  13. Steroids vs immunotherapy for allergic rhinitis

    DEFF Research Database (Denmark)

    Aasbjerg, Kristian; Backer, Vibeke

    2014-01-01

    Treatment for seasonal allergic rhinitis induced by airborne allergens can be divided into two major groups: symptom-dampening drugs, such as antihistamines and corticosteroids, and disease-modifying drugs in the form of immunotherapy. It has been speculated that depot-injection corticosteroids g...

  14. Genetically Modified T-Cell-Based Adoptive Immunotherapy in Hematological Malignancies

    Directory of Open Access Journals (Sweden)

    Baixin Ye

    2017-01-01

    Full Text Available A significant proportion of hematological malignancies remain limited in treatment options. Immune system modulation serves as a promising therapeutic approach to eliminate malignant cells. Cytotoxic T lymphocytes (CTLs play a central role in antitumor immunity; unfortunately, nonspecific approaches for targeted recognition of tumor cells by CTLs to mediate tumor immune evasion in hematological malignancies imply multiple mechanisms, which may or may not be clinically relevant. Recently, genetically modified T-cell-based adoptive immunotherapy approaches, including chimeric antigen receptor (CAR T-cell therapy and engineered T-cell receptor (TCR T-cell therapy, promise to overcome immune evasion by redirecting the specificity of CTLs to tumor cells. In clinic trials, CAR-T-cell- and TCR-T-cell-based adoptive immunotherapy have produced encouraging clinical outcomes, thereby demonstrating their therapeutic potential in mitigating tumor development. The purpose of the present review is to (1 provide a detailed overview of the multiple mechanisms for immune evasion related with T-cell-based therapies; (2 provide a current summary of the applications of CAR-T-cell- as well as neoantigen-specific TCR-T-cell-based adoptive immunotherapy and routes taken to overcome immune evasion; and (3 evaluate alternative approaches targeting immune evasion via optimization of CAR-T and TCR-T-cell immunotherapies.

  15. Active stream segregation specifically involves the left human auditory cortex.

    Science.gov (United States)

    Deike, Susann; Scheich, Henning; Brechmann, André

    2010-06-14

    An important aspect of auditory scene analysis is the sequential grouping of similar sounds into one "auditory stream" while keeping competing streams separate. In the present low-noise fMRI study we presented sequences of alternating high-pitch (A) and low-pitch (B) complex harmonic tones using acoustic parameters that allow the perception of either two separate streams or one alternating stream. However, the subjects were instructed to actively and continuously segregate the A from the B stream. This was controlled by the additional instruction to listen for rare level deviants only in the low-pitch stream. Compared to the control condition in which only one non-separable stream was presented the active segregation of the A from the B stream led to a selective increase of activation in the left auditory cortex (AC). Together with a similar finding from a previous study using a different acoustic cue for streaming, namely timbre, this suggests that the left auditory cortex plays a dominant role in active sequential stream segregation. However, we found cue differences within the left AC: Whereas in the posterior areas, including the planum temporale, activation increased for both acoustic cues, the anterior areas, including Heschl's gyrus, are only involved in stream segregation based on pitch.

  16. Early gene expression changes with rush immunotherapy

    Directory of Open Access Journals (Sweden)

    Barnett Sherry

    2011-09-01

    Full Text Available Abstract Background To examine whether whole genome expression profiling could reveal changes in mRNA expression of peripheral blood mononuclear cells (PBMC from allergic patients undergoing rush immunotherapy (RIT that might be manifest within the first few months of treatment. Methods For this study, PBMC from three allergic patients undergoing RIT were assessed at four timepoints: prior to RIT, at 1 week and 7 week post-RIT, during build-up and at 4 months, after establishment of a maintenance dose. PBMC mRNA gene expression changes over time were determined by oligonucleotide microarrays using the Illumina Human-6 BeadChip Platform, which simultaneously interrogates expression profiles of > 47,000 transcripts. Differentially expressed genes were identified using well-established statistical analysis for microarrays. In addition, we analyzed peripheral blood basophil high-affinity IgE receptor (Fc epsilon RI expression and T-regulatory cell frequency as detected by expression of CD3+CD4+CD25bright cells at each timepoint using flow cytometry. Results In comparing the initial 2 timepoints with the final 2 timepoints and analyzing for genes with ≥1.5-fold expression change (p less than or equal to 0.05, BH-FDR, we identified 507 transcripts. At a 2-fold change (p less than or equal to 0.05, BH-FDR, we found 44 transcripts. Of these, 28 were up-regulated and 16 were down-regulated genes. From these datasets, we have identified changes in immunologically relevant genes from both the innate and adaptive response with upregulation of expressed genes for molecules including IL-1β, IL-8, CD40L, BTK and BCL6. At the 4 month timepoint, we noted a downward trend in Fc epsilon RI expression in each of the three patients and increased allergen-specific IgG4 levels. No change was seen in the frequency of peripheral T-regulatory cells expressed over the four timepoints. Conclusions We observed significant changes in gene expression early in peripheral

