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Sample records for adoptive cancer immunotherapy

  1. Adoptive immunotherapy for cancer: building on success

    OpenAIRE

    Gattinoni, Luca; Powell, Daniel J.; Rosenberg, Steven A.; Restifo, Nicholas P

    2006-01-01

    Adoptive cell transfer after host preconditioning by lymphodepletion represents an important advance in cancer immunotherapy. Here, we describe how a lymphopaenic environment enables tumour-reactive T cells to destroy large burdens of metastatic tumour and how the state of differentiation of the adoptively transferred T cells can affect the outcome of treatment. We also discuss how the translation of these new findings might further improve the efficacy of adoptive cell transfer through the u...

  2. Adoptive immunotherapy against ovarian cancer

    OpenAIRE

    Mittica, Gloria; Capellero, Sonia; Genta, Sofia; Cagnazzo, Celeste; Aglietta, Massimo; Sangiolo, Dario; Valabrega, Giorgio

    2016-01-01

    The standard front-line therapy for epithelial ovarian cancer (EOC) is combination of debulking surgery and platinum-based chemotherapy. Nevertheless, the majority of patients experience disease recurrence. Although extensive efforts to find new therapeutic options, cancer cells invariably develop drug resistance and disease progression. New therapeutic strategies are needed to improve prognosis of patients with advanced EOC. Recently, several preclinical and clinical studies investigated fea...

  3. 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.

  4. 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.

  5. Adoptive cell transfer: a clinical path to effective cancer immunotherapy

    OpenAIRE

    Rosenberg, Steven A.; Restifo, Nicholas P; Yang, James C.; Morgan, Richard A.; Dudley, Mark E.

    2008-01-01

    Adoptive cell therapy (ACT) using autologous tumour-infiltrating lymphocytes has emerged as the most effective treatment for patients with metastatic melanoma and can mediate objective cancer regression in approximately 50% of patients. The use of donor lymphocytes for ACT is an effective treatment for immunosuppressed patients who develop post-transplant lymphomas. The ability to genetically engineer human lymphocytes and use them to mediate cancer regression in patients, which has recently ...

  6. Adoptive immunotherapy combined chemoradiotherapy for non-small-cell lung cancer: a meta-analysis.

    Science.gov (United States)

    Qian, Haili; Wang, Haijuan; Guan, Xiuwen; Yi, Zongbi; Ma, Fei

    2016-06-01

    The aim of this study was to compare the efficacies between adoptive immunotherapy combined chemoradiotherapy and chemoradiotherapy alone in patients with non-small-cell lung cancer (NSCLC). The databases PubMed, EMBASE, and Cochrane database were searched to identify eligible clinical trials. Data analyses were carried out using a comprehensive meta-analysis program, version 2 software. A total of seven articles were finally included in the analysis. Meta-analyses showed that compared with chemoradiotherapy alone, adoptive immunotherapy combined with chemoradiotherapy could improve the 2-year overall survival [odds ratio (OR)=2.45, 95% confidence interval (CI): 1.60-3.75, Pshiver, nausea, fatigue, etc. and severe toxicities were not observed. Adoptive immunotherapy combined with chemoradiotherapy can delay the recurrence of NSCLC and improve survival in patients, where the benefits are even more significant in patients with early-stage NSCLC. PMID:26872311

  7. DNA methyltransferase inhibition increases efficacy of adoptive cellular immunotherapy of murine breast cancer.

    Science.gov (United States)

    Terracina, Krista P; Graham, Laura J; Payne, Kyle K; Manjili, Masoud H; Baek, Annabel; Damle, Sheela R; Bear, Harry D

    2016-09-01

    Adoptive T cell immunotherapy is a promising approach to cancer treatment that currently has limited clinical applications. DNA methyltransferase inhibitors (DNAMTi) have known potential to affect the immune system through multiple mechanisms that could enhance the cytotoxic T cell responses, including: upregulation of tumor antigen expression, increased MHC class I expression, and blunting of myeloid derived suppressor cells (MDSCs) expansion. In this study, we have investigated the effect of combining the DNAMTi, decitabine, with adoptive T cell immunotherapy in the murine 4T1 mammary carcinoma model. We found that expression of neu, MHC class I molecules, and several murine cancer testis antigens (CTA) was increased by decitabine treatment of 4T1 cells in vitro. Decitabine also increased expression of multiple CTA in two human breast cancer cell lines. Decitabine-treated 4T1 cells stimulated greater IFN-gamma release from tumor-sensitized lymphocytes, implying increased immunogenicity. Expansion of CD11b + Gr1 + MDSC in 4T1 tumor-bearing mice was significantly diminished by decitabine treatment. Decitabine treatment improved the efficacy of adoptive T cell immunotherapy in mice with established 4T1 tumors, with greater inhibition of tumor growth and an increased cure rate. Decitabine may have a role in combination with existing and emerging immunotherapies for breast cancer. PMID:27416831

  8. 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.

  9. 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.

  10. Adoptive immunotherapy of cancer using CD4+ T cells

    OpenAIRE

    Muranski, Pawel; Restifo, Nicholas P

    2009-01-01

    CD4+ T cells are central to the function of the immune system but their role in tumor immunity remains underappreciated. It is becoming clear that there is an enormous diversity of CD4+ T cell polarization patterns including Th1, Th2, Th17, and regulatory T cells (Tregs). These functionally divergent T cell subsets can have opposing effects — they can trigger tumor rejection or inhibit treatment after adoptive cell transfer. Some polarized CD4+ cells have plasticity, and their phenotypes and ...

  11. 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.

  12. Adoptive immunotherapy for cancer: the next generation of gene-engineered immune cells.

    Science.gov (United States)

    Berry, L J; Moeller, M; Darcy, P K

    2009-10-01

    Adoptive cellular immunotherapy involving transfer of tumor-reactive T cells has shown some notable antitumor responses in a minority of cancer patients. In particular, transfer of tumor-infiltrating lymphocytes has resulted in long-term objective responses in patients with advanced melanoma. However, the inability to isolate sufficient numbers of tumor-specific T cells from most malignancies has restricted the broad utility of this approach. An emerging approach to circumvent this limitation involves the genetic modification of effector cells with T cell receptor (TCR) transgenes or chimeric single-chain variable fragment (scFv) receptors that can specifically redirect T cells to tumor. There has been much progress in the design of TCR and scFv receptors to enhance the antigen-specific activation of effector cells and their trafficking and persistence in vivo. Considerable effort has been directed toward improving the safety of this approach and reducing the immunogenicity of the receptor. This review discusses the latest developments in the field of adoptive immunotherapy using genetically modified immune cells that have been transduced with either TCR or scFv receptor transgenes and used in preclinical and clinical settings as anticancer agents. PMID:19775368

  13. Combining antiangiogenic therapy with adoptive cell immunotherapy exerts better antitumor effects in non-small cell lung cancer models.

    Directory of Open Access Journals (Sweden)

    Shujing Shi

    Full Text Available INTRODUCTION: Cytokine-induced killer cells (CIK cells are a heterogeneous subset of ex-vivo expanded T lymphocytes which are characterized with a MHC-unrestricted tumor-killing activity and a mixed T-NK phenotype. Adoptive CIK cells transfer, one of the adoptive immunotherapy represents a promising nontoxic anticancer therapy. However, in clinical studies, the therapeutic activity of adoptive CIK cells transfer is not as efficient as anticipated. Possible explanations are that abnormal tumor vasculature and hypoxic tumor microenvironment could impede the infiltration and efficacy of lymphocytes. We hypothesized that antiangiogenesis therapy could improve the antitumor activity of CIK cells by normalizing tumor vasculature and modulating hypoxic tumor microenvironment. METHODS: We combined recombinant human endostatin (rh-endostatin and CIK cells in the treatment of lung carcinoma murine models. Intravital microscopy, dynamic contrast enhanced magnetic resonance imaging, immunohistochemistry, and flow cytometry were used to investigate the tumor vasculature and hypoxic microenvironment as well as the infiltration of immune cells. RESULTS: Our results indicated that rh-endostatin synergized with adoptive CIK cells transfer to inhibit the growth of lung carcinoma. We found that rh-endostatin normalized tumor vasculature and reduced hypoxic area in the tumor microenvironment. Hypoxia significantly inhibited the proliferation, cytotoxicity and migration of CIK cells in vitro and impeded the homing of CIK cells into tumor parenchyma ex vivo. Furthermore, we found that treatment with rh-endostatin significantly increased the homing of CIK cells and decreased the accumulation of suppressive immune cells in the tumor tissue. In addition, combination therapy produced higher level of tumor-infiltration lymphocytes compared with other treatments. CONCLUSIONS: Our results demonstrate that rh-endostatin improves the therapeutic effect of adoptive CIK cells

  14. Combining Antiangiogenic Therapy with Adoptive Cell Immunotherapy Exerts Better Antitumor Effects in Non-Small Cell Lung Cancer Models

    Science.gov (United States)

    Shi, Shujing; Wang, Rui; Chen, Yitian; Song, Haizhu; Chen, Longbang; Huang, Guichun

    2013-01-01

    Introduction Cytokine-induced killer cells (CIK cells) are a heterogeneous subset of ex-vivo expanded T lymphocytes which are characterized with a MHC-unrestricted tumor-killing activity and a mixed T-NK phenotype. Adoptive CIK cells transfer, one of the adoptive immunotherapy represents a promising nontoxic anticancer therapy. However, in clinical studies, the therapeutic activity of adoptive CIK cells transfer is not as efficient as anticipated. Possible explanations are that abnormal tumor vasculature and hypoxic tumor microenvironment could impede the infiltration and efficacy of lymphocytes. We hypothesized that antiangiogenesis therapy could improve the antitumor activity of CIK cells by normalizing tumor vasculature and modulating hypoxic tumor microenvironment. Methods We combined recombinant human endostatin (rh-endostatin) and CIK cells in the treatment of lung carcinoma murine models. Intravital microscopy, dynamic contrast enhanced magnetic resonance imaging, immunohistochemistry, and flow cytometry were used to investigate the tumor vasculature and hypoxic microenvironment as well as the infiltration of immune cells. Results Our results indicated that rh-endostatin synergized with adoptive CIK cells transfer to inhibit the growth of lung carcinoma. We found that rh-endostatin normalized tumor vasculature and reduced hypoxic area in the tumor microenvironment. Hypoxia significantly inhibited the proliferation, cytotoxicity and migration of CIK cells in vitro and impeded the homing of CIK cells into tumor parenchyma ex vivo. Furthermore, we found that treatment with rh-endostatin significantly increased the homing of CIK cells and decreased the accumulation of suppressive immune cells in the tumor tissue. In addition, combination therapy produced higher level of tumor-infiltration lymphocytes compared with other treatments. Conclusions Our results demonstrate that rh-endostatin improves the therapeutic effect of adoptive CIK cells therapy against lung

  15. 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

  16. Trends in Cancer Immunotherapy

    OpenAIRE

    Murphy, Joseph F.

    2010-01-01

    Modulation of the immune system for therapeutic ends has a long history, stretching back to Edward Jenner’s use of cowpox to induce immunity to smallpox in 1796. Since then, immunotherapy, in the form of prophylactic and therapeutic vaccines, has enabled doctors to treat and prevent a variety of infectious diseases, including cholera, poliomyelitis, diphtheria, measles and mumps. Immunotherapy is now increasingly being applied to oncology. Cancer immunotherapy attempts to harness the power an...

  17. 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

  18. BRAIN CANCER IMMUNOTHERAPY (REVIEW)

    OpenAIRE

    Yashin К.S.; Medyanik I.А.

    2014-01-01

    The review analyzes Russian and foreign reports concerned with a rapidly developing brain cancer treatment technique — immunotherapy. There has been presented a current view on the basic concept of antitumor immunity, on the problem of immune system interaction with a tumor in general and under the conditions of an immunologically privileged nervous system, shown the theoretical background of efficiency of immunotherapy used against brain cancer (the capability of tumor antigens and activated...

  19. Immunotherapy for metastatic colorectal cancer

    DEFF Research Database (Denmark)

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

    2012-01-01

    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 and...

  20. 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.

  1. Adoptive immunotherapy of human pancreatic cancer with lymphokine-activated killer cells and interleukin-2 in a nude mouse model

    International Nuclear Information System (INIS)

    A pancreatic cancer cell line was grown in orthotopic and heterotopic positions in young Swiss/NIH nude mice, which were tested with adoptive immunotherapy. Mice were injected with 1 x 10(7) human cancer cells in the subcutaneous tissue and duodenal lobe of the pancreas. The mice were randomly divided into four groups: group IA (LAK + IL-2) (N = 25) received 2 X 10(7) human lymphokine-activated killer (LAK) cells from normal donors by tail vein injection followed by 10,000 units of human recombinant interleukin-2 (IL-2) given intraperitoneally every 12 hours for 28 days; group IB (IL-2) (N = 27) was given the same dose of IL-2 alone; group IC (RPMI-1640) (N = 18) received a placebo consisting of 1 ml of RPMI-1640 intraperitoneally every 12 hours; and group ID (LAK) (N = 14) received 2 X 10(7) LAK cells but no IL-2. Toxicity was significantly higher in group IB, with a mortality rate of 45.5% (10/22 animals) versus a 0% mortality (0/25) in group IA. None of the group IA or IB animals died of pancreatic cancer during the experiment. The animals that did not receive IL-2 died before 28 days in 14.2% of group IC and in 16.7% of group ID. The area under the growth curve of subcutaneous tumors during the course of treatment and the pancreatic tumor weight at the end of treatment were compared in each group. Subcutaneous tumors had a reduced rate of growth in group IA animals compared to all the other treatments. Pancreatic tumor growth was slowed in group IA. The animals treated with IL-2 alone (group IB) showed some slowing of tumor growth that was intermediate between group IA, group IC, and group ID. A similar experiment was done with irradiated (375 rad) mice. Nine nude mice with tumors were treated with LAK + IL-2 (group IIA), eight received IL-2 alone (group IIB), and seven received placebo (group IIC)

  2. Immunotherapy of Brain Cancer.

    Science.gov (United States)

    Roth, Patrick; Preusser, Matthias; Weller, Michael

    2016-01-01

    The brain has long been considered an immune-privileged site precluding potent immune responses. Nevertheless, because of the failure of conventional anti-cancer treatments to achieve sustained control of intracranial neoplasms, immunotherapy has been considered as a promising strategy for decades. However, several efforts aimed at exploiting the immune system as a therapeutic weapon were largely unsuccessful. The situation only changed with the introduction of the checkpoint inhibitors, which target immune cell receptors that interfere with the activation of immune effector cells. Following the observation of striking effects of drugs that target CTLA-4 or PD-1 against melanoma and other tumor entities, it was recognized that these drugs may also be active against metastatic tumor lesions in the brain. Their therapeutic activity against primary brain tumors is currently being investigated within clinical trials. In parallel, other immunotherapeutics such as peptide vaccines are at an advanced stage of clinical development. Further immunotherapeutic strategies currently under investigation comprise adoptive immune cell transfer as well as inhibitors of metabolic pathways involved in the local immunosuppression frequently found in brain tumors. Thus, the ongoing implementation of immunotherapeutic concepts into clinical routine may represent a powerful addition to the therapeutic arsenal against various brain tumors. PMID:27260656

  3. CCL21 Cancer Immunotherapy

    International Nuclear Information System (INIS)

    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

  4. Brain Cancer Immunotherapy (Review

    Directory of Open Access Journals (Sweden)

    Yashin К.S.

    2014-12-01

    Full Text Available The review analyzes Russian and foreign reports concerned with a rapidly developing brain cancer treatment technique — immunotherapy. There has been presented a current view on the basic concept of antitumor immunity, on the problem of immune system interaction with a tumor in general and under the conditions of an immunologically privileged nervous system, shown the theoretical background of efficiency of immunotherapy used against brain cancer (the capability of tumor antigens and activated lymphocytes to penetrate the blood-brain barrier. There has been demonstrated the role of a transforming growth factor β, interleukin 10, cyclooxygenase-2, prostaglandin Е2, protein MCP-1, interactions Fas-receptor/Fas-ligand, antigen-4 cytotoxic Т-lymphocytes in tumor immunoresistance development. The review presents a current classification of the types of active and passive immunotherapy, each of the types being considered separately specifying the characteristics, the results of preclinical and clinical trials of each type efficiency, and possible side effects. Special attention has been paid to a new concept of a key role of tumor stem cells in the pathogenesis of cerebral gliomas and the target action on these cells.

  5. Construction and characterisation of a stably transfected BHK cell line permanently secreting the canine interleukin 12 as a source for adoptive cancer immunotherapy in dogs

    OpenAIRE

    Kocoski, Vladimir

    2008-01-01

    BACKGROUND AND AIM OF THE STUDY: The dog represents the most important tumor patient in the veterinary medicine. Furthermore, the growing knowledge of tumor biology and immunology in dogs increases the interest of this species as a promising model in studies of tumor immunotherapy in human. Concerning the tumor treatment, one of the latest therapeutical approaches is the tumor immunotherapy, especially the adoptive immunotherapy, which is based on in vitro lymphocyte activation by cytokines. ...

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

    OpenAIRE

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

    2016-01-01

    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 succe...

  7. 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

  8. Immunotherapy for bladder cancer

    Directory of Open Access Journals (Sweden)

    Fuge O

    2015-05-01

    Full Text Available Oliver Fuge,1 Nikhil Vasdev,1 Paula Allchorne,2 James SA Green2 1Department of Urology, Lister Hospital, Stevenage, UK; 2Department of Urology, Bartshealth NHS Trust, Whipps Cross Rd, London, UK Abstract: It is nearly 40 years since Bacillus Calmette–Guérin (BCG was first used as an immunotherapy to treat superficial bladder cancer. Despite its limitations, to date it has not been surpassed by any other treatment. As a better understanding of its mechanism of action and the clinical response to it have evolved, some of the questions around optimal dosing and treatment protocols have been answered. However, its potential for toxicity and failure to produce the desired clinical effect in a significant cohort of patients presents an ongoing challenge to clinicians and researchers alike. This review summarizes the evidence behind the established mechanism of action of BCG in bladder cancer, highlighting the extensive array of immune molecules that have been implicated in its action. The clinical aspects of BCG are discussed, including its role in reducing recurrence and progression, the optimal treatment regime, toxicity and, in light of new evidence, whether or not there is a superior BCG strain. The problems of toxicity and non-responders to BCG have led to development of new techniques aimed at addressing these pitfalls. The progress made in the laboratory has led to the identification of novel targets for the development of new immunotherapies. This includes the potential augmentation of BCG with various immune factors through to techniques avoiding the use of BCG altogether; for example, using interferon-activated mononuclear cells, BCG cell wall, or BCG cell wall skeleton. The potential role of gene, virus, or photodynamic therapy as an alternative to BCG is also reviewed. Recent interest in the immune check point system has led to the development of monoclonal antibodies against proteins involved in this pathway. Early findings suggest

  9. Biologic Therapy (Immunotherapy) for Kidney Cancer

    Science.gov (United States)

    ... for kidney cancer Targeted therapies for kidney cancer Biologic therapy (immunotherapy) for kidney cancer Chemotherapy for kidney cancer Pain control for kidney cancer Treatment choices by stage for ...

  10. Immunotherapy for bladder cancer.

    Science.gov (United States)

    Fuge, Oliver; Vasdev, Nikhil; Allchorne, Paula; Green, James Sa

    2015-01-01

    It is nearly 40 years since Bacillus Calmette-Guérin (BCG) was first used as an immunotherapy to treat superficial bladder cancer. Despite its limitations, to date it has not been surpassed by any other treatment. As a better understanding of its mechanism of action and the clinical response to it have evolved, some of the questions around optimal dosing and treatment protocols have been answered. However, its potential for toxicity and failure to produce the desired clinical effect in a significant cohort of patients presents an ongoing challenge to clinicians and researchers alike. This review summarizes the evidence behind the established mechanism of action of BCG in bladder cancer, highlighting the extensive array of immune molecules that have been implicated in its action. The clinical aspects of BCG are discussed, including its role in reducing recurrence and progression, the optimal treatment regime, toxicity and, in light of new evidence, whether or not there is a superior BCG strain. The problems of toxicity and non-responders to BCG have led to development of new techniques aimed at addressing these pitfalls. The progress made in the laboratory has led to the identification of novel targets for the development of new immunotherapies. This includes the potential augmentation of BCG with various immune factors through to techniques avoiding the use of BCG altogether; for example, using interferon-activated mononuclear cells, BCG cell wall, or BCG cell wall skeleton. The potential role of gene, virus, or photodynamic therapy as an alternative to BCG is also reviewed. Recent interest in the immune check point system has led to the development of monoclonal antibodies against proteins involved in this pathway. Early findings suggest benefit in metastatic disease, although the role in superficial bladder cancer remains unclear. PMID:26000263

  11. Immunotherapy

    Science.gov (United States)

    ... Help raise $300,000 this month to find cures. Loading... Immunotherapy Immunotherapy SHARE: Print Glossary Immunotherapy, also ... destroy the antigens. In most circumstances, the body's natural immune system seems unable to identify cancer as ...

  12. 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.

  13. Development of cancer immunotherapy

    International Nuclear Information System (INIS)

    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

  14. 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.

  15. Prospects for chimeric antigen receptor (CAR) γδ T cells: A potential game changer for adoptive T cell cancer immunotherapy.

    Science.gov (United States)

    Mirzaei, Hamid Reza; Mirzaei, Hamed; Lee, Sang Yun; Hadjati, Jamshid; Till, Brian G

    2016-10-01

    Excitement is growing for therapies that harness the power of patients' immune systems to combat their diseases. One approach to immunotherapy involves engineering patients' own T cells to express a chimeric antigen receptor (CAR) to treat advanced cancers, particularly those refractory to conventional therapeutic agents. Although these engineered immune cells have made remarkable strides in the treatment of patients with certain hematologic malignancies, success with solid tumors has been limited, probably due to immunosuppressive mechanisms in the tumor niche. In nearly all studies to date, T cells bearing αβ receptors have been used to generate CAR T cells. In this review, we highlight biological characteristics of γδ T cells that are distinct from those of αβ T cells, including homing to epithelial and mucosal tissues and unique functions such as direct antigen recognition, lack of alloreactivity, and ability to present antigens. We offer our perspective that these features make γδ T cells promising for use in cellular therapy against several types of solid tumors, including melanoma and gastrointestinal cancers. Engineered γδ T cells should be considered as a new platform for adoptive T cell cancer therapy for mucosal tumors. PMID:27392648

  16. 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. PMID:27471638

  17. Advances of Immunotherapy in Small Cell Lung Cancer

    Directory of Open Access Journals (Sweden)

    Jingjing LIU

    2014-06-01

    Full Text Available Small cell lung cancer (SCLC is complex heterogeneous due to unclear biological characteristics in terms of cell origin, pathogenesis and driver genes etc. Diagnosis and treatment of SCLC has been slowly improved and few breakthroughs have been discovered up to now. Therefore new strategies are urgently needed to improve the efficacy of SCLC treatment. Tumor immunotherapy has potential to restore and trigger the immune system to recognize and eliminate tumor cells, notably it has only minimal adverse impact on normal tissue. Cancer vaccine, adoptive immunotherapy, cytokines and checkpoint inhibitors have now been launched for clinical treatment of SCLC. Ipilimumab is the most promising medicine of immunotherapy. Immunotherapy is expected to bring new vision to the treatment of SCLC. And further researches are needed on such problems affecting efficacy of immunotherapy as the heterogeneity of SCLC, the uncertainty of target for immunotherapy, the immune tolerance, etc.

  18. Advances in cancer immunology and cancer immunotherapy.

    Science.gov (United States)

    Voena, Claudia; Chiarle, Roberto

    2016-02-01

    After decades of setbacks, cancer immunology is living its Golden Age. Recent advances in cancer immunology have provided new therapeutic approaches to treat cancer. The objective clinical response observed in patients treated with antibodies that block the immune checkpoints, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell-death protein 1 (PD-1)/programmed cell-death 1 ligand 1 (PD-L1) pathways, has led to their FDA approval for the treatment of melanoma in 2011 and in 2014, respectively. The anti-PD-1 antibody nivolumab has received the FDA-approval in March 2015 for squamous lung cancer treatment. In addition, antibodies targeting PD-1 or PD-L1 have demonstrated their efficacy and safety in additional tumors, including non-small cell lung carcinoma (NSCLC), renal cell carcinoma (RCC), bladder cancer, and Hodgkin's lymphoma. Almost at the same time, the field of adoptive cell transfer has exploded. The chimeric antigen receptor (CAR) T technology has provided strong evidence of efficacy in the treatment of B cell malignancies, and different T cell based treatments are currently under investigation for different types of tumors. In this review we will discuss the latest advances in cancer immunology and immunotherapy as well as new treatments now under development in the clinic and potential strategies that have shown promising results in preclinical models. PMID:27011048

  19. Bladder cancer immunotherapy.

    Science.gov (United States)

    Lamm, D L; Thor, D E; Stogdill, V D; Radwin, H M

    1982-11-01

    A randomized controlled prospective evaluation of intravesical and percutaneous bacillus Calmette-Guerin immunotherapy was done in 57 patients with transitional cell carcinoma of the bladder. In addition, 9 patients at high risk for tumor recurrence were treated with bacillus Calmette-Guerin produced a self-limited cystitis and 1 complication (hydronephrosis) of immunotherapy was observed. Of the 57 randomized patients 54 were followed for 3 to 30 months. Tumor recurrence was documented in 13 of 26 controls (50 per cent) and only 6 of 28 patients (21 per cent) treated with bacillus Calmette-Guerin (p equals 0.027, chi-square). The interval free of disease was prolonged significantly with bacillus Calmette-Guerin treatment (p equals 0.014, generalized Wilcoxon test). Importantly, a simple purified protein derivative skin test distinguished those patients who responded to bacillus Calmette-Guerin immunotherapy from those who did not. Only 1 of 17 treated patients (6 per cent) whose purified protein derivative test converted from negative to positive had tumor recurrence compared to 5 recurrences (38 per cent) among the 13 patients whose test remained negative or had been positive before treatment (p equals 0.022, chi-square). Bacillus Calmette-Guerin was given to 10 patients with stage B transitional cell carcinoma who were not candidates for cystectomy and 7 are free of disease. Of 5 patients with carcinoma in situ 3 remain free of tumor after bacillus Calmette-Guerin treatment and 5 of 6 who had multiple recurrences after intravesical chemotherapy responded favorably to bacillus Calmette-Guerin immunotherapy. PMID:6757467

  20. NK-92: an 'off-the-shelf therapeutic' for adoptive natural killer cell-based cancer immunotherapy.

    Science.gov (United States)

    Suck, Garnet; Odendahl, Marcus; Nowakowska, Paulina; Seidl, Christian; Wels, Winfried S; Klingemann, Hans G; Tonn, Torsten

    2016-04-01

    Natural killer (NK) cells are increasingly considered as immunotherapeutic agents in particular in the fight against cancers. NK cell therapies are potentially broadly applicable and, different from their T cell counterparts, do not cause graft-versus-host disease. Efficacy and clinical in vitro or in vivo expansion of primary NK cells will however always remain variable due to individual differences of donors or patients. Long-term storage of clinical NK cell lots to allow repeated clinical applications remains an additional challenge. In contrast, the established and well-characterized cell line NK-92 can be easily and reproducibly expanded from a good manufacturing practice (GMP)-compliant cryopreserved master cell bank. Moreover, no cost-intensive cell purification methods are required. To date, NK-92 has been intensively studied. The cells displayed superior cytotoxicity against a number of tumor types tested, which was confirmed in preclinical mouse studies. Subsequent clinical testing demonstrated safety of NK-92 infusions even at high doses. Despite the phase I nature of the trials conducted so far, some efficacy was noted, particularly against lung tumors. Furthermore, to overcome tumor resistance and for specific targeting, NK-92 has been engineered to express a number of different chimeric antigen receptors (CARs), including targeting, for example, CD19 or CD20 (anti-B cell malignancies), CD38 (anti-myeloma) or human epidermal growth factor receptor 2 (HER2; ErbB2; anti-epithelial cancers). The concept of an NK cell line as an allogeneic cell therapeutic produced 'off-the-shelf' on demand holds great promise for the development of effective treatments. PMID:26559813

  1. Specificity in cancer immunotherapy

    OpenAIRE

    Schietinger, Andrea; Philip, Mary; Schreiber, Hans

    2008-01-01

    From the earliest days in the field of tumor immunology three questions have been asked: do cancer cells express tumor-specific antigens, does the immune system recognize these antigens, and if so, what is their biochemical nature? We now know that truly tumor-specific antigens exist, that they are caused by somatic mutations, and that these antigens can induce both humoral and cell-mediated immune responses. Because tumor-specific antigens are exclusively expressed by the cancer cell and are...

  2. [Dendritic cells in cancer immunotherapy].

    Science.gov (United States)

    Gato, M; Liechtenstein, T; Blanco-Luquín, I; Zudaire, M I; Kochan, G; Escors, D

    2015-01-01

    Since the beginning of the 20th century, biomedical scientists have tried to take advantage of the natural anti-cancer activities of the immune system. However, all the scientific and medical efforts dedicated to this have not resulted in the expected success. In fact, classical antineoplastic treatments such as surgery, radio and chemotherapy are still first line treatments. Even so, there is a quantity of experimental evidence demonstrating that cancer cells are immunogenic. However, the effective activation of anti-cancer T cell responses closely depends on an efficient antigen presentation carried out by professional antigen presenting cells such as DC. Although there are a number of strategies to strengthen antigen presentation by DC, anti-cancer immunotherapy is not as effective as we would expect according to preclinical data accumulated in recent decades. We do not aim to make an exhaustive review of DC immunotherapy here, which is an extensive research subject already dealt with in many specialised reviews. Instead, we present the experimental approaches undertaken by our group over the last decade, by modifying DC to improve their anti-tumour capacities. PMID:26486534

  3. Cancer Immunotherapy: A Review

    OpenAIRE

    Anna Meiliana; Nurrani Mustika Dewi; Andi Wijaya

    2016-01-01

    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 targetin...

  4. Advances in Cancer Immunotherapy

    OpenAIRE

    Snook, Adam E.; Waldman, Scott A.

    2013-01-01

    Our immune system is characterized by remarkable specificity, potency and memory – the ability of a single vaccine treatment to provide life-long protection. No pharmacologic treatment for any indication can provide the same level of safety, efficacy and long-lasting effect that a vaccine can. Thus, researchers and clinicians alike have sought to apply these characteristics to the treatment of cancer. Yet, for the last 125 years, the field has failed to realize this potential. Here, we will r...

  5. Immunotherapy of Cancer: Towards a New Era

    Directory of Open Access Journals (Sweden)

    John B.A.G. Haanen

    2014-11-01

    Full Text Available In the past two decades, immunotherapy of cancer has developed into an established treatment option. At first, the development of monoclonal antibodies – targeting overexpressed cell surface molecules on tumour cells – resulted in improved survival when combined with standard chemotherapy or radiotherapy. More recently, T cell immunotherapy has impacted on survival of certain cancer types. In melanoma especially, but now also in renal cell cancer and non-small cell lung cancer, immune checkpoint inhibitors, such as cytotoxic T lymphocyte–associated antigen-4 (anti-CTLA4 and blockade of programmed death receptor-1-PD- ligand 1 (PD1-PD-L1 interaction, represent a completely new treatment paradigm, lowering the threshold for an anticancer immune response and breaking self-tolerance. Adoptive T cell transfer using tumour- infiltrating lymphocytes or genetically modified T cells are under development, but have shown impressive clinical efficacy in several Phase II studies. These emerging but highly promising treatments can give rise to durable tumour control in diseases that were lethal in all patients only a few years ago.

  6. 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. PMID:27121882

  7. Novel Approaches to Pediatric Cancer: Immunotherapy

    Directory of Open Access Journals (Sweden)

    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.

  8. Particle platforms for cancer immunotherapy

    Directory of Open Access Journals (Sweden)

    Serda RE

    2013-04-01

    Full Text Available Rita Elena Serda Department of Nanomedicine, The Methodist Hospital Research Institute, Houston, TX, USA Abstract: Elevated understanding and respect for the relevance of the immune system in cancer development and therapy has led to increased development of immunotherapeutic regimens that target existing cancer cells and provide long-term immune surveillance and protection from cancer recurrence. This review discusses using particles as immune adjuvants to create vaccines and to augment the anticancer effects of conventional chemotherapeutics. Several particle prototypes are presented, including liposomes, polymer nanoparticles, and porous silicon microparticles, the latter existing as either single- or multiparticle platforms. The benefits of using particles include immune-cell targeting, codelivery of antigens and immunomodulatory agents, and sustained release of the therapeutic payload. Nanotherapeutic-based activation of the immune system is dependent on both intrinsic particle characteristics and on the immunomodulatory cargo, which may include danger signals known as pathogen-associated molecular patterns and cytokines for effector-cell activation. Keywords: adjuvant, particle, immunotherapy, dendritic cell, cancer, vaccine

  9. 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.

  10. Chimeric antigen receptor engineering: a right step in the evolution of adoptive cellular immunotherapy.

    Science.gov (United States)

    Figueroa, Jose A; Reidy, Adair; Mirandola, Leonardo; Trotter, Kayley; Suvorava, Natallia; Figueroa, Alejandro; Konala, Venu; Aulakh, Amardeep; Littlefield, Lauren; Grizzi, Fabio; Rahman, Rakhshanda Layeequr; Jenkins, Marjorie R; Musgrove, Breeanna; Radhi, Saba; D'Cunha, Nicholas; D'Cunha, Luke N; Hermonat, Paul L; Cobos, Everardo; Chiriva-Internati, Maurizio

    2015-03-01

    Cancer immunotherapy comprises different therapeutic strategies that exploit the use of distinct components of the immune system, with the common goal of specifically targeting and eradicating neoplastic cells. These varied approaches include the use of specific monoclonal antibodies, checkpoint inhibitors, cytokines, therapeutic cancer vaccines and cellular anticancer strategies such as activated dendritic cell (DC) vaccines, tumor-infiltrating lymphocytes (TILs) and, more recently, genetically engineered T cells. Each one of these approaches has demonstrated promise, but their generalized success has been hindered by the paucity of specific tumor targets resulting in suboptimal tumor responses and unpredictable toxicities. This review will concentrate on recent advances on the use of engineered T cells for adoptive cellular immunotherapy (ACI) in cancer. PMID:25901860

  11. 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.

  12. 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....

  13. Immunotherapy for non-small cell lung cancer: current concepts and clinical trials.

    Science.gov (United States)

    Mayor, Marissa; Yang, Neng; Sterman, Daniel; Jones, David R; Adusumilli, Prasad S

    2016-05-01

    Recent successes in immunotherapeutic strategies are being investigated to combat cancers that have less than ideal responses to standard of care treatment, such as non-small-cell lung cancer. In this paper, we summarize concepts and the current status of immunotherapy for non-small cell lung cancer, including salient features of the major categories of immunotherapy-monoclonal antibody therapy, immune checkpoint blockade, immunotoxins, anticancer vaccines, and adoptive cell therapy. PMID:26516195

  14. Dendritic cell-based cancer immunotherapy for colorectal cancer

    OpenAIRE

    Kajihara, Mikio; Takakura, Kazuki; Kanai, Tomoya; Ito, Zensho; Saito, Keisuke; Takami, Shinichiro; Shimodaira, Shigetaka; Okamoto, Masato; Ohkusa, Toshifumi; Koido, Shigeo

    2016-01-01

    Colorectal cancer (CRC) is one of the most common cancers and a leading cause of cancer-related mortality worldwide. Although systemic therapy is the standard care for patients with recurrent or metastatic CRC, the prognosis is extremely poor. The optimal sequence of therapy remains unknown. Therefore, alternative strategies, such as immunotherapy, are needed for patients with advanced CRC. This review summarizes evidence from dendritic cell-based cancer immunotherapy strategies that are curr...

  15. Prostate cancer immunotherapy: beyond immunity to curability.

    Science.gov (United States)

    Simons, Jonathan W

    2014-11-01

    Metastatic prostate cancer is the second leading cause of death from cancer in the United States. It is the first prevalent cancer in which overall survival in advanced disease is modestly, but objectively, improved with outpatient delivered dendritic cell-based immunotherapy. More prostate cancer patients have enrolled through Facebook and trusted-site Internet searches in clinical trials for prostate cancer vaccine-based immunotherapy than in immunotherapy trials for lung, breast, colon, pancreas, ovarian, and bladder cancer combined in the past 7 years. Exceptional responses to anti-CTLA-4 treatment have been documented in clinics, and prostate cancer neoantigen characterization and T-cell clonotyping are in their research ascendancy. The prostate is an accessory organ; it is not required for fertility, erectile function, or urinary continence. The true evolutionary advantage of having a prostate for male mammalian physiology is a topic of speculation in seminar rooms and on bar stools, but it remains unknown. Hundreds of prostate lineage-unique proteins (PLUP) exist among the >37,000 normal human prostate lineage-unique open reading frames that can be targeted for immunologic ablation of PLUP(+) prostate cancer cells by prostate-specific autoimmunity. This bioengineered graft-versus-prostate disease is a powerful strategy that can eliminate deaths from prostate cancer. Immunologic tolerance to prostate cancer can be overcome at every clinical stage of presentation. This Cancer Immunology at the Crossroads article aims to present advances in the past two decades of basic, translational, and clinical research in prostate cancer, including bioengineering B-cell and T-cell responses, and ongoing prostate cancer immunotherapy trials. PMID:25367978

  16. Bioinformatics for cancer immunotherapy target discovery

    DEFF Research Database (Denmark)

    Olsen, Lars Rønn; Campos, Benito; Barnkob, Mike Stein;

    2014-01-01

    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......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...... and co-targets for single-epitope and multi-epitope strategies. We provide examples of application to the well-known tumor antigen HER2 and suggest bioinformatics methods to ameliorate therapy resistance and ensure efficient and lasting control of tumors....

  17. Immunotherapy and Immune Evasion in Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Thakur, Archana, E-mail: thakur@karmanos.org; Vaishampayan, Ulka [Department of Oncology, Wayne State University, Detroit, MI 48201 (United States); Lum, Lawrence G., E-mail: thakur@karmanos.org [Department of Oncology, Wayne State University, Detroit, MI 48201 (United States); Department of Medicine, Wayne State University, Detroit, MI 48201 (United States); Department of Immunology and Microbiology, Wayne State University, Detroit, MI 48201 (United States)

    2013-05-24

    Metastatic prostate cancer remains to this day a terminal disease. Prostatectomy and radiotherapy are effective for organ-confined diseases, but treatment for locally advanced and metastatic cancer remains challenging. Although advanced prostate cancers treated with androgen deprivation therapy achieves debulking of disease, responses are transient with subsequent development of castration-resistant and metastatic disease. Since prostate cancer is typically a slowly progressing disease, use of immune-based therapies offers an advantage to target advanced tumors and to induce antitumor immunity. This review will discuss the clinical merits of various vaccines and immunotherapies in castrate resistant prostate cancer and challenges to this evolving field of immune-based therapies.

  18. Immunotherapy and Immune Evasion in Prostate Cancer

    International Nuclear Information System (INIS)

    Metastatic prostate cancer remains to this day a terminal disease. Prostatectomy and radiotherapy are effective for organ-confined diseases, but treatment for locally advanced and metastatic cancer remains challenging. Although advanced prostate cancers treated with androgen deprivation therapy achieves debulking of disease, responses are transient with subsequent development of castration-resistant and metastatic disease. Since prostate cancer is typically a slowly progressing disease, use of immune-based therapies offers an advantage to target advanced tumors and to induce antitumor immunity. This review will discuss the clinical merits of various vaccines and immunotherapies in castrate resistant prostate cancer and challenges to this evolving field of immune-based therapies

  19. Review on Immunotherapies for Lung Cancer

    Directory of Open Access Journals (Sweden)

    Sha JIN

    2012-10-01

    Full Text Available Lung cancer is a highly malignant disease with poor prognosis, most cases are diagnosed at a very late stage. More effective medications or therapies should be developed to improve its prognosis. The advancement of tumor immunity and tumor immunosuppression facilitated the feasibility of immunotherapies for lung cancer. Ipilimumab, antibody to Programmed death-1 (PD-1, Toll-like receptor agonists, liposomal BLP25 (L- BLP25, belagenpumatucel-L, melanoma-associated antigen A3 (MAGE-A3 vaccine and talactoferrin have been proved to be effective for lung cancer through early clinical trials, most of the drugs have moved forward to phase III trials, so as to collect much higher level evidence to support the immunotherapies incorporated into the multidisciplinary treatment of lung cancer. The selection of target patients at appropriate stages, breaking down of tumor immunosuppression as well as the objective measurement of tumor response to the therapy are major challenges for the development of immunotherapies for lung cancer. The clarifying of the mechanism of immune escape led to the above drug development, and immune-senescence has already become the hotspot in this field.

  20. Development of PROSTVAC immunotherapy in prostate cancer.

    Science.gov (United States)

    Singh, Parminder; Pal, Sumanta K; Alex, Anitha; Agarwal, Neeraj

    2015-01-01

    PROSTVAC immunotherapy is a heterologous prime-boost regimen of two different recombinant pox-virus vectors; vaccinia as the primary immunotherapy, followed by boosters employing fowlpox, to provoke immune responses against prostate-specific antigen. Both vectors contain transgenes for prostate-specific antigen and a triad of T-cell costimulatory molecules (TRICOM). In a placebo-controlled Phase II trial of men with minimally symptomatic, chemotherapy-naive metastatic castration-resistant prostate cancer, PROSTVAC was well tolerated and associated with a 44% reduction in death. With a novel mechanism of action, and excellent tolerability, PROSTVAC has the potential to dramatically alter the treatment landscape of prostate cancer, not only as a monotherapy, but also in combination with other novel agents, such as immune check point inhibitors and novel androgen receptor blockers. A Phase III trial recently completed accrual. PMID:26235179

  1. 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.

  2. Coinhibitory Pathways in Immunotherapy for Cancer.

    Science.gov (United States)

    Baumeister, Susanne H; Freeman, Gordon J; Dranoff, Glenn; Sharpe, Arlene H

    2016-05-20

    The immune system is capable of recognizing tumors and eliminates many early malignant cells. However, tumors evolve to evade immune attack, and the tumor microenvironment is immunosuppressive. Immune responses are regulated by a number of immunological checkpoints that promote protective immunity and maintain tolerance. T cell coinhibitory pathways restrict the strength and duration of immune responses, thereby limiting immune-mediated tissue damage, controlling resolution of inflammation, and maintaining tolerance to prevent autoimmunity. Tumors exploit these coinhibitory pathways to evade immune eradication. Blockade of the PD-1 and CTLA-4 checkpoints is proving to be an effective and durable cancer immunotherapy in a subset of patients with a variety of tumor types, and additional combinations are further improving response rates. In this review we discuss the immunoregulatory functions of coinhibitory pathways and their translation to effective immunotherapies for cancer. PMID:26927206

  3. Stem cells and cancer immunotherapy: Arrowhead’s 2nd annual cancer immunotherapy conference

    OpenAIRE

    Bot, Adrian; Chiriva-Internati, Maurizio; Cornforth, Andrew; Brian J Czerniecki; Ferrone, Soldano; Geles, Kenneth; Greenberg, Philip D.; Hurt, Elaine; Koya, Richard C.; Masoud H Manjili; Matsui, William; Morgan, Richard A.; Palena, Claudia M; Powell Jr, Daniel J; Restifo, Nicholas P

    2014-01-01

    Investigators from academia and industry gathered on April 4 and 5, 2013, in Washington DC at the Arrowhead’s 2nd Annual Cancer Immunotherapy Conference. Two complementary concepts were discussed: cancer “stem cells” as targets and therapeutic platforms based on stem cells.