  17. Activity Specific Knowledge Characteristics in the Internationalization Process

    DEFF Research Database (Denmark)

    Søberg, Peder Veng

    2012-01-01

    /methodology/approach – The paper presents a framework primarily based on knowledge management theory, which is illustrated in relation to interesting cases of four companies that are global leaders. Findings – An R&D knowledge gap still exists in China and India. Differences across business activities exist in terms......Purpose – The purpose of this paper is to investigate differences in the characteristics of knowledge, which is very important for the internationalization of different business activities. In particular, the focus is on internationalization in emerging markets such as China and India. Design...... is developed that illustrates differences between the most important knowledge for the internationalization of key business activities within MNCs. It is proposed that the technical dimension of tacit knowledge is more easily codified than the cognitive dimension of tacit knowledge. The cognitive dimension...

  18. Emerging Opportunities and Challenges in Cancer Immunotherapy.

    Science.gov (United States)

    Whiteside, Theresa L; Demaria, Sandra; Rodriguez-Ruiz, Maria E; Zarour, Hassane M; Melero, Ignacio

    2016-04-15

    Immunotherapy strategies against cancer are emerging as powerful weapons for treatment of this disease. The success of checkpoint inhibitors against metastatic melanoma and adoptive T-cell therapy with chimeric antigen receptor T cells against B-cell-derived leukemias and lymphomas are only two examples of developments that are changing the paradigms of clinical cancer management. These changes are a result of many years of intense research into complex and interrelated cellular and molecular mechanisms controling immune responses. Promising advances come from the discovery of cancer mutation-encoded neoantigens, improvements in vaccine development, progress in delivery of cellular therapies, and impressive achievements in biotechnology. As a result, radical transformation of cancer treatment is taking place in which conventional cancer treatments are being integrated with immunotherapeutic agents. Many clinical trials are in progress testing potential synergistic effects of treatments combining immunotherapy with other therapies. Much remains to be learned about the selection, delivery, and off-target effects of immunotherapy used alone or in combination. The existence of numerous escape mechanisms from the host immune system that human tumors have evolved still is a barrier to success. Efforts to understand the rules of immune cell dysfunction and of cancer-associated local and systemic immune suppression are providing new insights and fuel the enthusiasm for new therapeutic strategies. In the future, it might be possible to tailor immune therapy for each cancer patient. The use of new immune biomarkers and the ability to assess responses to therapy by noninvasive monitoring promise to improve early cancer diagnosis and prognosis. Personalized immunotherapy based on individual genetic, molecular, and immune profiling is a potentially achievable future goal. The current excitement for immunotherapy is justified in view of many existing opportunities for harnessing

  19. Ileal brake activation: Macronutrient-specific effects on eating behavior?

    NARCIS (Netherlands)

    Avesaat, M. van; Troost, F.J.; Ripken, D.; Hendriks, H.F.; Aam, M.

    2015-01-01

    BACKGROUND: Activation of the ileal brake, by infusing lipid directly into the distal part of the small intestine, alters gastrointestinal (GI) motility and inhibits food intake. The ileal brake effect on eating behavior of the other macronutrients is currently unknown. OBJECTIVE: The objective of t

  20. The specific activation of TRPC4 by Gi protein subtype.

    NARCIS (Netherlands)

    Jeon, J.P.; Lee, K.P.; Park, E.J.; Sung, T.S.; Kim, B.J.; Jeon, J.H.; So, I.

    2008-01-01

    The classical type of transient receptor potential channel (TRPC) is a molecular candidate for Ca(2+)-permeable cation channels in mammalian cells. Especially, TRPC4 has the similar properties to Ca(2+)-permeable nonselective cation channels (NSCCs) activated by muscarinic stimulation in visceral sm