  4. ATMPs for Cancer Immunotherapy: A Regulatory Overview.

    Science.gov (United States)

    Galli, Maria Cristina

    2016-01-01

    This chapter discusses European regulatory requirements for development of advanced therapy medicinal products (ATMP) for cancer immunotherapy approaches, describing the framework for clinical trials and for marketing authorization.Regulatory critical issues and challenges for developing ATMP are also discussed, with focus on potency determination, long-term follow-up, comparability, and insertional mutagenesis issues. Some of the most critical features of GMP application to ATMP are also described. PMID:27033211

  5. Dendritic cell-based cancer immunotherapy for colorectal cancer

    Science.gov (United States)

    Kajihara, Mikio; Takakura, Kazuki; Kanai, Tomoya; Ito, Zensho; Saito, Keisuke; Takami, Shinichiro; Shimodaira, Shigetaka; Okamoto, Masato; Ohkusa, Toshifumi; Koido, Shigeo

    2016-01-01

    Colorectal cancer (CRC) is one of the most common cancers and a leading cause of cancer-related mortality worldwide. Although systemic therapy is the standard care for patients with recurrent or metastatic CRC, the prognosis is extremely poor. The optimal sequence of therapy remains unknown. Therefore, alternative strategies, such as immunotherapy, are needed for patients with advanced CRC. This review summarizes evidence from dendritic cell-based cancer immunotherapy strategies that are currently in clinical trials. In addition, we discuss the possibility of antitumor immune responses through immunoinhibitory PD-1/PD-L1 pathway blockade in CRC patients. PMID:27158196

  6. [Immunotherapy opportunities in breast cancer].

    Science.gov (United States)

    Pusztai, Lajos; Ladányi, Andrea; Székely, Borbála; Dank, Magdolna

    2016-03-01

    The prognostic value of tumor infiltrating lymphocytes in breast cancer has long been recognized by histopathologists. These observations were reaffirmed by recent immunohistochemistry and gene expression profiling studies that also revealed an association between greater chemotherapy sensitivity and extensive lymphocytic infiltration in early stage breast cancers treated with neoadjuvant chemotherapy. These results suggest that local anti-tumor immune response can at least partially control cancer growth and may mediate the antitumor effects of chemotherapy. However, until recently, there was no direct clinical evidence to demonstrate that enhancing anti-tumor immune response could lead to clinical benefit in breast cancer patients. The recent development of clinically effective immune checkpoint inhibitors made it possible to test the therapeutic impact of augmenting the local anti-tumor immune response. Two Phase I clinical trials using single agent anti-PD-1 (MK-3475, pembrolizumab) and anti-PD-L1 (MPDL3280A, atezolizumab) antibodies demonstrated close to 20% tumor response rates in heavily pretreated, metastatic, triple negative breast cancers. The most remarkable feature of the responses was their long duration. Several patients had disease control close to a year, or longer, which has not previously been seen with chemotherapy regimens in this patient population. A large number of clinical trials are currently underway with these and similar drugs in the neoadjuvant, adjuvant and metastatic settings to define the role of this new treatment modality in breast cancer. PMID:26934349

  7. Challenges and future perspectives of T cell immunotherapy in cancer.

    Science.gov (United States)

    de Aquino, Maria Teresa P; Malhotra, Anshu; Mishra, Manoj K; Shanker, Anil

    2015-08-01

    Since the formulation of the tumour immunosurveillance theory, considerable focus has been on enhancing the effectiveness of host antitumour immunity, particularly with respect to T cells. A cancer evades or alters the host immune response by various ways to ensure its development and survival. These include modifications of the immune cell metabolism and T cell signalling. An inhibitory cytokine milieu in the tumour microenvironment also leads to immune suppression and tumour progression within a host. This review traces the development in the field and attempts to summarize the hurdles that the approach of adoptive T cell immunotherapy against cancer faces, and discusses the conditions that must be improved to allow effective eradication of cancer. PMID:26096822

  8. A stochastic model for immunotherapy of cancer.

    Science.gov (United States)

    Baar, Martina; Coquille, Loren; Mayer, Hannah; Hölzel, Michael; Rogava, Meri; Tüting, Thomas; Bovier, Anton

    2016-01-01

    We propose an extension of a standard stochastic individual-based model in population dynamics which broadens the range of biological applications. Our primary motivation is modelling of immunotherapy of malignant tumours. In this context the different actors, T-cells, cytokines or cancer cells, are modelled as single particles (individuals) in the stochastic system. The main expansions of the model are distinguishing cancer cells by phenotype and genotype, including environment-dependent phenotypic plasticity that does not affect the genotype, taking into account the effects of therapy and introducing a competition term which lowers the reproduction rate of an individual in addition to the usual term that increases its death rate. We illustrate the new setup by using it to model various phenomena arising in immunotherapy. Our aim is twofold: on the one hand, we show that the interplay of genetic mutations and phenotypic switches on different timescales as well as the occurrence of metastability phenomena raise new mathematical challenges. On the other hand, we argue why understanding purely stochastic events (which cannot be obtained with deterministic models) may help to understand the resistance of tumours to therapeutic approaches and may have non-trivial consequences on tumour treatment protocols. This is supported through numerical simulations. PMID:27063839

  9. Immune checkpoint‑targeted cancer immunotherapies

    Directory of Open Access Journals (Sweden)

    Julian Swatler

    2016-01-01

    Full Text Available Tumor cells may express on their surface various characteristic antigens that can induce antitumor immunity. However, cancer in human body may induce an immunosuppressive microenvironment that limits immune response to its antigens. For many years scientists have tried to develop an immunotherapy which would induce a potent antitumor immune response and lead to an elimination of the disease. One of the most promising immunotherapies is blockade of immune checkpoints, i.e. a group of costimulatory molecules negatively regulating the immune system. Their blockade would overcome immune tolerance in the tumor microenvironment and amplify antitumor immunity. What’s more, immune checkpoint blockade may turn out even more profitable, as some of immune checkpoints and their ligands are expressed on tumor surface and on tumor infiltrating lymphocytes, contributing to the immunosuppressive cancer microenvironment. Phase III clinical trials have confirmed efficacy of an anti‑CTLA‑4 antibody ipilimumab, thereby leading to its acceptance for the treatment of advanced melanoma. Thanks to promising results of the phase I clinical trials, a breakthrough therapy designation and an early approval for the treatment have been granted to anti‑PD‑1 antibodies ‑ nivolumab (for the treatment of advanced melanoma and advanced non‑small cell lung cancer and pembrolizumab (for the treatment of advanced melanoma and, in the treatment of advanced bladder cancer, an anti‑PD‑L1 antibody ‑ MPDL3280A as well. Other immune checkpoints, such as LAG‑3, TIM‑3, BTLA, B7‑H3 and B7‑H4, are also under early evaluation.

  10. INTRAPLEURAL IMMUNOTHERAPY FOR METASTATIC PLEURISIES IN PATIENTS WITH BREAST CANCER

    OpenAIRE

    K. S. Titov; L. V. Demidov; M. V. Kiselevsky; I. N. Mikhailova; I. Zh. Shubina; A. N. Gritsai; I. E. Sinelnikov; L. M. Rodionova

    2009-01-01

    Intrapleural immunotherapy for metastatic pleurisies demonstrates a high efficiency in the treatment of patients with breast cancer (BC). This immunotherapy modality is regarded as one of the stages of complex treatment in patients with disseminated BC and allows its capabilities to be extended for their further management.

  11. Regulation of cell death in cancer - possible implications for immunotherapy

    OpenAIRE

    Simone eFulda

    2013-01-01

    Since most anticancer therapies including immunotherapy trigger programmed cell death in cancer cells, defective cell death programs can lead to treatment resistance and tumor immune escape. Therefore, evasion of programmed cell death may provide one possible explanation as to why cancer immunotherapy has so far only shown modest clinical benefits for children with cancer. A better understanding of the molecular mechanisms that regulate sensitivity and resistance to programmed cell death is e...

  12. Personalized cancer immunotherapy using Systems Medicine approaches.

    Science.gov (United States)

    Gupta, Shailendra K; Jaitly, Tanushree; Schmitz, Ulf; Schuler, Gerold; Wolkenhauer, Olaf; Vera, Julio

    2016-05-01

    The immune system is by definition multi-scale because it involves biochemical networks that regulate cell fates across cell boundaries, but also because immune cells communicate with each other by direct contact or through the secretion of local or systemic signals. Furthermore, tumor and immune cells communicate, and this interaction is affected by the tumor microenvironment. Altogether, the tumor-immunity interaction is a complex multi-scale biological system whose analysis requires a systemic view to succeed in developing efficient immunotherapies for cancer and immune-related diseases. In this review we discuss the necessity and the structure of a systems medicine approach for the design of anticancer immunotherapies. We support the idea that the approach must be a combination of algorithms and methods from bioinformatics and patient-data-driven mathematical models conceived to investigate the role of clinical interventions in the tumor-immunity interaction. For each step of the integrative approach proposed, we review the advancement with respect to the computational tools and methods available, but also successful case studies. We particularized our idea for the case of identifying novel tumor-associated antigens and therapeutic targets by integration of patient's immune and tumor profiling in case of aggressive melanoma. PMID:26174229

  13. 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.

  14. Immunotherapy: Disrupting the Cancer Treatment World

    Science.gov (United States)

    ... ways to get the immune system to target cancer. Experimental adoptive cell transfer therapies involve removing immune cells from a patient’s body, reengineering them to learn to attack cancer, and then re-infusing them into the patient’s ...

  15. Aptamers: A Feasible Technology in Cancer Immunotherapy

    Science.gov (United States)

    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. PMID:27413756

  16. A case of malignant melanoma of the maxilla treated by adoptive immunotherapy after fast neutron therapy

    International Nuclear Information System (INIS)

    A 77-year-old male patient with malignant melanoma was treated by fast neutron therapy and immunotherapy. Total dose of fast neutron applied to the primary lesion was 1905 cGy per 21 fractionation for 46 days. For adoptive immunotherapy, lymphocytes were collected from the peripheral blood drawn from the patient 2 days after the injection of cyclophosphamide. T cells were further purified by passing the lymphocytes through nylon wool. Cytotoxic T cells were induced by incubating the T cells mixed with allogeneic malignant melanoma cells and a small number of patient's adherent cells, and activated with recombinant interleukin-2 (γ IL-2). Our patient and the patient from whom stimulating melanoma cells were derived shared A locous 24 and B locous 51 of MHC class I antigens in common. Thus prepared cytotoxic T cells were inoculated to the patient via the maxillary artery, 3 to 4 times a week for one month. Total amount of cells transferred was 5.6 x 108 (97% lymphocytes). Primary lesion reduced markedly by the therapies. During adoptive immunotherapy, increase in natural killer cells and decrease in both suppressor/inducer T-cells and macrophages were observed. However, lung metastases appeared 3 months after adoptive immunotherapy. While the nonspecific immunotherapy (OK-432 injection) was being conducted thereafter, growth of the metastatic lesions of the lung was kept gentle but became obvious after the suspension of the treatment. (author)

  17. 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

  18. Adoptive Immunotherapy for Hematological Malignancies Using T Cells Gene-Modified to Express Tumor Antigen-Specific Receptors

    Directory of Open Access Journals (Sweden)

    Hiroshi Fujiwara

    2014-12-01

    Full Text Available Accumulating clinical evidence suggests that adoptive T-cell immunotherapy could be a promising option for control of cancer; evident examples include the graft-vs-leukemia effect mediated by donor lymphocyte infusion (DLI and therapeutic infusion of ex vivo-expanded tumor-infiltrating lymphocytes (TIL for melanoma. Currently, along with advances in synthetic immunology, gene-modified T cells retargeted to defined tumor antigens have been introduced as “cellular drugs”. As the functional properties of the adoptive immune response mediated by T lymphocytes are decisively regulated by their T-cell receptors (TCRs, transfer of genes encoding target antigen-specific receptors should enable polyclonal T cells to be uniformly redirected toward cancer cells. Clinically, anticancer adoptive immunotherapy using genetically engineered T cells has an impressive track record. Notable examples include the dramatic benefit of chimeric antigen receptor (CAR gene-modified T cells redirected towards CD19 in patients with B-cell malignancy, and the encouraging results obtained with TCR gene-modified T cells redirected towards NY-ESO-1, a cancer-testis antigen, in patients with advanced melanoma and synovial cell sarcoma. This article overviews the current status of this treatment option, and discusses challenging issues that still restrain the full effectiveness of this strategy, especially in the context of hematological malignancy.

  19. Evolving synergistic combinations of targeted immunotherapies to combat cancer.

    Science.gov (United States)

    Melero, Ignacio; Berman, David M; Aznar, M Angela; Korman, Alan J; Pérez Gracia, José Luis; Haanen, John

    2015-08-01

    Immunotherapy has now been clinically validated as an effective treatment for many cancers. There is tremendous potential for synergistic combinations of immunotherapy agents and for combining immunotherapy agents with conventional cancer treatments. Clinical trials combining blockade of cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) may serve as a paradigm to guide future approaches to immuno-oncology combination therapy. In this Review, we discuss progress in the synergistic design of immune-targeting combination therapies and highlight the challenges involved in tailoring such strategies to provide maximal benefit to patients. PMID:26205340

  20. Improving cancer immunotherapy by targeting the STATe of MDSCs

    Science.gov (United States)

    de Haas, Nienke; de Koning, Coco; Spilgies, Lisanne; de Vries, I. Jolanda M.; Hato, Stanleyson V.

    2016-01-01

    ABSTRACT Cancer immunotherapy is a promising therapeutic avenue; however, in practice its efficacy is hampered by an immunosuppressive tumor microenvironment that consists of suppressive cell types like myeloid-derived suppressor cells (MDSCs). Eradication or reprogramming of MDSCs could therefore enhance clinical responses to immunotherapy. Here, we review clinically available drugs that target MDSCs, often through inhibition of STAT signaling, which is essential for MDSC accumulation and suppressive functions. Interestingly, several drugs used for non-cancerous indications and natural compounds similarly inhibit MDSCs by STAT inhibition, but have fewer side effects than anticancer drugs. Therefore, they show great potential for combination strategies with immunotherapy.

  1. Immunoinformatics and modeling perspective of T cell epitope-based cancer immunotherapy: a holistic picture.

    Science.gov (United States)

    Mishra, Seema; Sinha, Subhata

    2009-12-01

    Cancer immunotherapy is fast gaining global attention with its unique position as a potential therapy showing promise in cancer prevention and cure. It utilizes the natural system of immunity as opposed to chemotherapy and radiotherapy that utilize chemical drugs and radiation, respectively. Cancer immunotherapy essentially involves treatment and/or prevention with vaccines in the form of peptide vaccines (T and B cell epitopes), DNA vaccines and vaccination using whole tumor cells, dendritic cells, viral vectors, antibodies and adoptive transfer of T cells to harness the body's own immune system towards the targeting of cancer cells for destruction. Given the time, cost and labor involved in the vaccine discovery and development, researchers have evinced interest in the novel field of immunoinformatics to cut down the escalation of these critical resources. Immunoinformatics is a relatively new buzzword in the scientific circuit that is showing its potential and delivering on its promise in expediting the development of effective cancer immunotherapeutic agents. This review attempts to present a holistic picture of our race against cancer and time using the science and technology of immunoinformatics and molecular modeling in T cell epitope-based cancer immunotherapy. It also attempts to showcase some problem areas as well as novel ones waiting to be explored where development of novel immunoinformatics tools and simulations in the context of cancer immunotherapy would be highly welcome. PMID:19795913

  2. Immunotherapy: Shifting the Balance of Cell-Mediated Immunity and Suppression in Human Prostate Cancer

    International Nuclear Information System (INIS)

    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

  3. 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.

  4. DNA-based immunotherapy for HPV-associated head and neck cancer.

    Science.gov (United States)

    Aggarwal, Charu

    2016-10-01

    Squamous cell carcinoma of the head and neck (SCCHN) accounts for 3% of all cancers. Most patients present with locally advanced disease, where multimodality therapies are used with curative intent. Despite favorable early local treatment results, about one third of the patients will eventually develop metastatic disease. Immunotherapy offers a novel therapeutic strategy beyond cytotoxic chemotherapy, with initial approvals in melanoma and non-small-cell lung cancer. HPV-associated SCCHN is a distinct subset, with unique epidemiology and treatment outcomes. Both subsets of SCCHN (HPV-related or not) are particularly favorable for immunotherapy, as immune evasion and dysregulation have been shown to play a key role in the initiation and progression of disease. This review focuses on the latest developments in immunotherapy in SCCHN, with a particular focus on DNA-based approaches including vaccine and adoptive cellular therapies. PMID:27605067

  5. Workshop on immunotherapy combinations. Society for immunotherapy of cancer annual meeting Bethesda, November 3, 2011

    Directory of Open Access Journals (Sweden)

    Forero Ivan

    2012-05-01

    Full Text Available Abstract Although recent FDA approvals on ipilimumab and sipuleucel-T represent major milestones, the ultimate success of immunotherapy approaches will likely benefit from appropriate combinations with other immunotherapeutic and/or non-immunotherapeutic approaches. However, implementation of ideal combinations in the clinic may still face formidable challenges in regulatory, drug-availability and intellectual property aspects. The 2011 SITC annual meeting hosted a workshop on combination immunotherapy to discuss: 1 the most promising combinations found in the laboratory; 2 early success of combination immunotherapy in clinical trials; 3 industry perspectives on combination approaches, and 4 relevant regulatory issues. The integrated theme was how to accelerate the implementation of efficacious combined immunotherapies for cancer patients. Rodent animal models are providing many examples of synergistic combinations that typically include more than two agents. However, mouse and human immunology differ in a significant number of mechanisms and hence we might be missing opportunities peculiar to humans. Nonetheless, incisive animal experimentation with deep mechanistic insight remains the best compass that we can use to guide our paths in combinatorial immunotherapy. Combination immunotherapy clinical trials are already in progress and preliminary results are extremely promising. As a key to translate promising combinations into clinic, real and “perceived” business and regulatory hurdles were debated. A formidable step forward would be to be able to test combinations of investigational agents prior to individual approval. Taking together the FDA and the industrial perspective on combinatorial immunotherapy, the audience was left with the clear message that this is by no means an impossible task. The general perception is that the road ahead of us is full of combination clinical trials which hopefully will bring clinical benefit to our cancer

  6. Workshop on immunotherapy combinations. Society for Immunotherapy of Cancer annual meeting Bethesda, November 3, 2011.

    Science.gov (United States)

    Martinez Forero, Ivan; Okada, Hideho; Topalian, Suzanne L; Gajewski, Thomas F; Korman, Alan J; Melero, Ignacio

    2012-01-01

    Although recent FDA approvals on ipilimumab and sipuleucel-T represent major milestones, the ultimate success of immunotherapy approaches will likely benefit from appropriate combinations with other immunotherapeutic and/or non-immunotherapeutic approaches. However, implementation of ideal combinations in the clinic may still face formidable challenges in regulatory, drug-availability and intellectual property aspects. The 2011 SITC annual meeting hosted a workshop on combination immunotherapy to discuss: 1) the most promising combinations found in the laboratory; 2) early success of combination immunotherapy in clinical trials; 3) industry perspectives on combination approaches, and 4) relevant regulatory issues. The integrated theme was how to accelerate the implementation of efficacious combined immunotherapies for cancer patients. Rodent animal models are providing many examples of synergistic combinations that typically include more than two agents. However, mouse and human immunology differ in a significant number of mechanisms and hence we might be missing opportunities peculiar to humans. Nonetheless, incisive animal experimentation with deep mechanistic insight remains the best compass that we can use to guide our paths in combinatorial immunotherapy. Combination immunotherapy clinical trials are already in progress and preliminary results are extremely promising. As a key to translate promising combinations into clinic, real and "perceived" business and regulatory hurdles were debated. A formidable step forward would be to be able to test combinations of investigational agents prior to individual approval. Taking together the FDA and the industrial perspective on combinatorial immunotherapy, the audience was left with the clear message that this is by no means an impossible task. The general perception is that the road ahead of us is full of combination clinical trials which hopefully will bring clinical benefit to our cancer patients at a fast pace. PMID

  7. Less is more: lymphodepletion followed by hematopoietic stem cell transplant augments adoptive T-cell-based anti-tumor immunotherapy

    OpenAIRE

    Wrzesinski, Claudia; Restifo, Nicholas P

    2005-01-01

    Adoptive T-cell immunotherapy combined with non-myeloablative lymphodepletion has emerged as the most effective immunotherapy treatment for patients with metastatic melanoma (objective response rates of 50%). The mechanisms underlying this major advance in the field of immunotherapy include the elimination of regulatory elements and increased access to activating cytokines. This results in the activation of low-affinity T cells, enabling them to destroy tumors. We propose that a more complete...

  8. Driving an improved CAR for cancer immunotherapy.

    Science.gov (United States)

    Huang, Xiaopei; Yang, Yiping

    2016-08-01

    The recent clinical success of chimeric antigen receptor (CAR) T cell therapy for B cell malignancies represents a paradigm shift in cancer immunotherapy. Unfortunately, application of CAR T cell-mediated therapy for solid tumors has so far been disappointing, and the reasons for this poor response in solid tumors remain unknown. In this issue of the JCI, Cherkassky and colleagues report on their use of a murine model of human pleural mesothelioma to explore potential factors that limit CAR T cell efficacy. Their studies have uncovered the importance of the tumor microenvironment in the inhibition of CAR T cell functions, revealed a critical role for the programmed death-1 (PD-1) pathway in CAR T cell exhaustion within the tumor microenvironment, and demonstrated improved antitumor effects with a CAR T cell-intrinsic PD-1 blockade strategy using a dominant negative form of PD-1. Together, the results of this study lay the groundwork for further evaluation of mechanisms underlying CAR T cell immune evasion within the tumor microenvironment for the improvement of CAR T cell-mediated therapy for solid tumors. PMID:27454296

  9. Immunotherapy in colorectal cancer: What have we learned so far?

    Science.gov (United States)

    Sanchez-Castañón, María; Er, Tze-Kiong; Bujanda, Luis; Herreros-Villanueva, Marta

    2016-09-01

    After decades of progress based on chemotherapy and targeted agents, patients with metastatic colorectal cancer still have low long-term survival, with more than 500,000 deaths occurring worldwide every year. Recent results showing clinical evidence of efficacy using immunotherapy in other types of tumors, such as melanoma and lung cancer, have also made this a viable therapy for evaluation in colorectal cancer in clinical trials. The development of cancer immunotherapies is progressing quickly, with a variety of technological approaches. This review summarizes the current status of clinical trials testing immunotherapy in colorectal cancer and discusses what has been learned based on previous results. Immunotherapy strategies, such as various models of vaccines, effector-cell therapy and checkpoint inhibitor antibodies, provide protection against progression for a limited subset of patients diagnosed with colorectal cancer. A better understanding of particular immune cell types and pathways in each patient is still needed. These findings will enable the development of novel biomarkers to select the appropriate subset of patients to be treated with a particular immunotherapy, and the tendencies determined from recent results can guide clinical practice for oncologists in this new therapeutic area and in the design of the next round of clinical trials. PMID:27350293

  10. Cancer Immunotherapy: Selected Targets and Small-Molecule Modulators.

    Science.gov (United States)

    Weinmann, Hilmar

    2016-03-01

    There is a significant amount of excitement in the scientific community around cancer immunotherapy, as this approach has renewed hope for many cancer patients owing to some recent successes in the clinic. Currently available immuno-oncology therapeutics under clinical development and on the market are mostly biologics (antibodies, proteins, engineered cells, and oncolytic viruses). However, modulation of the immune system with small molecules offers several advantages that may be complementary and potentially synergistic to the use of large biologicals. Therefore, the discovery and development of novel small-molecule modulators is a rapidly growing research area for medicinal chemists working in cancer immunotherapy. This review provides a brief introduction into recent trends related to selected targets and pathways for cancer immunotherapy and their small-molecule pharmacological modulators. PMID:26836578

  11. [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. PMID:26469159

  12. Antiangiogenic immunotherapy targeting Flk-1, DNA vaccine and adoptive T cell transfer, inhibits ocular neovascularization

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Han [Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582 (Japan); Sonoda, Koh-Hei, E-mail: sonodak@med.kyushu-u.ac.jp [Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582 (Japan); Hijioka, Kuniaki; Qiao, Hong; Oshima, Yuji; Ishibashi, Tatsuro [Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582 (Japan)

    2009-04-17

    Ocular neovascularization (NV) is the primary cause of blindness in a wide range of ocular diseases. The exact mechanism underlying the pathogenesis of ocular NV is not yet well understood, and so there is no satisfactory therapy for ocular NV. Here, we describe a strategy targeting Flk-1, a self-antigen overexpressed on proliferating endothelial cells in ocular NV, by antiangiogenic immunotherapy-DNA vaccine and adoptive T cell therapy. An oral DNA vaccine encoding Flk-1 carried by attenuated Salmonella typhimurium markedly suppressed development of laser-induced choroidal NV. We further demonstrated that adoptive transfer of vaccine-induced CD8{sup +} T cells reduced pathological preretinal NV, with a concomitant facilitation of physiological revascularization after oxygen-induced retinal vessel obliteration. However, physiological retinal vascular development was unaffected in neonatal mice transferred with vaccine-induced CD8{sup +} T cells. These findings suggested that antiangiogenic immunotherapy targeting Flk-1 such as vaccination and adoptive immunotherapy may contribute to future therapies for ocular NV.

  13. Antiangiogenic immunotherapy targeting Flk-1, DNA vaccine and adoptive T cell transfer, inhibits ocular neovascularization

    International Nuclear Information System (INIS)

    Ocular neovascularization (NV) is the primary cause of blindness in a wide range of ocular diseases. The exact mechanism underlying the pathogenesis of ocular NV is not yet well understood, and so there is no satisfactory therapy for ocular NV. Here, we describe a strategy targeting Flk-1, a self-antigen overexpressed on proliferating endothelial cells in ocular NV, by antiangiogenic immunotherapy-DNA vaccine and adoptive T cell therapy. An oral DNA vaccine encoding Flk-1 carried by attenuated Salmonella typhimurium markedly suppressed development of laser-induced choroidal NV. We further demonstrated that adoptive transfer of vaccine-induced CD8+ T cells reduced pathological preretinal NV, with a concomitant facilitation of physiological revascularization after oxygen-induced retinal vessel obliteration. However, physiological retinal vascular development was unaffected in neonatal mice transferred with vaccine-induced CD8+ T cells. These findings suggested that antiangiogenic immunotherapy targeting Flk-1 such as vaccination and adoptive immunotherapy may contribute to future therapies for ocular NV.

  14. New modalities of cancer treatment for NSCLC: focus on immunotherapy

    International Nuclear Information System (INIS)

    Recent advances in the understanding of immunology and antitumor immune responses have led to the development of new immunotherapies, including vaccination approaches and monoclonal antibodies that inhibit immune checkpoint pathways. These strategies have shown activity in melanoma and are now being tested in lung cancer. The antibody drugs targeting cytotoxic T-lymphocyte-associated antigen-4 and programmed cell death protein-1 immune checkpoint pathways work by restoring immune responses against cancer cells, and are associated with unconventional response patterns and immune-related adverse events as a result of their mechanism of action. As these new agents enter the clinic, nurses and other health care providers will require an understanding of the unique efficacy and safety profiles with immunotherapy to optimize potential patient benefits. This paper provides a review of the new immunotherapeutic agents in development for lung cancer, and strategies for managing patients on immunotherapy

  15. IL-12 gene therapy for cancer: in synergy with other immunotherapies

    OpenAIRE

    Melero, I; Mazzolini, G; Narvaiza, I; Qian, C.; Chen, L.; Prieto, J

    2001-01-01

    In preclinical models of cancer, gene therapy with interleukin 12 (IL-12) has reached unprecedented levels of success when combined with immunotherapy approaches such as gene transfer of other cytokines and/or chemokines, costimulatory molecules or adoptive cell therapy. These combinations have been found to produce synergistic rather than additive effects. Meanwhile, IL-12 gene therapy is beginning clinical testing as a single agent, but combination strategies are at hand.

  16. Thyroid dysfunction associated with immunotherapy for patients with cancer.

    Science.gov (United States)

    Schwartzentruber, D J; White, D E; Zweig, M H; Weintraub, B D; Rosenberg, S A

    1991-12-01

    The authors performed a prospective study to evaluate thyroid dysfunction in 130 patients with cancer who were receiving interleukin-2 (IL-2)-based immunotherapy. Primary hypothyroidism was the most common abnormality, occurring in 12% of patients before, 38% during, and 23% after immunotherapy. Hyperthyroidism occurred in 1%, 4%, and 7% of patients at those time intervals. Among patients initially euthyroid (n = 111), primary hypothyroidism developed in 32% during and 14% after immunotherapy, persisting a median of 54 days. Three patients required levothyroxine. Hyperthyroidism developed in 2% of patients during immunotherapy and 6% after. Thyroid dysfunction was not a function of sex, diagnosis, type of treatment, or response to immunotherapy. Elevated titers of antithyroglobulin and antithyroid microsomal antibodies were detected after treatment in 9% and 7%, respectively, of all patients without prior antibody abnormalities and did not correlate with response to therapy. The high incidence of therapy-induced thyroid dysfunction suggests that thyroid function should be carefully monitored in all patients receiving IL-2-based immunotherapy. PMID:1933775

  17. Adoptive immunotherapy for acute leukemia:New insights in chimeric antigen receptors

    Institute of Scientific and Technical Information of China (English)

    Ma?l; Heiblig; Mohamed; Elhamri; Mauricette; Michallet; Xavier; Thomas

    2015-01-01

    Relapses remain a major concern in acute leukemia. It is well known that leukemia stem cells(LSCs) hide in hematopoietic niches and escape to the immune system surveillance through the outgrowth of poorly immunogenic tumor-cell variants and the suppression of the active immune response. Despitethe introduction of new reagents and new therapeutic approaches, no treatment strategies have been able to definitively eradicate LSCs. However, recent adoptive immunotherapy in cancer is expected to revolutionize our way to fight against this disease, by redirecting the immune system in order to eliminate relapse issues. Initially described at the onset of the 90’s, chimeric antigen receptors(CARs) are recombinant receptors transferred in various T cell subsets, providing specific antigens binding in a non-major histocompatibility complex restricted manner, and effective on a large variety of human leukocyte antigen-divers cell populations. Once transferred, engineered T cells act like an expanding "living drug" specifically targeting the tumor-associated antigen, and ensure long-term antitumor memory. Over the last decades, substantial improvements have been made in CARs design. CAR T cells have finally reached the clinical practice and first clinical trials have shown promising results. In acute lymphoblastic leukemia, high rate of complete and prolonged clinical responses have been observed after anti-CD19 CAR T cell therapy, with specific but manageable adverse events. In this review, our goal was to describe CAR structures and functions, and to summarize recent data regarding pre-clinical studies and clinical trials in acute leukemia.

  18. Immunotherapy in human colorectal cancer: Challenges and prospective.

    Science.gov (United States)

    Sun, Xuan; Suo, Jian; Yan, Jun

    2016-07-28

    Human colorectal cancer (CRC) is the third most commonly diagnosed malignancies and the prognosis for patients with recurrent or metastatic disease is extremely poor. Although new chemotherapeutic regimen improves survival rates, therapy with better efficacy and less adverse effects is drastically needed. Immunotherapy has been investigated in human CRC for decades with limited success. However, recent developments of immunotherapy, particularly immune checkpoint inhibitor therapy, have achieved promising clinical benefits in many types of cancer and revived the hope for utilizing such therapy in human CRC. In this review, we will discuss important immunological landscape within the CRC microenvironment and introduce immunoscore system to better describe immunophenotyping in CRC. We will also discuss different immunotherapeutic approaches currently utilized in different phases of clinical trials. Some of those completed or ongoing trials are summarized. Finally, we provide a brief prospective on the future human CRC immunotherapy. PMID:27605872

  19. The Role of Surgical Pathology in Guiding Cancer Immunotherapy.

    Science.gov (United States)

    Lovitch, Scott B; Rodig, Scott J

    2016-05-23

    The recognition that the immune system can identify and destroy tumor cells has driven a paradigm shift in our understanding of human cancer. Therapies designed to enhance this capacity, including cancer vaccines and coinhibitory receptor blockade, have demonstrated clinical efficacy in treating tumors refractory to conventional therapy. In this review, we discuss how the analysis of the immune microenvironment in primary tissue biopsy samples can be used to stratify patients according to clinical outcome, identify patients likely to benefit from specific immunotherapies, and tailor combination immunotherapy to individual patients and tumor types. As immunotherapy gains in complexity and is used in combination with agents that target oncogenic, intracellular signaling pathways, diagnostic pathologists will play an increasingly important part in identifying and quantifying cellular and molecular biomarkers in tissue samples that reflect the nature and magnitude of the antitumor immune response. PMID:27193453

  20. Adapting Cancer Immunotherapy Models for the Real World.

    Science.gov (United States)

    Klevorn, Lauryn E; Teague, Ryan M

    2016-06-01

    Early experiments in mice predicted the success of checkpoint blockade immunotherapy in cancer patients. However, these same animal studies failed to accurately predict many of the limitations and toxicities of treatment. One of the likely reasons for this discrepancy is the nearly universal use of young healthy mice, which stand in stark contrast to diverse patient populations varying in age, weight, diet, and hygiene. Because these variables impact immunity and metabolism, they also influence outcomes during immunotherapy and should be incorporated into the study design of preclinical experiments. Here, we discuss recent findings that highlight how efficacy and toxicity of cancer immunotherapy are affected by patient variation, and how distinct host environments can be better modeled in animal studies. PMID:27105824

  1. Nanoparticle Targeting of Neutrophils for Improved Cancer Immunotherapy

    OpenAIRE

    Chu, Dafeng; Zhao, Qi; Yu, Jian; Zhang, Faya; Zhang, Hui; Wang, Zhenjia

    2016-01-01

    Cancer immunotherapy using tumor specific monoclonal antibodies (mAbs) presents a novel approach for cancer treatment. A monoclonal antibody TA99 specific for gp75 antigen of melanoma, initiates neutrophil recruitment in tumor responsible for cancer therapy. Here we report a strategy for hijacking neutrophils in vivo using nanoparticles (NPs) to deliver therapeutics into tumor. In a mouse model of melanoma, we showed that systemically delivered albumin NPs increased in tumor when TA99 antibod...

  2. New modalities of cancer treatment for NSCLC: focus on immunotherapy

    Directory of Open Access Journals (Sweden)

    Davies M

    2014-02-01

    Full Text Available Marianne Davies Smilow Cancer Hospital at Yale-New Haven Hospital, New Haven, CT, USA Abstract: Recent advances in the understanding of immunology and antitumor immune responses have led to the development of new immunotherapies, including vaccination approaches and monoclonal antibodies that inhibit immune checkpoint pathways. These strategies have shown activity in melanoma and are now being tested in lung cancer. The antibody drugs targeting cytotoxic T-lymphocyte-associated antigen-4 and programmed cell death protein-1 immune checkpoint pathways work by restoring immune responses against cancer cells, and are associated with unconventional response patterns and immune-related adverse events as a result of their mechanism of action. As these new agents enter the clinic, nurses and other health care providers will require an understanding of the unique efficacy and safety profiles with immunotherapy to optimize potential patient benefits. This paper provides a review of the new immunotherapeutic agents in development for lung cancer, and strategies for managing patients on immunotherapy. Keywords: immunotherapy, lung cancer, vaccination, nivolumab, ipilimumab, nursing

  3. Immune Modulation by Chemotherapy or Immunotherapy to Enhance Cancer Vaccines

    Directory of Open Access Journals (Sweden)

    Marc Mansour

    2011-08-01

    Full Text Available Chemotherapy has been a mainstay in cancer treatment for many years. Despite some success, the cure rate with chemotherapy remains unsatisfactory in some types of cancers, and severe side effects from these treatments are a concern. Recently, understanding of the dynamic interplay between the tumor and immune system has led to the development of novel immunotherapies, including cancer vaccines. Cancer vaccines have many advantageous features, but their use has been hampered by poor immunogenicity. Many developments have increased their potency in pre-clinical models, but cancer vaccines continue to have a poor clinical track record. In part, this could be due to an inability to effectively overcome tumor-induced immune suppression. It had been generally assumed that immune-stimulatory cancer vaccines could not be used in combination with immunosuppressive chemotherapies, but recent evidence has challenged this dogma. Chemotherapies could be used to condition the immune system and tumor to create an environment where cancer vaccines have a better chance of success. Other types of immunotherapies could also be used to modulate the immune system. This review will discuss how immune modulation by chemotherapy or immunotherapy could be used to bolster the effects of cancer vaccines and discuss the advantages and disadvantages of these treatments.

  4. Immune Modulation by Chemotherapy or Immunotherapy to Enhance Cancer Vaccines

    Energy Technology Data Exchange (ETDEWEB)

    Weir, Genevieve M. [Suite 411, 1344 Summer St., Immunovaccine Inc., Halifax, NS, B3H 0A8 (Canada); Room 11-L1, Sir Charles Tupper Building, Department of Microbiology & Immunology, Dalhousie University, 5850 College St, Halifax, NS, B3H 1X5 (Canada); Liwski, Robert S. [Room 11-L1, Sir Charles Tupper Building, Department of Microbiology & Immunology, Dalhousie University, 5850 College St, Halifax, NS, B3H 1X5 (Canada); Room 206E, Dr. D. J. Mackenzie Building, Department of Pathology, Dalhousie University, 5788 University Avenue, Halifax, NS, B3H 2Y9 (Canada); Mansour, Marc [Suite 411, 1344 Summer St., Immunovaccine Inc., Halifax, NS, B3H 0A8 (Canada)

    2011-08-05

    Chemotherapy has been a mainstay in cancer treatment for many years. Despite some success, the cure rate with chemotherapy remains unsatisfactory in some types of cancers, and severe side effects from these treatments are a concern. Recently, understanding of the dynamic interplay between the tumor and immune system has led to the development of novel immunotherapies, including cancer vaccines. Cancer vaccines have many advantageous features, but their use has been hampered by poor immunogenicity. Many developments have increased their potency in pre-clinical models, but cancer vaccines continue to have a poor clinical track record. In part, this could be due to an inability to effectively overcome tumor-induced immune suppression. It had been generally assumed that immune-stimulatory cancer vaccines could not be used in combination with immunosuppressive chemotherapies, but recent evidence has challenged this dogma. Chemotherapies could be used to condition the immune system and tumor to create an environment where cancer vaccines have a better chance of success. Other types of immunotherapies could also be used to modulate the immune system. This review will discuss how immune modulation by chemotherapy or immunotherapy could be used to bolster the effects of cancer vaccines and discuss the advantages and disadvantages of these treatments.

  5. Immune Modulation by Chemotherapy or Immunotherapy to Enhance Cancer Vaccines

    International Nuclear Information System (INIS)

    Chemotherapy has been a mainstay in cancer treatment for many years. Despite some success, the cure rate with chemotherapy remains unsatisfactory in some types of cancers, and severe side effects from these treatments are a concern. Recently, understanding of the dynamic interplay between the tumor and immune system has led to the development of novel immunotherapies, including cancer vaccines. Cancer vaccines have many advantageous features, but their use has been hampered by poor immunogenicity. Many developments have increased their potency in pre-clinical models, but cancer vaccines continue to have a poor clinical track record. In part, this could be due to an inability to effectively overcome tumor-induced immune suppression. It had been generally assumed that immune-stimulatory cancer vaccines could not be used in combination with immunosuppressive chemotherapies, but recent evidence has challenged this dogma. Chemotherapies could be used to condition the immune system and tumor to create an environment where cancer vaccines have a better chance of success. Other types of immunotherapies could also be used to modulate the immune system. This review will discuss how immune modulation by chemotherapy or immunotherapy could be used to bolster the effects of cancer vaccines and discuss the advantages and disadvantages of these treatments

  6. Cancer immunotherapy utilizing gene-modified T cells: From the bench to the clinic.

    Science.gov (United States)

    Duong, Connie P M; Yong, Carmen S M; Kershaw, Michael H; Slaney, Clare Y; Darcy, Phillip K

    2015-10-01

    The immune system plays a critical role in the elimination and suppression of pathogens. Although the endogenous immune system is capable of immune surveillance resulting in the elimination of cancer cells, tumor cells have developed a variety of mechanisms to escape immune recognition often resulting in tumor outgrowth. The presence of immune infiltrate in tumors has been correlated with a good prognosis following treatment (Sato et al., 2005; Loi et al., 2013; Clemente et al., 1996; Galon et al., 2006). As such, immune cells such as T cells, have been harnessed in order to target cancer. Tumor reactive lymphocytes, called tumor-infiltrating lymphocytes (TILs) have been isolated and expanded from the tumor and reinfused back into patients for the treatment of melanoma. The promise of adoptive immunotherapy utilizing TILs as a robust treatment for cancer has been highlighted in patients with advanced melanoma with greater than 50% of patients responding to treatment (Dudley et al., 2005). Although TIL therapy has shown promising results in melanoma patients, it has proved difficult to translate this approach to other cancers, given that the numbers of TILs that can be isolated are generally low. To broaden this therapy for other cancers, T cells have been genetically modified to endow them with tumor reactivity using either a T cell receptor (TCR) (Parkhurst et al., 2009, 2011; Chinnasamy et al., 2011) or a chimeric antigen receptor (CAR) (Grupp et al., 2013; Park et al., 2007). This review will outline the origins and development of adoptive immunotherapy utilizing TILs leading to genetic modification strategies to redirect T cells to cancer. Potential hurdles and novel strategies will be discussed for realizing the full potential of adoptive immunotherapy becoming a standard of care treatment for cancer. PMID:25595028

  7. Successful adoptive immunotherapy for relapse of AML 9 years after T-cell-depleted BMT.

    Science.gov (United States)

    Bertz, H; Kunzman, R; Bunjes, D; Finke, J

    1998-11-01

    Relapse is one of the main problems which can occur following allogeneic transplantation for haematological malignancies. In this situation the enhancement of the graft-versus-leukaemia effect by transfusion of donor buffy coats with or without cytokines may lead to complete remission especially in myeloid leukaemias. FISH (fluorescence in situ hybridization) is a sensitive method to monitor chimaerism in gender-different transplantation. We report a case of successful buffy coat transfer therapy > 9 years after bone marrow transplantation. This is the longest interval reported, to our knowledge, between transplantation to relapse, which was treated by adoptive immunotherapy. Complete donor chimaerism was confirmed by FISH. PMID:9827936

  8. Priming the pancreatic cancer tumor microenvironment for checkpoint-inhibitor immunotherapy

    OpenAIRE

    Lutz, Eric R.; Kinkead, Heather; Jaffee, Elizabeth M.; Zheng, Lei

    2014-01-01

    Single agent immunotherapy is effective against several cancers, but has failed against poorly immunogenic cancers, including pancreatic cancer. Evaluation of pancreatic tumors following treatment with an experimental vaccine (Lutz et al. Cancer Immunology Research 2014) suggests that vaccination primes the tumor microenvironment (TME) for checkpoint-inhibitor immunotherapy, and supports a new platform for evaluating checkpoint-inhibitors in poorly immunogenic cancers.

  9. 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

  10. Induced pluripotent stem cells: Challenges and opportunities for cancer immunotherapy

    Directory of Open Access Journals (Sweden)

    Patty eSachamitr

    2014-04-01

    Full Text Available Despite recent advances in cancer treatment over the past 30 years, therapeutic options remain limited and do not always offer a cure for malignancy. Given that tumour associated antigens (TAA are, by definition, self-proteins, the need to productively engage autoreactive T cells remains at the heart of strategies for cancer immunotherapy. These have traditionally focussed on the administration of autologous monocyte-derived dendritic cells (moDC pulsed with TAA, or the ex vivo expansion and adoptive transfer of tumour infiltrating lymphocytes (TIL as a source of TAA-specific cytotoxic T cells (CTL. Although such approaches have shown some efficacy, success has been limited by the poor capacity of moDC to cross-present exogenous TAA to the CD8+ T cell repertoire and the potential for exhaustion of CTL expanded ex vivo. Recent advances in induced pluripotency offer opportunities to generate patient-specific stem cell lines with the potential to differentiate in vitro into cell types whose properties may help address these issues. Here we review recent success in the differentiation of NK cells from human induced pluripotent stem (iPS cells as well as minor subsets of DC with therapeutic potential, including CD141+XCR1+ DC, capable of cross-presenting TAA to naïve CD8+ T cells. Furthermore, we review recent progress in the use of TIL as the starting material for the derivation of iPSC lines, thereby capturing their antigen specificity in a self-renewing stem cell line, from which potentially unlimited numbers of naïve TAA-specific T cells may be differentiated, free of the risks of exhaustion.

  11. IL15 and T-cell Stemness in T-cell-Based Cancer Immunotherapy.

    Science.gov (United States)

    Pilipow, Karolina; Roberto, Alessandra; Roederer, Mario; Waldmann, Thomas A; Mavilio, Domenico; Lugli, Enrico

    2015-12-15

    Preclinical models revealed that the immune system can mediate rejection of established tumors, but direct evidence in humans has been limited to largely immunogenic tumors, such as melanoma. The recent success of immune checkpoint inhibitors and adoptive T-cell transfer immunotherapy in clinical trials has instilled new hope for the use of T-cell immunotherapy in the treatment of cancer. IL15, a potent immunostimulatory cytokine, both potentiates host T-cells and natural killer (NK) cell immune responses and promotes the generation of long-lived memory T cells with superior functional capacity, with potential use in adoptive T-cell transfer protocols. IL15 has been recently tested in the clinic and showed dramatic effects at the level of responding NK and CD8(+) memory T cells. The recent advances in the knowledge of IL15-dependent regulation of T-cell responses, gene expression, and metabolic adaptation have important implications for the use of IL15 in T-cell-based immunotherapy of cancer. PMID:26627006

  12. Immuno senescence: implications for cancer immunotherapy in elderly patients

    International Nuclear Information System (INIS)

    The aging process produces functional and developmental changes in the immune system. Those changes may occur at different levels or at different moments, from lymphopoiesis up to the final response of the immune system facing a certain disease. The response of the adaptive immune system is most strongly affected by the aging process, particularly at the level of the effector T-cells. These changes can have a negative impact on the immune response of elderly patients during cancer immunotherapy. The present paper is an updated review of the bibliography on the most important modifications produced in the immune system during aging, as well as on the relevance of these modifications for the design of new strategies for cancer immunotherapy. (Author)

  13. Advances in immunotherapy for non-small cell lung cancer.

    Science.gov (United States)

    Reckamp, Karen L

    2015-12-01

    In most patients, lung cancer presents as advanced disease with metastases to lymph nodes and/or distant organs, and survival is poor. Lung cancer is also a highly immune-suppressing malignancy with numerous methods to evade antitumor immune responses, including deficiencies in antigen processing and presentation, release of immunomodulatory cytokines, and inhibition of T-cell activation. Advances in understanding the complex interactions of the immune system and cancer have led to novel therapies that promote T-cell activation at the tumor site, resulting in prolonged clinical benefit. Immune checkpoint inhibitors, specifically programmed death receptor 1 pathway antibodies, have demonstrated impressively durable responses and improved survival in patients with non-small cell lung cancer. This article will review the recent progress made in immunotherapy for lung cancer with data from trials evaluating programmed death receptor 1 and cytotoxic T-lymphocyte-associated protein 4 monoclonal antibodies in addition to cancer vaccines. The review will focus on studies that have been published and the latest randomized trials exploring immune therapy in lung cancer. These results form the framework for a new direction in the treatment of lung cancer toward immunotherapy. PMID:27058851

  14. Immunotherapy of cancer with polymeric prodrugs: from dream to reality

    Czech Academy of Sciences Publication Activity Database

    Říhová, Blanka; Etrych, Tomáš; Kovář, Marek; Strohalm, Jiří; Kovář, Lubomír; Hovorka, Ondřej; Šírová, Milada; Plocová, Daniela; Chytil, Petr; Šubr, Vladimír; Ulbrich, Karel

    MALDEN : WILEY-BLACKWELL, 2009. s. 86-86. ISSN 1742-464X. [FEBS Congress "Life´s Molecular Interactions /34./. 04.07.2009-09.07.2009, Praha] R&D Projects: GA AV ČR KAN200200651; GA AV ČR IAAX00500803 Institutional research plan: CEZ:AV0Z50200510; CEZ:AV0Z40500505 Keywords : cancer * prodrugs * immunotherapy Subject RIV: EC - Immunology

  15. Genetically Engineered Immunotherapy for Advanced Cancer

    Science.gov (United States)

    In this trial, doctors will collect T lymphocytes from patients with advanced mesothelin-expressing cancer and genetically engineer them to recognize mesothelin. The gene-engineered cells will be multiplied and infused into the patient to fight the cancer

  16. Ex vivo expansion of tumor-infiltrating lymphocytes from nasopharyngeal carcinoma patients for adoptive immunotherapy

    Directory of Open Access Journals (Sweden)

    Jiang Li

    2012-06-01

    Full Text Available Establishing Epstein-Barr virus(EBV-specific cytolytic T lymphocytes(EBV-CTLs from peripheral blood mononuclear cells(PBMCs for adoptive immunotherapy has been reported in EBV-associated malignancies including Hodgkin's lymphoma and nasopharyngeal carcinoma(NPC. In the current study, we performed ex vivo expansion of tumor-infiltrating lymphocytes(TILs obtained from NPC biopsy specimens with a rapid expansion protocol using anti-CD3 monoclonal antibody(OKT3, recombinant human interleukin(IL-2, and irradiated PBMCs from healthy donors to initiate the growth of TILs. Young TIL cultures comprised of more than 90% of CD3+ T cells, a variable percentage of CD3+CD8+ and CD3+CD4+ T cells, and less than 10% of CD3-CD16+ natural killer cells, a similar phenotype of EBV-CTL cultures from PBMCs. Interestingly, TIL cultures secreted high levels of the Th1 cytokines, interferon gamma (IFNγ and tumor necrosis factor-alpha (TNF-α, and low levels of the Th2 cytokines, IL-4 and IL-10. Moreover, young TILs could recognize autologous EBV-transformed B lymphoblast cell lines, but not autologous EBV-negative blast cells or allogeneic EBV-negative tumor cells. Taken together, these data suggest that ex vivo expansion of TILs from NPC biopsy tissue is an appealing alternative method to establish T cell-based immunotherapy for NPC.

  17. Immunotherapy and Immune Evasion in Prostate Cancer

    OpenAIRE

    Archana Thakur; Ulka Vaishampayan; Lum, Lawrence G.

    2013-01-01

    Metastatic prostate cancer remains to this day a terminal disease. Prostatectomy and radiotherapy are effective for organ-confined diseases, but treatment for locally advanced and metastatic cancer remains challenging. Although advanced prostate cancers treated with androgen deprivation therapy achieves debulking of disease, responses are transient with subsequent development of castration-resistant and metastatic disease. Since prostate cancer is typically a slowly progressing disease, use o...

  18. Cancer immunotherapy: moving beyond current vaccines

    OpenAIRE

    Rosenberg, Steven A.; Yang, James C.; Restifo, Nicholas P

    2004-01-01

    Great progress has been made in the field of tumor immunology in the past decade, but optimism about the clinical application of currently available cancer vaccine approaches is based more on surrogate endpoints than on clinical tumor regression. In our cancer vaccine trials of 440 patients, the objective response rate was low (2.6%), and comparable to the results obtained by others. We consider here results in cancer vaccine trials and highlight alternate strategies that mediate cancer regre...

  19. A mathematical prognosis model for pancreatic cancer patients receiving immunotherapy.

    Science.gov (United States)

    Li, Xuefang; Xu, Jian-Xin

    2016-10-01

    Pancreatic cancer is one of the most deadly types of cancer since it typically spreads rapidly and can seldom be detected in its early stage. Pancreatic cancer therapy is thus a challenging task, and appropriate prognosis or assessment for pancreatic cancer therapy is of critical importance. In this work, based on available clinical data in Niu et al. (2013) we develop a mathematical prognosis model that can predict the overall survival of pancreatic cancer patients who receive immunotherapy. The mathematical model incorporates pancreatic cancer cells, pancreatic stellate cells, three major classes of immune effector cells CD8+ T cells, natural killer cells, helper T cells, and two major classes of cytokines interleukin-2 (IL-2) and interferon-γ (IFN-γ). The proposed model describes the dynamic interaction between tumor and immune cells. In order for the model to be able to generate appropriate prognostic results for disease progression, the distribution and stability properties of equilibria in the mathematical model are computed and analysed in absence of treatments. In addition, numerical simulations for disease progression with or without treatments are performed. It turns out that the median overall survival associated with CIK immunotherapy is prolonged from 7 to 13months compared with the survival without treatment, this is consistent with the clinical data observed in Niu et al. (2013). The validity of the proposed mathematical prognosis model is thus verified. Our study confirms that immunotherapy offers a better prognosis for pancreatic cancer patients. As a direct extension of this work, various new therapy methods that are under exploration and clinical trials could be assessed or evaluated using the newly developed mathematical prognosis model. PMID:27338302

  20. Ovarian cancer immunotherapy: opportunities, progresses and challenges.

    Science.gov (United States)

    Liu, Bei; Nash, John; Runowicz, Carolyn; Swede, Helen; Stevens, Richard; Li, Zihai

    2010-01-01

    Due to the low survival rates from invasive ovarian cancer, new effective treatment modalities are urgently needed. Compelling evidence indicates that the immune response against ovarian cancer may play an important role in controlling this disease. We herein summarize multiple immune-based strategies that have been proposed and tested for potential therapeutic benefit against advanced stage ovarian cancer. We will examine the evidence for the premise that an effective therapeutic vaccine against ovarian cancer is useful not only for inducing remission of the disease but also for preventing disease relapse. We will also highlight the questions and challenges in the development of ovarian cancer vaccines, and critically discuss the limitations of some of the existing immunotherapeutic strategies. Finally, we will summarize our own experience on the use of patient-specific tumor-derived heat shock protein-peptide complex for the treatment of advanced ovarian cancer. PMID:20146807

  1. Ovarian cancer immunotherapy: opportunities, progresses and challenges

    Directory of Open Access Journals (Sweden)

    Stevens Richard

    2010-02-01

    Full Text Available Abstract Due to the low survival rates from invasive ovarian cancer, new effective treatment modalities are urgently needed. Compelling evidence indicates that the immune response against ovarian cancer may play an important role in controlling this disease. We herein summarize multiple immune-based strategies that have been proposed and tested for potential therapeutic benefit against advanced stage ovarian cancer. We will examine the evidence for the premise that an effective therapeutic vaccine against ovarian cancer is useful not only for inducing remission of the disease but also for preventing disease relapse. We will also highlight the questions and challenges in the development of ovarian cancer vaccines, and critically discuss the limitations of some of the existing immunotherapeutic strategies. Finally, we will summarize our own experience on the use of patient-specific tumor-derived heat shock protein-peptide complex for the treatment of advanced ovarian cancer.

  2. New Approaches to Immunotherapy for HPV Associated Cancers

    Directory of Open Access Journals (Sweden)

    Deepak Mittal

    2011-09-01

    Full Text Available Cervical cancer is the second most common cancer of women worldwide and is the first cancer shown to be entirely induced by a virus, the human papillomavirus (HPV, major oncogenic genotypes HPV-16 and -18. Two recently developed prophylactic cervical cancer vaccines, using virus-like particles (VLP technology, have the potential to prevent a large proportion of cervical cancer associated with HPV infection and to ensure long-term protection. However, prophylactic HPV vaccines do not have therapeutic effects against pre-existing HPV infections and do not prevent their progression to HPV-associated malignancy. In animal models, therapeutic vaccines for persisting HPV infection can eliminate transplantable tumors expressing HPV antigens, but are of limited efficacy in inducing rejection of skin grafts expressing the same antigens. In humans, clinical trials have reported successful immunotherapy of HPV lesions, providing hope and further interest. This review discusses possible new approaches to immunotherapy for HPV associated cancer, based on recent advances in our knowledge of the immunobiology of HPV infection, of epithelial immunology and of immunoregulation, with a brief overview on previous and current HPV vaccine clinical trials.

  3. Establishment of Adoptive Immunotherapy Transfusion Time of Cytokine-induced Killer Cells

    Institute of Scientific and Technical Information of China (English)

    Wu Changping; Deng Haifeng; Jiang Jingting

    2013-01-01

    Objective:To investigate the variation of immunophenotype and cytotoxic activity of autologous cytokine-induced killer (CIK) cells in patients with malignant tumors, and explore the best time of adoptive immunotherapy infusion of CIK cells. Methods:Peripheral blood mononuclear cells (PBMC) in 40 patients with malignant tumors were collected and cultivated into CIK cells in vitro by biotechnology under induction of several kinds of cytokines including interferon γ (IFN-γ), recombinant human interleukin 1α (rhIL-1α), CD3 monoclonal antibody (CD3McAb) and recombinant human interleukin 2 (rhIL-2). Immunophenotypes were dynamically monitored by lfow cytometry (FCM), and cytotoxic activity was analyzed by methyl thiazolyl tetrazolium (MTT) method. Results:After induction and expansion at different time, CD3+, CD3+CD8+and CD3+CD56+in mononuclear cells (MNC) had an up-regulated tendency. CD3+CD4+reached the peak on day 7, and then decreased slowly;CD25 reached the peak in earlier period of cultivation (3-7 days), and decreased slowly in 7-14 days, and then decreased rapidly in 14-21 days. Human leukocyte antigen DR (HLA-DR) was on the rise in 0-14 days, and decreased rapidly after reaching the peak on day 14. The cytotoxic activity of mature CIK cells was signiifcantly higher than that of non-activated PBMC, and the difference was statistically signiifcant (P Conclusion:PBMC can be induced into typical CIK cells for about 14 days when CD3+CD56+cells are at the logarithmic phase. The best time of CIK cell adoptive immunotherapy transfusion for the patients with malignant tumors is on day 14.

  4. Establishment of Adoptive Immunotherapy Transfusion Time of Cytokine-induced Killer Cells

    Directory of Open Access Journals (Sweden)

    Changping Wu

    2013-09-01

    Full Text Available Objective: To investigate the variation of immunophenotype and cytotoxic activity of autologous cytokine-induced killer (CIK cells in patients with malignant tumors, and explore the best time of adoptive immunotherapy infusion of CIK cells. Methods: Peripheral blood mononuclear cells (PBMC in 40 patients with malignant tumors were collected and cultivated into CIK cells in vitro by biotechnology under induction of several kinds of cytokines including interferon γ (IFN-γ, recombinant human interleukin 1α (rhIL- 1α, CD3 monoclonal antibody (CD3McAb and recombinant human interleukin 2 (rhIL-2. Immunophenotypes were dynamically monitored by flow cytometry (FCM, and cytotoxic activity was analyzed by methyl thiazolyl tetrazolium (MTT method. Results: After induction and expansion at different time, CD3+, CD3+CD8+ and CD3+CD56+ in mononuclear cells (MNC had an up-regulated tendency. CD3+CD4+ reached the peak on day 7, and then decreased slowly; CD25 reached the peak in earlier period of cultivation (3-7 days, and decreased slowly in 7-14 days, and then decreased rapidly in 14-21 days. Human leukocyte antigen DR (HLA-DR was on the rise in 0-14 days, and decreased rapidly after reaching the peak on day 14. The cytotoxic activity of mature CIK cells was significantly higher than that of non-activated PBMC, and the difference was statistically significant (P < 0.01. Conclusion: PBMC can be induced into typical CIK cells for about 14 days when CD3+CD56+ cells are at the logarithmic phase. The best time of CIK cell adoptive immunotherapy transfusion for the patients with malignant tumors is on day 14.

  5. Addition of Interleukin-21 for Expansion of T-Cells for Adoptive Immunotherapy of Murine Melanoma

    Directory of Open Access Journals (Sweden)

    Christine Kathryn Zoon

    2015-04-01

    Full Text Available We previously demonstrated that interleukin (IL-7/15 was superior to IL-2 for expansion of T cells in vitro for adoptive immunotherapy. We sought to ascertain whether IL-21 would further improve yield and therapeutic efficacy of T cells in culture. Naïve T cell receptor (TcR transgenic splenocytes or antigen-sensitized lymph node cells were harvested from PMEL-1 mice and exposed to bryostatin-1 and ionomycin (B/I for 18 h. Cells were then cultured in IL-2, IL-21, IL-7/15 or IL-7/15/21 for six days. Harvested cells were analyzed by flow cytometry and used to treat C57Bl/6 mice injected intravenously with B16 melanoma. Lungs were harvested and metastases counted 14 days after treatment. Culturing lymphocytes in IL-7/15/21 increased expansion compared to IL-2 or IL-7/15. IL-21 and IL-7/15/21 increased CD8+ cells compared to IL-2 or IL-7/15. IL-21 preferentially expanded a CD8+CD44−CD62L+ T “naïve” population, whereas IL-7/15/21 increased CD8+CD44+CD62Lhigh central-memory T cells. T cells grown in IL-7/15/21 were more effective at reducing metastases than IL-2. The addition of IL-21 to IL-7/15 induced greater expansion of lymphocytes in culture and increased the yield of CD8+ T central-memory cells vs. IL-7/15 alone. This may have significant impact on future clinical trials of adoptive immunotherapy, particularly for generating adequate numbers of lymphocytes for treatment.

  6. Cancer Immunotherapy Using Engineered Hematopoietic Stem Cells

    OpenAIRE

    Gschweng, Eric Hans

    2015-01-01

    Engineering the immune system against cancer ideally provides surgical precision against the antigen bearing target cell while avoiding the systemic, off-target toxicity of chemotherapy. Successful treatment of patients in the clinic has been achieved by the expression of anti-cancer T-cell receptors (TCR) and chimeric antigen receptors (CAR) in T cells followed by infusion of these cells into cancer patients. Unfortunately, while many patients initially respond showing anti-tumor efficacy, t...

  7. Assays for predicting and monitoring responses to lung cancer immunotherapy

    OpenAIRE

    Teixidó, Cristina; Karachaliou, Niki; González-Cao, Maria; Morales-Espinosa, Daniela; Rosell, Rafael

    2015-01-01

    Immunotherapy has become a key strategy for cancer treatment, and two immune checkpoints, namely, programmed cell death 1 (PD-1) and its ligand (PD-L1), have recently emerged as important targets. The interaction blockade of PD-1 and PD-L1 demonstrated promising activity and antitumor efficacy in early phase clinical trials for advanced solid tumors such as non-small cell lung cancer (NSCLC). Many cell types in multiple tissues express PD-L1 as well as several tumor types, thereby suggesting ...

  8. HEAT SHOCK PROTEIN gp96 AND CANCER IMMUNOTHERAPY

    Institute of Scientific and Technical Information of China (English)

    岳培彬; 杨树德; 黄常志

    2002-01-01

    Heat shock protein gp96 is a highly conserved and monomorphic glycoprotein in the endoplasmic reticulum.It functions as molecular chaperone and can associate with a variety of antigenic peptides noncovalently in vivo and in vitro. Recent studies have indicated that gp96 molecules participate in major histocompatibility complex class I - restricted antigen presentation pathway. Immunization of mice with gp96 preparations isolated from cancer cells can elicit a cancer - specific protective T cell immune response that is recallable, which is a prerequisite for gp96 as a therapeutic vaccine against cancers. The immunogenicity of gp96 molecules has been attributed to the antigenic peptides associated with them. These phenomena provide a new pathway for cancer immunotherapy. The mechanism that the gp96 -peptide complex induces specific immune response and the explorations for gp96 - peptide complex as a therapeutic cancer vaccine are reviewed.

  9. A Perspective of Immunotherapy for Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Ida Silvestri

    2016-07-01

    Full Text Available In cancer patients, the immune system is often altered with an excess of inhibitory factors, such as immunosuppressive cytokines, produced by regulatory T cells (Treg or myeloid-derived suppressor cells (MDSC. The manipulation of the immune system has emerged as one of new promising therapies for cancer treatment, and also represents an attractive strategy to control prostate cancer (PCa. Therapeutic cancer vaccines and immune checkpoint inhibitors have been the most investigated in clinical trials. Many trials are ongoing to define the effects of immune therapy with established treatments: androgen deprivation therapy (ADT and chemotherapy (CT or radiotherapy (RT. This article discusses some of these approaches in the context of future treatments for PCa.

  10. A Perspective of Immunotherapy for Prostate Cancer.

    Science.gov (United States)

    Silvestri, Ida; Cattarino, Susanna; Giantulli, Sabrina; Nazzari, Cristina; Collalti, Giulia; Sciarra, Alessandro

    2016-01-01

    In cancer patients, the immune system is often altered with an excess of inhibitory factors, such as immunosuppressive cytokines, produced by regulatory T cells (Treg) or myeloid-derived suppressor cells (MDSC). The manipulation of the immune system has emerged as one of new promising therapies for cancer treatment, and also represents an attractive strategy to control prostate cancer (PCa). Therapeutic cancer vaccines and immune checkpoint inhibitors have been the most investigated in clinical trials. Many trials are ongoing to define the effects of immune therapy with established treatments: androgen deprivation therapy (ADT) and chemotherapy (CT) or radiotherapy (RT). This article discusses some of these approaches in the context of future treatments for PCa. PMID:27399780

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

    OpenAIRE

    D. K. Kenbayeva; A. F. Lazarev

    2012-01-01

    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 co...

  12. Plasma Onco-Immunotherapy: Novel Approach to Cancer Treatment

    Science.gov (United States)

    Fridman, Alexander

    2015-09-01

    Presentation is reviewing the newest results obtained by researchers of A.J. Drexel Plasma Institute on direct application of non-thermal plasma for direct treatment of different types of cancer by means of specific stimulation of immune system in the frameworks of the so-called onco-immunotherapy. Especial attention is paid to analysis of depth of penetration of different plasma-medical effects, from ROS, RNS, and ions to special biological signaling and immune system related processes. General aspects of the plasma-stimulation of immune system are discussed, pointing out specific medical applications. Most of experiments have been carried out using nanosecond pulsed DBD at low power and relatively low level of treatment doses, guaranteeing non-damage no-toxicity treatment regime. The nanosecond pulsed DBD physics is discussed mostly regarding its space uniformity and control of plasma parameters relevant to plasma medical treatment, and especially relevant to depth of penetration of different plasma medical effects. Detailed mechanism of the plasma-induced onco-immunotherapy has been suggested based upon preliminary in-vitro experiments with DBD treatment of different cancer cells. Sub-elements of this mechanism related to activation of macrophages and dendritic cells, specific stressing of cancer cells and the immunogenic cell death (ICD) are to be discussed based on results of corresponding in-vitro experiments. In-vivo experiments focused on the plasma-induced onco-immunotherapy were carried out in collaboration with medical doctors from Jefferson University hospital of Philadelphia. Todays achievements and nearest future prospective of clinical test focused on plasma-controlled cancer treatment are discussed in conclusion.

  13. The promising alliance of anti-cancer electrochemotherapy with immunotherapy.

    Science.gov (United States)

    Calvet, Christophe Y; Mir, Lluis M

    2016-06-01

    Anti-tumor electrochemotherapy, which consists in increasing anti-cancer drug uptake by means of electroporation, is now implanted in about 140 cancer treatment centers in Europe. Its use is supported by the English National Institute for Health and Care Excellence for the palliative treatment of skin metastases, and about 13,000 cancer patients were treated by this technology by the end of 2015. Efforts are now focused on turning this local anti-tumor treatment into a systemic one. Electrogenetherapy, that is the electroporation-mediated transfer of therapeutic genes, is currently under clinical evaluation and has brought excitement to enlarge the anti-cancer armamentarium. Among the promising electrogenetherapy strategies, DNA vaccination and cytokine-based immunotherapy aim at stimulating anti-tumor immunity. We review here the interests and state of development of both electrochemotherapy and electrogenetherapy. We then emphasize the potent beneficial outcome of the combination of electrochemotherapy with immunotherapy, such as immune checkpoint inhibitors or strategies based on electrogenetherapy, to simultaneously achieve excellent local debulking anti-tumor responses and systemic anti-metastatic effects. PMID:26993326

  14. Nanoparticle Targeting of Neutrophils for Improved Cancer Immunotherapy

    Science.gov (United States)

    Chu, Dafeng; Zhao, Qi; Yu, Jian; Zhang, Faya; Zhang, Hui; Wang, Zhenjia

    2016-01-01

    Cancer immunotherapy using tumor specific monoclonal antibodies (mAbs) presents a novel approach for cancer treatment. A monoclonal antibody TA99 specific for gp75 antigen of melanoma, initiates neutrophil recruitment in tumor responsible for cancer therapy. Here we report a strategy for hijacking neutrophils in vivo using nanoparticles (NPs) to deliver therapeutics into tumor. In a mouse model of melanoma, we showed that systemically delivered albumin NPs increased in tumor when TA99 antibody was injected; and the nanoparticle tumor accumulation was mediated by neutrophils. After the administration of pyropheophorbide-a (Ppa) loaded albumin NPs and TA99, photodynamic therapy significantly suppressed the tumor growth and increased mouse survival compared with treatment with the NPs or TA99. The study reveals a new avenue to treat cancer by nanoparticle hitchhiking of immune systems to enhance delivery of therapeutics into tumor sites. PMID:26989887

  15. 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.

  16. 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 mov...

  17. Aptamers: A Feasible Technology in Cancer Immunotherapy

    OpenAIRE

    Soldevilla, M. M.; H. Villanueva; Pastor, F. (Fernando)

    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 immun...

  18. 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.

  19. Gene transfer approaches in cancer immunotherapy.

    Science.gov (United States)

    Larin, S S; Georgiev, G P; Kiselev, S L

    2004-10-01

    The idea of enhancing or establishing effective immune response against endogenously developed tumor cells is not novel. More than a hundred years ago, bacterial components were used to develop antitumor immune response. Later, when a number of immune system-effecting cytokines had been discovered, they were used for systemic treatment of cancer patients. However, systemic treatment often resulted in even negative outcome. Recent developments of genetic approaches of cell modifications allowed developing of modern techniques of targeted tumor cell elimination. In the present paper, we review modern trends of the antitumor response enhancement based on immunoregulatory gene transfer into different cell types both in vivo and in vitro. Almost all these approaches are based on the activation of the adaptive arm of the immune system in response to tumor cells. However, recent studies indicate that the innate arm of the immune system, as well as adaptive arm, is involved in tumor suppression. The innate immune system uses nonrearranging germline receptors, which could trigger cellular effector responses that are conditional (or instructive) to the subsequent adaptive immune response. Last years' viewpoints on 'self' and 'non-self' recognition and primary induction of the immune response have changed. The key role of lymphocytes is pathogen recognition and, following immune response induction, switched on the central role of dendritic cells in 'non-self' recognition and induction of both innate and adaptive responses. Moreover, innate response is supposed to be an essential starting point in induction of successful and effective acquired response. Most cancer vaccines do not have 'non-self' marks presentation due to their endogenous origin, thus lacking their effectiveness in the induction of the specific long-lasting immune response. Taking this point into consideration, we can conclude that to make cancer vaccine more effective we have to present tumor antigens

  20. A microfluidic approach towards hybridoma generation for cancer immunotherapy.

    Science.gov (United States)

    Lu, Yen-Ta; Pendharkar, Gaurav Prashant; Lu, Chung-Huan; Chang, Chia-Ming; Liu, Cheng-Hsien

    2015-11-17

    Dendritic cells/tumor fusions have shown to elicit anti-cancer immunity in different cancer types. However, the application of these vaccines for human cancer immunotherapy are limited by the instable quality and insufficient quanity of fusion cells. We present a cell electrofusion chip fabricated using soft lithography technique, which combines the rapid and precise cell pairing microstructures and the high yield electrofusion micro-electrodes to improve the cell fusion. The design uses hydrodynamic trapping in combination with positive dielectrophoretic force (pDEP) to achieve cell fusion. The chip consists of total 960 pairs of trapping channels, which are capable of pairing and fusing both homogeneous and heterogeneous types of cells. The fused cells can be easily taken out of the chip that makes this device a distinguishable from other designs. We observe pairing efficiency of 68% with fusion efficiency of 64%. PMID:26462149

  1. Checkpoint Blockade in Cancer Immunotherapy: Squaring the Circle

    Directory of Open Access Journals (Sweden)

    Maria A.V. Marzolini

    2015-03-01

    Full Text Available Manipulating the complex interaction between the immune system and tumour cells has been the focus of cancer research for many years, but it is only in the past decade that significant progress has been made in the field of cancer immunotherapy resulting in clinically effective treatments. The blockade of co-inhibitory immune checkpoints, essential for maintaining lymphocyte homeostasis and self-tolerance, by immunomodulatory monoclonal antibodies has resulted in the augmentation of anti-tumour responses. The greatest successes so far have been seen with the blockade of cytotoxic T lymphocyte associated antigen-4, which has resulted in the first Phase III clinical trial showing an overall survival benefit in metastatic melanoma, and in the blockade of the programmed cell death protein-1 axis. This concise review will focus on the clinical advances made by the blockade of these two pathways and their role in current cancer treatment strategies.

  2. Indoleamine 2, 3-dioxygenase: potential in cancer immunotherapy

    International Nuclear Information System (INIS)

    Indoleamine 2, 3-dioxygenase (IDO) is a potent immunosuppressive enzyme that has a significant role in different types of cancers. There is evidence that shows its involvement in a number of infectious diseases and auto-immune disorders. In vitro and in vivo studies indicate that 1-methyl tryptophan, being a competitive inhibitor, has shown to actively control the conditions in which IDO is over-expressed. Dendritic cells are the natural site of secretion of IDO in the host immune system. However, the expression takes place only in the presence of tolerogenic signals that lead to suppression of T-cell mediated immunogenic responses. Different therapies are being designed by employing the role of IDO in conditions such as stress, depression, cancer, pregnancy, and organ transplant, which reflect the promising role of this new target in cancer immunotherapy. (author)

  3. Dielectrophoresis-assisted 3D nanoelectroporation for non-viral cell transfection in adoptive immunotherapy.

    Science.gov (United States)

    Chang, Lingqian; Gallego-Perez, Daniel; Zhao, Xi; Bertani, Paul; Yang, Zhaogang; Chiang, Chi-Ling; Malkoc, Veysi; Shi, Junfeng; Sen, Chandan K; Odonnell, Lynn; Yu, Jianhua; Lu, Wu; Lee, L James

    2015-08-01

    Current transfection technologies lead to significant inter-clonal variations. Previously we introduced a unique electrotransfection technology, Nanochannel-Electroporation (NEP), which can precisely and benignly transfect small cell populations (~100-200 cells) with single-cell resolution. Here we report on the development of a novel 3D NEP system for large scale transfection. A properly-engineered array of nanochannels, capable of handling/transfecting ~60 000 cells cm(-2), was fabricated using cleanroom technologies. Positive dielectrophoresis was used to selectively position cells on the nanochannels, thus allowing highly efficient transfection. Single-cell dosage control was demonstrated using both small and large molecules, and different cell types. The potential clinical relevance of this system was tested with difficult-to-transfect natural killer cell suspensions, and plasmids encoding for the chimeric antigen receptor (CAR), a model of high relevance for adoptive immunotherapy. Our results show significantly higher CAR transfection efficiencies for the DEP-NEP system (>70% vs. <30%), as well as enhanced cell viabilities. PMID:26105628

  4. Memory T cell–driven differentiation of naive cells impairs adoptive immunotherapy

    Science.gov (United States)

    Klebanoff, Christopher A.; Scott, Christopher D.; Leonardi, Anthony J.; Yamamoto, Tori N.; Cruz, Anthony C.; Ouyang, Claudia; Ramaswamy, Madhu; Roychoudhuri, Rahul; Ji, Yun; Eil, Robert L.; Sukumar, Madhusudhanan; Crompton, Joseph G.; Palmer, Douglas C.; Borman, Zachary A.; Clever, David; Thomas, Stacy K.; Patel, Shashankkumar; Yu, Zhiya; Muranski, Pawel; Liu, Hui; Wang, Ena; Marincola, Francesco M.; Gros, Alena; Gattinoni, Luca; Rosenberg, Steven A.; Siegel, Richard M.; Restifo, Nicholas P.

    2015-01-01

    Adoptive cell transfer (ACT) of purified naive, stem cell memory, and central memory T cell subsets results in superior persistence and antitumor immunity compared with ACT of populations containing more-differentiated effector memory and effector T cells. Despite a clear advantage of the less-differentiated populations, the majority of ACT trials utilize unfractionated T cell subsets. Here, we have challenged the notion that the mere presence of less-differentiated T cells in starting populations used to generate therapeutic T cells is sufficient to convey their desirable attributes. Using both mouse and human cells, we identified a T cell–T cell interaction whereby antigen-experienced subsets directly promote the phenotypic, functional, and metabolic differentiation of naive T cells. This process led to the loss of less-differentiated T cell subsets and resulted in impaired cellular persistence and tumor regression in mouse models following ACT. The T memory–induced conversion of naive T cells was mediated by a nonapoptotic Fas signal, resulting in Akt-driven cellular differentiation. Thus, induction of Fas signaling enhanced T cell differentiation and impaired antitumor immunity, while Fas signaling blockade preserved the antitumor efficacy of naive cells within mixed populations. These findings reveal that T cell subsets can synchronize their differentiation state in a process similar to quorum sensing in unicellular organisms and suggest that disruption of this quorum-like behavior among T cells has potential to enhance T cell–based immunotherapies. PMID:26657860

  5. Potentiating Cancer Immunotherapy Using Papaya Mosaic Virus-Derived Nanoparticles.

    Science.gov (United States)

    Lebel, Marie-Ève; Chartrand, Karine; Tarrab, Esther; Savard, Pierre; Leclerc, Denis; Lamarre, Alain

    2016-03-01

    The recent development of novel immunotherapies is revolutionizing cancer treatment. These include, for example, immune checkpoint blockade, immunomodulation, or therapeutic vaccination. Although effective on their own, combining multiple approaches will most likely be required in order to achieve the maximal therapeutic benefit. In this regard, the papaya mosaic virus nanoparticle (PapMV) has shown tremendous potential as (i) an immunostimulatory molecule, (ii) an adjuvant, and (iii) a vaccine platform through its intrinsic capacity to activate the innate immune response in an IFN-α-dependent manner. Here, we demonstrate that intratumor administration of PapMV significantly slows down melanoma progression and prolongs survival. This correlates with enhanced chemokine and pro-inflammatory-cytokine production in the tumor and increased immune-cell infiltration. Proportions of total and tumor-specific CD8(+) T cells dramatically increase following PapMV treatment whereas those of myeloid-derived suppressor cells (MDSC) concomitantly decrease. Moreover, systemic PapMV administration prevents metastatic tumor-implantation in the lungs. Importantly, PapMV also synergistically improves the therapeutic benefit of dendritic cell (DC)-based vaccination and PD-1 blockade by potentiating antitumor immune responses. This study illustrates the immunostimulatory potential of a plant virus-derived nanoparticle for cancer therapy either alone or in conjunction with other promising immunotherapies in clinical development. PMID:26891174

  6. Programmed death-1 & its ligands: promising targets for cancer immunotherapy.

    Science.gov (United States)

    Shrimali, Rajeev K; Janik, John E; Abu-Eid, Rasha; Mkrtichyan, Mikayel; Khleif, Samir N

    2015-01-01

    Novel strategies for cancer treatment involving blockade of immune inhibitors have shown significant progress toward understanding the molecular mechanism of tumor immune evasion. The preclinical findings and clinical responses associated with programmed death-1 (PD-1) and PD-ligand pathway blockade seem promising, making these targets highly sought for cancer immunotherapy. In fact, the anti-PD-1 antibodies, pembrolizumab and nivolumab, were recently approved by the US FDA for the treatment of unresectable and metastatic melanoma resistant to anticytotoxic T-lymphocyte antigen-4 antibody (ipilimumab) and BRAF inhibitor. Here, we discuss strategies of combining PD-1/PD-ligand interaction inhibitors with other immune checkpoint modulators and standard-of-care therapy to break immune tolerance and induce a potent antitumor activity, which is currently a research area of key scientific pursuit. PMID:26250412

  7. Cancer-testis antigens and immunotherapy in the light of cancer complexity.

    Science.gov (United States)

    Grizzi, F; Mirandola, L; Qehajaj, D; Cobos, E; Figueroa, J A; Chiriva-Internati, M

    2015-03-01

    The ability of immunotherapy to evoke successful antitumor immune responses has been well documented over the past decade. Despite abundant preclinical data, it is only with the recent approval by the Food and Drug Administration (FDA) of the drugs such as sipuleucel-T and ipilimumab that immunotherapy is finally being recognized as a viable alternative to traditional therapies for treatment of various cancers. Despite the ability of immunotherapy to elicit successful antitumor immune responses, its efficacy is hindered by several factors. Among these are the paucity of tumor-associated antigens (TAA) that can be used as effective targets and the systemic toxicities that often lead to treatment interruption. Indeed, such adverse effects, which can be immunological and/or parenchymal, can be particularly severe and even fatal to some patients. A family of TAA called cancer-testis antigens (CTA) has been identified and their encoding genes have been extensively investigated. CTA expression has been demonstrated in a variety of human cancer tissues, and at least 19 CTA have been found to elicit humoral and/or cellular immune responses in cancer patients. Here we discuss how CTA and immunotherapy will most likely play a major role in the cure of cancer in the light of cancer complexity. PMID:25901859

  8. Combination therapy with radiation and OK-432 immunotherapy of cancer patients

    International Nuclear Information System (INIS)

    We treated cancer patients with radiotherapy alone and with radiation plus immunotherapy at the Department of Radiology, Keio University Hospital. In all of the cancer patients who had radiationtherapy alone, a general depression in their immune reactivity was seen, but not seen in those who received radiationtherapy plus immunotherapy. Immunotherapy is defined as a stimulator of cancer patient's immune reaction. Usually radiationtherapy caused lymphopenia in which mainly T lymphocytes were decreased in number selectively, but there was no lymphopenia in cases treated with immunotherapy. We have performed nonspecific immunotherapy with OK-432. The result indicated that T lymphocytes were increased by OK-432 in spite of radiationtherapy. From this fact, OK-432 will be useful for suppression of metastasis and regression of tumors. (auth.)

  9. Graft-versus-leukemia, donor selection for adoptive immunotherapy in mice

    International Nuclear Information System (INIS)

    The optimal donor for adoptive immunotherapy would exhibit great antitumor reactivity and no antihost reactivity. Immunocompetent cells from 11 strains of mice were tested in vivo for their reactivity against a long-passage AKR acute lymphoblastic leukemia and against immunosuppressed nonleukemic AKR mice. Donor mice were syngeneic, unprimed H-2 compatible, primed H-2 compatible, congenic, or H-2 incompatible with AKR. Bioassays were used to evaluate the relative graft-vs.-leukemia (GvL) reactivity and the relative graft-vs.-host (GvH) reactivity of transplanted bone marrow and lymph-node cells from the panel of donors. No significant GvL reactivity was found when cells from syngeneic, unprimed H-2 compatible, or congenic donors were tested. H-2 compatible donors that were immunized with γ-irradiated AKR leukemic spleen cells showed modest GvL reactivity, but associated with the immunization was a disproportionate increase in acute and delayed GvH mortality. Among the H-2 mismatched donors, mice of the SJL strain appeared to most closely approach the ideal because of least intense GvH reactivity and maximal GvL reactivity. As measured in these experiments there was no correlation between the severity of GvH disease and the efficacy of the GvL reaction; GvL reactivity in unprimed donors was always associated with H-2 incompatibility; disparity between donor and recipient at H-2 did not guarantee an effective GvL reaction; and the increase in GvL reactivity obtained by immunizing H-2 compatible donors was overshadowed by the increase in GvH disease

  10. 2015 Guidance on cancer immunotherapy development in early‐phase clinical studies

    OpenAIRE

    ,; Arato, Teruyo; Daimon, Takashi; Heike, Yuji; Ishii, Ken; Itho, Kyogo; KAGEYAMA, SHINICHI; Kawakami, Yutaka; Nakayama, Eiichi; Ozawa, Keiya; Sato, Noriyuki; Shiku, Hiroshi; Takeuchi, Masahiro; Tani, Kenzaburo; Tamada, Koji

    2015-01-01

    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 check...

  11. Rationale for a multimodality strategy to enhance the efficacy of dendritic cell-based cancer immunotherapy

    OpenAIRE

    Jashodeep eDatta; Erik eBerk; Jessica A Cintolo; Shuwen eXu; Roses, Robert E; Czerniecki, Brian J.

    2015-01-01

    Dendritic cells (DC), master antigen-presenting cells that orchestrate interactions between the adaptive and innate immune arms, are increasingly utilized in cancer immunotherapy. Despite remarkable progress in our understanding of DC immunobiology, as well as several encouraging clinical applications — such as DC-based sipuleucel-T for metastatic castration-resistant prostate cancer — clinically effective DC-based immunotherapy as monotherapy for a majority of tumors remains a distant goal. ...

  12. Rationale for a Multimodality Strategy to Enhance the Efficacy of Dendritic Cell-Based Cancer Immunotherapy

    OpenAIRE

    Datta, Jashodeep; Berk, Erik; Jessica A Cintolo; Xu, Shuwen; Roses, Robert E; Czerniecki, Brian J.

    2015-01-01

    Dendritic cells (DC), master antigen-presenting cells that orchestrate interactions between the adaptive and innate immune arms, are increasingly utilized in cancer immunotherapy. Despite remarkable progress in our understanding of DC immunobiology, as well as several encouraging clinical applications – such as DC-based sipuleucel-T for metastatic castration-resistant prostate cancer – clinically effective DC-based immunotherapy as monotherapy for a majority of tumors remains a distant goal. ...

  13. Lentiviral Vectors for Cancer Immunotherapy and Clinical Applications

    Directory of Open Access Journals (Sweden)

    David Escors

    2013-07-01

    Full Text Available The success of immunotherapy against infectious diseases has shown us the powerful potential that such a treatment offers, and substantial work has been done to apply this strategy in the fight against cancer. Cancer is however a fiercer opponent than pathogen-caused diseases due to natural tolerance towards tumour associated antigens and tumour-induced immunosuppression. Recent gene therapy clinical trials with viral vectors have shown clinical efficacy in the correction of genetic diseases, HIV and cancer. The first successful gene therapy clinical trials were carried out with onco(g-retroviral vectors but oncogenesis by insertional mutagenesis appeared as a serious complication. Lentiviral vectors have emerged as a potentially safer strategy, and recently the first clinical trial of patients with advanced leukemia using lentiviral vectors has proven successful. Additionally, therapeutic lentivectors have shown clinical efficacy for the treatment of HIV, X-linked adrenoleukodystrophy, and b-thalassaemia. This review aims at describing lentivectors and how they can be utilized to boost anti-tumour immune responses by manipulating the effector immune cells.

  14. Lentiviral Vectors for Cancer Immunotherapy and Clinical Applications

    International Nuclear Information System (INIS)

    The success of immunotherapy against infectious diseases has shown us the powerful potential that such a treatment offers, and substantial work has been done to apply this strategy in the fight against cancer. Cancer is however a fiercer opponent than pathogen-caused diseases due to natural tolerance towards tumour associated antigens and tumour-induced immunosuppression. Recent gene therapy clinical trials with viral vectors have shown clinical efficacy in the correction of genetic diseases, HIV and cancer. The first successful gene therapy clinical trials were carried out with onco(γ-)retroviral vectors but oncogenesis by insertional mutagenesis appeared as a serious complication. Lentiviral vectors have emerged as a potentially safer strategy, and recently the first clinical trial of patients with advanced leukemia using lentiviral vectors has proven successful. Additionally, therapeutic lentivectors have shown clinical efficacy for the treatment of HIV, X-linked adrenoleukodystrophy, and β-thalassaemia. This review aims at describing lentivectors and how they can be utilized to boost anti-tumour immune responses by manipulating the effector immune cells

  15. Lentiviral Vectors for Cancer Immunotherapy and Clinical Applications

    Energy Technology Data Exchange (ETDEWEB)

    Liechtenstein, Therese, E-mail: t.liechtenstein.12@ucl.ac.uk [University College London, 5 University Street, London, WC1E 6JF (United Kingdom); Perez-Janices, Noemi; Escors, David [University College London, 5 University Street, London, WC1E 6JF (United Kingdom); Navarrabiomed Fundacion Miguel Servet, 3 Irunlarrea St., Hospital Complex of Navarra, 31008 Pamplona, Navarra (Spain)

    2013-07-02

    The success of immunotherapy against infectious diseases has shown us the powerful potential that such a treatment offers, and substantial work has been done to apply this strategy in the fight against cancer. Cancer is however a fiercer opponent than pathogen-caused diseases due to natural tolerance towards tumour associated antigens and tumour-induced immunosuppression. Recent gene therapy clinical trials with viral vectors have shown clinical efficacy in the correction of genetic diseases, HIV and cancer. The first successful gene therapy clinical trials were carried out with onco(γ-)retroviral vectors but oncogenesis by insertional mutagenesis appeared as a serious complication. Lentiviral vectors have emerged as a potentially safer strategy, and recently the first clinical trial of patients with advanced leukemia using lentiviral vectors has proven successful. Additionally, therapeutic lentivectors have shown clinical efficacy for the treatment of HIV, X-linked adrenoleukodystrophy, and β-thalassaemia. This review aims at describing lentivectors and how they can be utilized to boost anti-tumour immune responses by manipulating the effector immune cells.

  16. Interleukin-33 in tumorigenesis, tumor immune evasion, and cancer immunotherapy.

    Science.gov (United States)

    Lu, Binfeng; Yang, Min; Wang, Qingqing

    2016-05-01

    Interleukin-33 (IL-33) is a member of the IL-1 gene family and mainly expressed in the nucleus of tissue lining cells, stromal cells, and activated myeloid cells. IL-33 is considered a damage-associated molecular pattern (DAMP) molecule and plays an important role in many physiological and pathological settings such as tissue repair, allergy, autoimmune disease, infectious disease, and cancer. The biological functions of IL-33 include maintaining tissue homeostasis, enhancing type 1 and 2 cellular immune responses, and mediating fibrosis during chronic inflammation. IL-33 exerts diverse functions through signaling via its receptor ST2, which is expressed in many types of cells including regulatory T cells (Treg), group 2 innate lymphoid cells (ILC2s), myeloid cells, cytotoxic NK cells, Th2 cells, Th1 cells, and CD8(+) T cells. Tumor development results in downregulation of IL-33 in epithelial cells but upregulation of IL-33 in the tumor stroma and serum. The current data suggest that IL-33 expression in tumor cells increases immunogenicity and promotes type 1 antitumor immune responses through CD8(+) T cells and NK cells, whereas IL-33 in tumor stroma and serum facilitates immune suppression via Treg and myeloid-derived suppressor cell (MDSC). Understanding the role of IL-33 in cancer immunobiology sheds lights on targeting this cytokine for cancer immunotherapy. PMID:26922618

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

    International Nuclear Information System (INIS)

    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+ cytotoxic T lymphocytes (CTLs) efficiently recognize and destroy tumor cells. CD4+ 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

  18. Clinical effects of laser immunotherapy on metastatic cancer patients

    Science.gov (United States)

    Naylor, Mark F.; Lam, Anh K.; Bahavar, Cody F.; Nordquist, Robert E.; Chen, Wei R.

    2016-03-01

    Clinical trials of late-stage breast cancer patients and late-stage melanoma patients treated by laser immunotherapy (LIT) have shown promising results. In a 2010 study of Li et al, eleven late-stage melanoma patients received LIT in one or multiple 6-week treatment cycles applied to a 200-cm2 treatment site, which usually contained multiple cutaneous metastases. Long-term, positive response was observed in six patients. All lesions in the treatment area of the patients responded to LIT, eight of which achieved complete local response (CLR). CLR was observed in the non-treatment site (regional) lesions in four patients. Five patients were still alive at the time of last follow-up. The probability of 12-month overall survival was 70%.2 In 2011, Li et al, treated ten late stage breast cancer patients with LIT.1 In 8 patients available for evaluation, the objective response rate was 62.5% and the clinical beneficial response rate was 75%.1 This review demonstrates that LIT is safe and well tolerated, so it can be easily applied on an outpatient basis and can be combined with other pharmaceutical modalities to improve the therapeutic response of metastatic cancers.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  20. Chimeric Antigen Receptor-Engineered T Cells for Immunotherapy of Cancer

    Directory of Open Access Journals (Sweden)

    Marc Cartellieri

    2010-01-01

    Full Text Available CD4+ and CD8+ T lymphocytes are powerful components of adaptive immunity, which essentially contribute to the elimination of tumors. Due to their cytotoxic capacity, T cells emerged as attractive candidates for specific immunotherapy of cancer. A promising approach is the genetic modification of T cells with chimeric antigen receptors (CARs. First generation CARs consist of a binding moiety specifically recognizing a tumor cell surface antigen and a lymphocyte activating signaling chain. The CAR-mediated recognition induces cytokine production and tumor-directed cytotoxicity of T cells. Second and third generation CARs include signal sequences from various costimulatory molecules resulting in enhanced T-cell persistence and sustained antitumor reaction. Clinical trials revealed that the adoptive transfer of T cells engineered with first generation CARs represents a feasible concept for the induction of clinical responses in some tumor patients. However, further improvement is required, which may be achieved by second or third generation CAR-engrafted T cells.

  1. Specific immunotherapy generates CD8(+) CD196(+) T cells to suppress lung cancer growth in mice.

    Science.gov (United States)

    Zhang, Jian; Liu, Jing; Chen, Huiguo; Wu, Weibin; Li, Xiaojun; Wu, Yonghui; Wang, Zhigang; Zhang, Kai; Li, Yun; Weng, Yimin; Liao, Hongying; Gu, Lijia

    2016-08-01

    That specific immunotherapy can inhibit cancer growth has been recognized; its efficiency is to be improved. This study aimed to inhibit lung cancer (LC) growth in a mouse model by using an LC-specific vaccination. In this study, a LC mouse model was created by adoptive transplantation with LC cells. The tumor-bearing mice were vaccinated with LC cell extracts plus adjuvant TNBS or adoptive transplantation with specific CD8(+) CD196(+) T cells. The results showed that the vaccination with LC extracts (LCE)/TNBS markedly inhibited the LC growth and induced CD8(+) CD196(+) T cells in LC tissue and the spleen. These CD8(+) CD196(+) T cells proliferated and produce high levels of perforin upon exposure to LCE and specifically induced LC cell apoptosis. Exposure to TNBS induced RAW264.7 cells to produce macrophage inflammatory protein-3α; the latter activated signal transducer and activator of transcription 3 and further induced perforin expression in the CD8(+) CD196(+) T cells. Adoptive transfer with specific CD8(+) CD196(+) T cells suppressed LC growth in mice. In conclusion, immunization with LC extracts and TNBS can induce LC-specific CD8(+) CD196(+) T cells in LC-bearing mice and inhibit LC growth. PMID:26910585

  2. Nonmuscle invasive bladder cancer: a primer on immunotherapy

    Science.gov (United States)

    Maruf, Mahir; Brancato, Sam J.; Agarwal, Piyush K.

    2016-01-01

    Intravesical Bacillus Calmette-Guérin (BCG) has long been the gold standard treatment of nonmuscle invasive bladder cancer. Recently, there has been an emergence of novel immunotherapeutic agents, which have shown promise in the treatment of urothelial cell carcinoma. These agents aim to augment, modify, or enhance the immune response. Such strategies include recombinant BCG, monoclonal antibodies, vaccines, gene therapy, and adoptive T-cell therapy. Here, we review the emerging immunotherapeutics in the treatment of nonmuscle invasive bladder cancer.

  3. A2aR antagonists: Next generation checkpoint blockade for cancer immunotherapy

    Directory of Open Access Journals (Sweden)

    Robert D. Leone

    2015-01-01

    Full Text Available The last several years have witnessed exciting progress in the development of immunotherapy for the treatment of cancer. This has been due in great part to the development of so-called checkpoint blockade. That is, antibodies that block inhibitory receptors such as CTLA-4 and PD-1 and thus unleash antigen-specific immune responses against tumors. It is clear that tumors evade the immune response by usurping pathways that play a role in negatively regulating normal immune responses. In this regard, adenosine in the immune microenvironment leading to the activation of the A2a receptor has been shown to represent one such negative feedback loop. Indeed, the tumor microenvironment has relatively high concentrations of adenosine. To this end, blocking A2a receptor activation has the potential to markedly enhance anti-tumor immunity in mouse models. This review will present data demonstrating the ability of A2a receptor blockade to enhance tumor vaccines, checkpoint blockade and adoptive T cell therapy. Also, as several recent studies have demonstrated that under certain conditions A2a receptor blockade can enhance tumor progression, we will also explore the complexities of adenosine signaling in the immune response. Despite important nuances to the A2a receptor pathway that require further elucidation, studies to date strongly support the development of A2a receptor antagonists (some of which have already been tested in phase III clinical trials for Parkinson Disease as novel modalities in the immunotherapy armamentarium.

  4. 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.

  5. Novel Antibody-Based Proteins for Cancer Immunotherapy

    International Nuclear Information System (INIS)

    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

  6. Assays for predicting and monitoring responses to lung cancer immunotherapy

    Institute of Scientific and Technical Information of China (English)

    Cristina Teixid; Niki Karachaliou; Maria Gonzlez-Cao; Daniela Morales-Espinosa; Rafael Rosell

    2015-01-01

    AbstrAct Immunotherapy has become a key strategy for cancer treatment, and two immune checkpoints, namely, programmed cell death 1 (PD-1) and its ligand (PD-L1), have recently emerged as important targets. hTe interaction blockade of PD-1 and PD-L1 demonstrated promising activity and antitumor effcacy in early phase clinical trials for advanced solid tumors such as non-small cell lung cancer (NSCLC). Many cell types in multiple tissues express PD-L1 as well as several tumor types, thereby suggesting that the ligand may play important roles in inhibiting immune responses throughout the body. hTerefore, PD-L1 is a critical immunomodulating component within the lung microenvironment, but the correlation between PD-L1 expression and prognosis is controversial. More evidence is required to support the use of PD-L1 as a potential predictive biomarker. Clinical trials have measured PD-L1 in tumor tissues by immunohistochemistry (IHC) with different antibodies, but the assessment of PD-L1 is not yet standardized. Some commercial antibodies lack speciifcity and their reproducibility has not been fully evaluated. Further studies are required to clarify the optimal IHC assay as well as to predict and monitor the immune responses of the PD-1/PD-L1 pathway.

  7. Assays for predicting and monitoring responses to lung cancer immunotherapy

    International Nuclear Information System (INIS)

    Immunotherapy has become a key strategy for cancer treatment, and two immune checkpoints, namely, programmed cell death 1 (PD-1) and its ligand (PD-L1), have recently emerged as important targets. The interaction blockade of PD-1 and PD-L1 demonstrated promising activity and antitumor efficacy in early phase clinical trials for advanced solid tumors such as non-small cell lung cancer (NSCLC). Many cell types in multiple tissues express PD-L1 as well as several tumor types, thereby suggesting that the ligand may play important roles in inhibiting immune responses throughout the body. Therefore, PD-L1 is a critical immunomodulating component within the lung microenvironment, but the correlation between PD-L1 expression and prognosis is controversial. More evidence is required to support the use of PD-L1 as a potential predictive biomarker. Clinical trials have measured PD-L1 in tumor tissues by immunohistochemistry (IHC) with different antibodies, but the assessment of PD-L1 is not yet standardized. Some commercial antibodies lack specificity and their reproducibility has not been fully evaluated. Further studies are required to clarify the optimal IHC assay as well as to predict and monitor the immune responses of the PD-1/PD-L1 pathway

  8. Targeting cancer testis antigens for biomarkers and immunotherapy in colorectal cancer: Current status and challenges

    Institute of Scientific and Technical Information of China (English)

    Anil; Suri; Nirmala; Jagadish; Shikha; Saini; Namita; Gupta

    2015-01-01

    Colorectal cancer ranks third among the estimatedcancer cases and cancer related mortalities in United States in 2014. Early detection and efficient therapy remains a significant clinical challenge for this disease. Therefore, there is a need to identify novel tumor asso-ciated molecules to target for biomarker development and immunotherapy. In this regard, cancer testis antigens have emerged as a potential targets for developing novel clinical biomarkers and immunotherapy for various malignancies. These germ cell specific proteins exhibit aberrant expression in cancer cells and contribute in tumorigenesis. Owing to their unique expression profile and immunogenicity in cancer patients, cancer testis antigens are clinically referred as the most promising tumor associated antigens. Several cancer testis antigens have been studied in colorectal cancer but none of them could be used in clinical practice. This review is an attempt to address the promising cancer testis antigens in colorectal cancer and their possible clinical implications as biomarkers and immunotherapeutic targets with particular focus on challenges and future interventions.

  9. Immunotherapy for genitourinary cancer: state of the art and new perspectives.

    Science.gov (United States)

    Cattrini, Carlo; Dellepiane, Chiara; Cavo, Alessia; Buzzatti, Giulia; Tolomeo, Francesco; Messina, Carlo; Boccardo, Francesco

    2016-08-01

    In the last few years, cancer immunotherapy has changed the natural history and treatment strategies of a number of solid tumors, including melanoma and lung cancer. The anti-PD-1 nivolumab showed a survival benefit compared with everolimus in the second-line treatment of renal cell carcinoma, resulting in a radical shift in perspective in the treatment of this neoplasia and suggesting a new scenario beyond tyrosine kinase inhibitors. Checkpoint inhibitors might also improve the treatment of urothelial cancer, considering the promising results achieved so far and the relatively low efficacy of currently available treatments. Sipuleucel-T was the first approved immunotherapy for prostate cancer, showing a clear benefit in overall survival, and paved the way for the clinical testing of other novel cancer vaccines. This review provides a comprehensive overview of the current knowledge and new perspectives of immunotherapy in the treatment of urogenital malignancies. PMID:27183027

  10. Bacillus Calmette-Guerin immunotherapy of superficial bladder cancer.

    Science.gov (United States)

    Lamm, D L; Thor, D E; Harris, S C; Reyna, J A; Stogdill, V D; Radwin, H M

    1980-07-01

    Thirty-seven patients were enrolled in a randomized prospective study to compare standard surgical therapy for superficial bladder cancer to standard therapy plus bacillus Calmette-Guerin (BCG). Side effects of BCG have been tolerated well and include dysuria in 95 per cent of the patients, urinary frequency in 83 per cent, hematuria in 39 per cent, fever in 22 per cent and nausea in 22 per cent. Of 19 control patients 8 (42 per cent) had recurrent tumors in the followup period, compared to 3 of 18 patients (17 per cent) treated with BCG. One patient treated wih BCG had 2 recurrences, yielding a recurrence rate of 22 per cent in the group receiving BCG compared to 42 per cent in controls. When the incidence of recurrent tumors in matched intervals before and after entry into the protocol is compared, no change in the rate of tumor recurrence (p equals 0.726 chi-square) occurred in controls, whereas tumor recurrences were reduced significantly in the group treated with BCG (p equals 0.010 chi-square). The reduction in tumor recurrence in patients treated with BCG compared to controls is statistically significant (p equals 0.029 chi-square). Of 4 patients who presented with new bladder tumors remain free of tumor after BCG therapy, while 2 of 5 comparable control patients developed recurrent tumors. Intravesical and percutaneous BCG immunotherapy appears to decrease the rate of tumor recurrence in patients followed for 1 year. PMID:6997513

  11. Structural pathways of cytokines may illuminate their roles in regulation of cancer development and immunotherapy

    OpenAIRE

    Emine Guven-Maiorov; Saliha Ece Acuner-Ozbabacan; Ozlem Keskin; Attila Gursoy; Ruth Nussinov

    2014-01-01

    Cancers 2014, 6, 663-683; doi:10.3390/cancers6020663 cancers ISSN 2072-6694 www.mdpi.com/journal/cancers Review Structural Pathways of Cytokines May Illuminate Their Roles in Regulation of Cancer Development and Immunotherapy Emine Guven-Maiorov 1, Saliha Ece Acuner-Ozbabacan 1, Ozlem Keskin 1, Attila Gursoy 1 and Ruth Nussinov 2,3,* 1 Center for Computational Biology and Bioinformatics and College of Engineering, Koc University, Rumelifeneri Yolu, 34450 Sariyer ...

  12. The alpha immunotherapy - A successful solution in cancer treatment

    International Nuclear Information System (INIS)

    Full text: Radiation has been used in cancer therapy for many years. While, in the past the treatment involved mainly use of relatively low energy beta-emitters, more recently it was shown that isotopes emitting alpha particles have been more effective and selective against blood-borne cancers, widespread tumors and residual cells remaining after surgical intervention. This study shows that radioimmunotherapy (RIT) with α emitters may be therapeutically more effective than RIT with conventional β emitters. In the process of designing and developing the radioimmunotherapy procedures, the selection of the isotope is a major factor. This selection depends on a number of criteria and parameters, affecting usefulness and feasibility. Usefulness is directly related to the radiological performance of the ionising radiation in relation to tissue and its morphology, with a major distinction between the effects of alpha and beta-particles. Usefulness is also related to the pharmacodynamic performance of the isotope-carrier (e.g. antibody) complex, where the proper choice of isotope radiodecay half-life is essential. Feasibility depends on availability of the components in the isotope-ligand-carrier complex, and also on convenience and safety aspects in the preparation and the handling of the materials as well as in their application in patients. Alpha immunotherapy is based on emission of alpha particles by radionuclides. Due to its short physical t1/2, 213Bi appears to be especially suitable for use in conjunction with fast-clearing fragments; its 440-keV α emission also can be used for quantitation by external scintigraphy. Bismuth-213, a short-lived alpha particle emitting radionuclide, is generated from the decay of 225Ac, which has a half-life of 10 days. The development of a clinical 225Ac/213Bi generator and the preparation of a 213Bi radiolabeled antibody for radioimmunotherapy of leukemia is reported. Alpha emitting radionuclides are amongst the most promising

  13. Workshop on immunotherapy combinations. Society for immunotherapy of cancer annual meeting Bethesda, November 3, 2011

    OpenAIRE

    Forero Ivan; Okada Hideho; Topalian Suzanne L; Gajewski Thomas F; Korman Alan J; Melero Ignacio

    2012-01-01

    Abstract Although recent FDA approvals on ipilimumab and sipuleucel-T represent major milestones, the ultimate success of immunotherapy approaches will likely benefit from appropriate combinations with other immunotherapeutic and/or non-immunotherapeutic approaches. However, implementation of ideal combinations in the clinic may still face formidable challenges in regulatory, drug-availability and intellectual property aspects. The 2011 SITC annual meeting hosted a workshop on combination imm...

  14. Combined immunotherapy and antiangiogenic therapy of cancer with microencapsulated cells.

    Science.gov (United States)

    Cirone, Pasquale; Bourgeois, Jacqueline M; Shen, Feng; Chang, Patricia L

    2004-10-01

    An alternative form of gene therapy involves immunoisolation of a nonautologous cell line engineered to secrete a therapeutic product. Encapsulation of these cells in a biocompatible polymer serves to protect these allogeneic cells from host-versus-graft rejection while recombinant products and nutrients are able to pass by diffusion. This strategy was applied to the treatment of cancer with some success by delivering either interleukin 2 or angiostatin. However, as cancer is a complex, multifactorial disease, a multipronged approach is now being developed to attack tumorigenesis via multiple pathways in order to improve treatment efficacy. A combination of immunotherapy with angiostatic therapy was investigated by treating B16-F0/neu melanoma-bearing mice with intraperitoneally implanted, microencapsulated mouse myoblasts (C2C12) genetically modified to deliver angiostatin and an interleukin 2 fusion protein (sFvIL-2). The combination treatment resulted in improved survival, delayed tumor growth, and increased histological indices of antitumor activity (apoptosis and necrosis). In addition to improved efficacy, the combination treatment also ameliorated some of the undesirable side effects from the individual treatments that have led to the previous failure of the single treatments, for example, inflammatory response to IL-2 or vascular mimicry due to angiostatin. In conclusion, the combination of immuno- and antiangiogenic therapies delivered by immunoisolated cells was superior to individual treatments for antitumorigenesis activity, not only because of their known mechanisms of action but also because of unexpected protection against the adverse side effects of the single treatments. Thus, the concept of a "cocktail" strategy, with microencapsulation delivering multiple antitumor recombinant molecules to improve efficacy, is validated. PMID:15585110

  15. [Targeted Therapy and Immunotherapy for Non-small Cell Lung Cancer 
with Brain Metastasis].

    Science.gov (United States)

    Song, Qi; Jiao, Shunchang; Li, Fang

    2016-08-20

    Brain metastasis, a common complication of non-small cell lung cancer (NSCLC) with an incidence rate of 30%-50%, significantly affects the patients' quality of life. The prognosis of patients of NSCLC with brain metastasis is extremely poor, the average median survival is only 1 m-2 m without treatment. The targeted therapy based on lung cancer driven gene is a new treatment. Besides, the immunotherapy which can enhance the effect of anti-cancer by simulating the immune system is a new approach. The combination of targeted therapy and immunotherapy can greatly benefit patients in clinical work. PMID:27561803

  16. Immunotherapy using dendritic cells and cytokine-induced killer for kidney cancer

    International Nuclear Information System (INIS)

    Objective: To investigate the clinical efficacy of immunotherapy using dendritic cells (DC) and cytokine-induced killer (CIK)in treatment of patients with kidney cancer. Methods: Sixty patients with kidney cancer were divided into 2 groups randomly: the control group and immunotherapy group. Peripheral blood mononuclear cells (PBMC) were seperated from the patients who received immunotherapy first, then DC and CIK were induced and cultured with GM-CSF and IL4 in vitro. The immunotherapy group received DC four times and CIK twice at an interval of 14 days after routine treatment. The control group received only chemotherapy. T lymphocyte subtypes and NK cells in peripheral blood, the white cells and the values of liver and kidney biochemistry of two group of patients were analyzed and clinical efficacy were ob- served, so were side effects. Results: Clinical efficacy showed significant statistical difference between the two groups (P+, CD4+, CD4+/CD8+ and NK cell in the immunotherapy group increased after treatment, which showed significant statistical difference compared with those before treatment(P value was 0.010, 0.026, 0.021, 0.016, respectively). Changes in cell immune indexes (CD3+, CD4+, CD4+/CD8+) in immunotherapy group and Control group showed significant statistical difference (P value was 0.001,0.023,0.012, respectively). Conclusion: Immunotherapy using dendritic cells and cytokine-induced killer combined with routine treatment can improve T lymphocyte subtypes and NK cell ratio in peripheral blood of the patients with kidney cancer, and may play an important role in the treatment of kidney cancer. It can enhance clinical efficacy in patients with kidney cancer and can improve prognosis. (authors)

  17. 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

  18. A prospective highlight on exosomal nanoshuttles and cancer immunotherapy and vaccination

    Directory of Open Access Journals (Sweden)

    Mohammad A. Rafi

    2015-08-01

    Conclusions: As complex systems, these vesicular micro-/nano-machines convey important cellular messages dependent upon the cells/tissue setting(s. In addition to their potential in diagnosis of cancers, they have been exploited for cancer immunotherapy/vaccination. However, such treatment strategies need to be carefully designed to attain desired clinical outcomes.

  19. Sorting through subsets: Which T cell populations mediate highly effective adoptive immunotherapy?

    Science.gov (United States)

    Klebanoff, Christopher A.; Gattinoni, Luca; Restifo, Nicholas P.

    2012-01-01

    CD8+ T cells have been described as being naïve (TN) or one of four antigen-experienced subtypes representing a continuum of differentiation and maturation: stem cell memory (TSCM), central memory (TCM), effector memory (TEM), and terminally differentiated effector T cells (TEFF). In mice, adoptive cell transfer (ACT) of less differentiated TN, TSCM and TCM subsets have consistently demonstrated superior in vivo expansion, persistence, and antitumor capacities relative to the more differentiated TEM and TEFF cells. Retrospective analyses from human ACT trials have confirmed that transfer of less differentiated T cell subsets is highly correlated with objective clinical responses. These findings, combined with the recent ability to convey de novo antigen reactivity with high efficiency through genetic engineering of exogenous T cell or chimeric antigen receptors, now challenge the field with three important questions: 1) how should less differentiated T cell subsets be isolated for human clinical trials?; 2) what is the best means of expanding T cells ex vivo in such a way as to not corrupt the beneficial traits of the younger subsets?; and 3) is it necessary to physically separate younger subsets from their more differentiated counterparts? Answering these questions will allow for the rational development of the next generation of highly effective and potentially curative T cell therapies for the treatment of cancer. PMID:23090074

  20. Cancer immunotherapy and immune-related response assessment: The role of radiologists in the new arena of cancer treatment

    Energy Technology Data Exchange (ETDEWEB)

    Nishino, Mizuki, E-mail: Mizuki_Nishino@DFCI.HARVARD.EDU [Department of Radiology, Brigham and Women' s Hospital and Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215 (United States); Tirumani, Sree H.; Ramaiya, Nikhil H. [Department of Radiology, Brigham and Women' s Hospital and Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215 (United States); Hodi, F. Stephen [Department of Medical Oncology and Department of Medicine, Dana-Farber Cancer Institute and Brigham and Women' s Hospital, 450 Brookline Ave., Boston, MA 02215 (United States)

    2015-07-15

    Highlights: • The successful clinical application of cancer immunotherapy has opened a new arena for the treatment of advanced cancers. • Cancer immunotherapy is associated with a variety of important radiographic features in the assessments of tumor response and immune-related adverse events. • The state-of-the art knowledge of immunotherapy and the related radiologic manifestations are essential for radiologists. - Abstract: The recent advances in the clinical application of anti-cancer immunotherapeutic agents have opened a new arena for the treatment of advanced cancers. Cancer immunotherapy is associated with a variety of important radiographic features in the assessments of tumor response and immune-related adverse events, which calls for radiologists’ awareness and in-depth knowledge on the topic. This article will provide the state-of-the art review and perspectives of cancer immunotherapy, including its molecular mechanisms, the strategies for immune-related response assessment on imaging and their pitfalls, and the emerging knowledge of radiologic manifestations of immune-related adverse events. The cutting edge clinical and radiologic investigations are presented to provide future directions.

  1. Cancer immunotherapy and immune-related response assessment: The role of radiologists in the new arena of cancer treatment

    International Nuclear Information System (INIS)

    Highlights: • The successful clinical application of cancer immunotherapy has opened a new arena for the treatment of advanced cancers. • Cancer immunotherapy is associated with a variety of important radiographic features in the assessments of tumor response and immune-related adverse events. • The state-of-the art knowledge of immunotherapy and the related radiologic manifestations are essential for radiologists. - Abstract: The recent advances in the clinical application of anti-cancer immunotherapeutic agents have opened a new arena for the treatment of advanced cancers. Cancer immunotherapy is associated with a variety of important radiographic features in the assessments of tumor response and immune-related adverse events, which calls for radiologists’ awareness and in-depth knowledge on the topic. This article will provide the state-of-the art review and perspectives of cancer immunotherapy, including its molecular mechanisms, the strategies for immune-related response assessment on imaging and their pitfalls, and the emerging knowledge of radiologic manifestations of immune-related adverse events. The cutting edge clinical and radiologic investigations are presented to provide future directions

  2. Advance of Cellular Immunotherapy in Clinical and Translational Medicine of Lung Cancer

    Institute of Scientific and Technical Information of China (English)

    YAN Fei; YU Shao-rong; FENG Ji-feng

    2016-01-01

    Lung cancer is one of the most common cancers and ranks the ifrst in the mortality worldwide. The core of immunotherapy, especially cellular immunotherapy, is to activate the T cell-mediated tumor-killing effect in patients with tumors, so as to increase their anti-tumor effect. Surgery and radio- and chemotherapy cannot radically eliminate cancerous cells, but immunotherapy is an important supplementary method in killing tumor stem cells and non-proliferating cells. Cellular immunotherapy contains dendritic cells (DC), cytokine-induced killer (CIK), DC-CIK, natural killer T cells (NKT) and γδ T cells, which provides new techniques for the comprehensive treatment of lung cancer. Using CIK combined with DC, radiochemotherapy, radiofrequency ablation and monomers of Chinese medicine to induce CIK cells that directionally migrate to cancerous nest can increase tumor-killing ability and immunoregulatory ability of CIK cells, reduce adverse and toxic reactions and increase patients’ quality of life, and NKT cell and γδ T cell therapies have also been gradually perfected and promoted in clinical translation. This study mainly introduced the clinical translation of DC vaccines, CIK cells and DC-CIK treatment for lung cancer, hoping to provide new pathways and reference for the clinical treatment of lung cancer.

  3. Autologous MUC1-Specific Th1 Effector Cell Immunotherapy Induce Differential Levels of Systemic TReg Cell Subpopulations That Result in Increased Ovarian Cancer Patient Survival

    OpenAIRE

    Dobrzanski, Mark J.; Rewers-Felkins, Kathleen A.; Quinlin, Imelda S.; Samad, Khaliquzzaman A.; Phillips, Catherine A.; Robinson, William; Dobrzanski, David J.; Wright, Stephen E.

    2009-01-01

    Adoptive T cell immunotherapy using autologous lymphocytes is a viable treatment for patients with cancer and requires participation of Ag-specific CD4 and CD8 T cells. Here, we assessed the immunotherapeutic effects of autologous MUC1 peptide-stimulated CD4+ effector cells following adoptive transfer in patients with ovarian cancer. Using MUC1 peptide and IL-2 for ex vivo CD4+/Th1 effector cell generation, we show that three monthly treatment cycles of peripheral blood T cell restimulation a...

  4. Exploiting IL-17-producing CD4+ and CD8+ T cells to improve cancer immunotherapy in the clinic.

    Science.gov (United States)

    Majchrzak, Kinga; Nelson, Michelle H; Bailey, Stefanie R; Bowers, Jacob S; Yu, Xue-Zhong; Rubinstein, Mark P; Himes, Richard A; Paulos, Chrystal M

    2016-03-01

    Cancer immunotherapy is one the most effective approaches for treating patients with tumors, as it bolsters the generation and persistence of memory T cells. In preclinical work, it has been reported that adoptively transferred CD4+ and CD8+ lymphocytes that secrete IL-17A (i.e., Th17 and Tc17 cells) regress tumors to a greater extent than IFN-γ(+)Th1 or Tc1 cells in vivo. Herein, we review the mechanisms underlying how infused Th17 and Tc17 cells regress established malignancies in clinically relevant mouse models of cancer. We also discuss how unique signaling cues--such as co-stimulatory molecules (ICOS and 41BB), cytokines (IL-12 and IL-23) or pharmaceutical reagents (Akt inhibitors, etc.)--can be exploited to bolster the therapeutic potential of IL-17(+) lymphocytes with an emphasis on using this knowledge to improve next-generation clinical trials for patients with cancer. PMID:26825102

  5. Patient-recognition data-mining model for BCG-plus interferon immunotherapy bladder cancer treatment.

    Science.gov (United States)

    Shah, Shital C; Kusiak, Andrew; O'Donnell, Michael A

    2006-06-01

    Bladder cancer is the fifth most common malignant disease in the United States with an annual incidence of around 63,210 new cases and 13,180 deaths. The cost for providing care for patients with bladder cancer disease is high. Bladder cancer treatment options such as immunotherapy, chemotherapy, radiation therapy, transurethral resection, and cystectomy, are used with varying success rates. In this research, data from a nationwide bacillus Calmette-Gue rin (BCG) plus interferon-alpha (IFN-alpha) immunotherapy clinical trial was considered. Data mining algorithms were used to analyze the effectiveness of immunotherapy treatment and to understand the prominent parameters and their interactions. The extracted knowledge was used to build a patient recognition model for prediction of treatment outcomes. The data was analyzed to understand the impact of various parameters on the treatment outcome. A list of significant parameters such as cumulative tumor size, presence of residual disease, stages of prior bladder cancer, current state of bladder cancer, and the presence of current bladder cancer (T1) is provided. The decision-making approach outlined in the paper supplemented with additional knowledge bases will lead to a comprehensive analytical road map of the BCG/IFN-alpha immunotherapy treatment. It will provide individualized guidelines for each stage of the treatment as well as measure the success of the treatment. PMID:15978568

  6. Dendritic cell vaccines in cancer immunotherapy: from biology to translational medicine

    Institute of Scientific and Technical Information of China (English)

    Hongmei Xu; Xuetao Cao

    2011-01-01

    According to the GLOBOCAN reports,there were about 12.7 million cancer cases and 7.6 million cancer deaths in 2008,and the cancer burden continues to increase worldwide [1].At present,the common treatments for cancer include surgery,chemotherapy,radiotherapy,and immunotherapy.Immunotherapy aims to enhance or regulate the patient's own immune response to fight against tumors.It represents a novel and effective strategy in cancer treatments,but,generally,its efficacy needs to be improved [2].Cancer vaccination is an important and promising approach in cancer immunotherapy.For many years,prophylactic vaccines have exhibited profound accomplishment in preventing serious infectious diseases in humankind,including polio,small pox,and diphtheria.However,cancer vaccines are vastly different from the prophylactic vaccines in that they are aimed to eliminate preexisting tumors.Furthermore,the immune system is immunosuppressed in most cancer patients,so it is much more difficult to develop effective cancer vaccines.

  7. Progress in Adaptive Immunotherapy for Cancer in Companion Animals: Success on the Path to a Cure

    OpenAIRE

    Anderson, Katie L.; Modiano, Jaime F.

    2015-01-01

    Harnessing the ability of the immune system to eradicate cancer has been a long-held goal of oncology. Work from the last two decades has finally brought immunotherapy into the forefront for cancer treatment, with demonstrable clinical success for aggressive tumors where other therapies had failed. In this review, we will discuss a range of therapies that are in different stages of clinical or preclinical development for companion animals with cancer, and which share the common objective of ...

  8. Local immunotherapy based on agonistic CD40 antibodies effectively inhibits experimental bladder cancer

    OpenAIRE

    Sandin, Linda C; Tötterman, Thomas H; Sara M. Mangsbo

    2014-01-01

    Local immunotherapy resurfaces in the field of cancer as a potential way to cure localized and metastatic disease with limited toxic effects. We have recently demonstrated that local administration of agonistic CD40 antibodies can cure localized as well as disseminated bladder neoplasms. This approach reduces the circulating concentrations of antibodies that would result from systemic delivery, hence resulting in limited toxicity.

  9. Natural killer (NK cells for cancer immunotherapy: pluripotent stem cells-derived NK cells as an immunotherapeutic perspective

    Directory of Open Access Journals (Sweden)

    Cristina eEguizabal

    2014-09-01

    Full Text Available Natural killer (NK cells play an essential role in the fight against tumor development. Over the last years, the progress made in the NK cell biology field and in deciphering how NK cell function is regulated, is driving efforts to utilize NK cell-based immunotherapy as a promising approach for the treatment of malignant diseases. Therapies involving NK cells may be accomplished by activating and expanding endogenous NK cells by means of cytokine treatment or by transferring exogenous cells by adoptive cell therapy and/or by hematopoietic stem cell transplantation (HSCT. NK cells that are suitable for adoptive cell therapy can be derived from different sources, including ex vivo expansion of autologous NK cells, unstimulated or expanded allogeneic NK cells from peripheral blood, derived from CD34+ hematopoietic progenitors from peripheral blood and umbilical cord blood, and NK cell lines. Besides, genetically modified NK cells expressing chimeric antigen receptors (CARs or cytokines genes may also have a relevant future as therapeutic tools. Recently, it has been described the derivation of large numbers of functional and mature NK cells from pluripotent stem cells (PSCs, both embryonic stem cells (ESCs and induced pluripotent stem cells (iPSCs, which adds another tool to the expanding NK cell-based cancer immunotherapy arsenal.

  10. Synopsis of the 6th Walker's Cay Colloquium on Cancer Vaccines and Immunotherapy

    Directory of Open Access Journals (Sweden)

    Marincola Francesco M

    2004-06-01

    Full Text Available Abstract The 6th annual Cancer Vaccines and Immunotherapy Colloquium at Walker's Cay was held under the auspices of the Albert B. Sabin Vaccine Institute on March 10–13, 2004. The Colloquium consisted of a select group of 34 scientists representing academia, biotechnology and pharmaceutical industry. The main goal of this gathering was to promote in a peaceful and comfortable environment exchanges between basic and clinical science. The secondary benefit was to inspire novel bench to bedside ventures and at the same time provide feed back about promising and/or disappointing clinical results that could help re-frame some scientific question or guide the design of future trials. Several topics were covered that included tumor antigen discovery and validation, platforms for vaccine development, tolerance, immune suppression and tumor escape mechanisms, adoptive T cell therapy and dendritic cell-based therapies, clinical trials and assessment of response. Here we report salient points raised by speakers or by the audience during animated discussion that followed each individual presentation.

  11. Cancer immunotherapy in clinical practice-the past, present, and future

    Institute of Scientific and Technical Information of China (English)

    Gaurav Goel; Weijing Sun

    2014-01-01

    Considerable progress has been made in the field of cancer immunotherapy in recent years. This has been made possible in large part by the identification of new immune-based cellular targets and the development of novel approaches aimed at stimulating the immune system. The role played by the immunosuppressive microenvironment in the development of tumors has been established. The success of checkpoint-inhibiting antibodies and cancer vaccines has marked the beginning of a new era in cancer treatment. This review highlights the clinically relevant principles of cancer immunology and various immunotherapeutic approaches that have either already entered mainstream oncologic practice or are currently in the process of being evaluated in clinical trials. Furthermore, the current barriers to the development of effective immunotherapies and the potential strategies of overcoming them are also discussed.

  12. Society for immunotherapy of cancer (SITC) statement on the proposed changes to the common rule.

    Science.gov (United States)

    Kaufman, Howard L; Butterfield, Lisa H; Coulie, Pierre G; Demaria, Sandra; Ferris, Robert L; Galon, Jérôme; Khleif, Samir N; Mellman, Ira; Ohashi, Pamela S; Overwijk, Willem W; Topalian, Suzanne L; Marincola, Francesco M

    2016-01-01

    The Common Rule is a set of ethical principles that provide guidance on the management of human subjects taking part in biomedical and behavioral research in the United States. The elements of the Common Rule were initially developed in 1981 following a revision of the Declaration of Helsinki in 1975. Most academic facilities follow the Common Rule in the regulation of clinical trials research. Recently, the government has suggested a revision of the Common Rule to include more contemporary and streamlined oversight of clinical research. In this commentary, the leadership of the Society for Immunotherapy of Cancer (SITC) provides their opinion on this plan. While the Society recognizes the considerable contribution of clinical research in supporting progress in tumor immunotherapy and supports the need for revisions to the Common Rule, there is also some concern over certain elements which may restrict access to biospecimens and clinical data at a time when high throughput technologies, computational biology and assay standardization is allowing major advances in understanding cancer biology and providing potential predictive biomarkers of immunotherapy response. The Society values its professional commitment to patients for improving clinical outcomes with tumor immunotherapy and supports continued discussion with all stakeholders before implementing changes to the Common Rule in order to ensure maximal patient protections while promoting continued clinical research at this historic time in cancer research. PMID:27330810

  13. Combined Treatment Effects of Radiation and Immunotherapy: Studies in an Autochthonous Prostate Cancer Model

    Energy Technology Data Exchange (ETDEWEB)

    Wada, Satoshi [Department of Oncology, James Buchanan Brady Urological Institute, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Harris, Timothy J.; Tryggestad, Erik [Department of Radiation Oncology and Molecular Radiation Sciences, James Buchanan Brady Urological Institute, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Yoshimura, Kiyoshi [Department of Oncology, James Buchanan Brady Urological Institute, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Zeng, Jing [Department of Radiation Oncology and Molecular Radiation Sciences, James Buchanan Brady Urological Institute, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Yen, Hung-Rong; Getnet, Derese; Grosso, Joseph F.; Bruno, Tullia C. [Department of Oncology, James Buchanan Brady Urological Institute, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); De Marzo, Angelo M. [Department of Pathology, James Buchanan Brady Urological Institute, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland (United States); and others

    2013-11-15

    Purpose: To optimize the combination of ionizing radiation and cellular immunotherapy using a preclinical autochthonous model of prostate cancer. Methods and Materials: Transgenic mice expressing a model antigen under a prostate-specific promoter were treated using a platform that integrates cone-beam CT imaging with 3-dimensional conformal therapy. Using this technology we investigated the immunologic and therapeutic effects of combining ionizing radiation with granulocyte/macrophage colony-stimulating factor-secreting cellular immunotherapy for prostate cancer in mice bearing autochthonous prostate tumors. Results: The combination of ionizing radiation and immunotherapy resulted in a significant decrease in pathologic tumor grade and gross tumor bulk that was not evident with either single-modality therapy. Furthermore, combinatorial therapy resulted in improved overall survival in a preventive metastasis model and in the setting of established micrometastases. Mechanistically, combined therapy resulted in an increase of the ratio of effector-to-regulatory T cells for both CD4 and CD8 tumor-infiltrating lymphocytes. Conclusions: Our preclinical model establishes a potential role for the use of combined radiation-immunotherapy in locally advanced prostate cancer, which warrants further exploration in a clinical setting.

  14. Melittin-MIL-2 fusion protein as a candidate for cancer immunotherapy

    OpenAIRE

    Liu, Mingjun; Wang, Haitao; Liu, Linjie; Wang, Bin; Sun, Guirong

    2016-01-01

    Background Cytokine fusion protein that modulates the immune response holds great potential for cancer immunotherapy. IL-2 is an effective treatment against advanced cancers. However, the therapeutic efficacy of IL-2 is limited by severe systemic toxicity. Several mutants recombinant IL-2 can increase antitumor activity and minimize systemic toxicity. Melittin is an attractive anticancer candidate because of its wide-spectrum lytic properties. We previously generated a bifunctional fusion pro...

  15. Adoptive Immunotherapy of Established Pulmonary Metastases with LAK Cells and Recombinant Interleukin-2

    Science.gov (United States)

    Mule, James J.; Shu, Suyu; Schwarz, Susan L.; Rosenberg, Steven A.

    1984-09-01

    The activation of human peripheral blood leukocytes or murine splenocytes with interleukin-2 (IL-2) generated cells that were lytic in vitro for a variety of fresh tumor cells. The adoptive transfer of such lymphokine-activated killer (LAK) cells to mice with established pulmonary sarcoma metastases was highly effective in reducing the number (and size) of these tumor nodules when combined with repeated injections of recombinant IL-2. These findings provide a rationale for clinical trials of the infusion of human LAK cells generated with recombinant IL-2 as well as Phase I trials of the infusion of recombinant IL-2 systemically into humans.

  16. Alloreactive natural killer cells for the treatment of acute myeloid leukemia: from stem cell transplantation to adoptive immunotherapy

    Directory of Open Access Journals (Sweden)

    Loredana eRuggeri

    2015-10-01

    Full Text Available Natural killer cells express activating and inhibitory receptors which recognize MHC class I alleles, termed Killer cell Immunoglobulin-like Receptors (KIRs. Preclinical and clinical data from haploidentical T-cell depleted stem cell transplantation have demonstrated that alloreactive KIR-L mismatched natural killer cells play a major role as effectors against acute myeloid leukemia. Outside the transplantation setting, several reports have proven the safety and feasibility of natural killer cell infusion in acute myeloid leukemia patients and, in some cases, provided evidence that transferred NK cells are functionally alloreactive and may have a role in disease control. Aim of the present work is to briefly summarize the most recent advances in the field by moving from the first preclinical and clinical demonstration of donor NK alloreactivity in the transplantation setting to the most recent attempts of exploiting the use of alloreactive NK cell infusion as a means of adoptive immunotherapy against acute myeloid leukemia. Altogether, these data highlight the pivotal role of NK cells for the development of novel immunological approaches in the clinical management of acute myeloid leukemia.

  17. Induced Pluripotent Stem Cell as a New Source for Cancer Immunotherapy.

    Science.gov (United States)

    Rami, Farzaneh; Mollainezhad, Halimeh; Salehi, Mansoor

    2016-01-01

    The immune system consists of cells, proteins, and other molecules that beside each other have a protective function for the host against foreign pathogens. One of the most essential features of the immune system is distinguishability between self- and non-self-cells. This function has an important role in limiting development and progression of cancer cells. In this case, the immune system can detect tumor cell as a foreign pathogen; so, it can be effective in elimination of tumors in their early phases of development. This ability of the immune system resulted in the development of a novel therapeutic field for cancer treatment using host immune components which is called cancer immunotherapy. The main purpose of cancer immunotherapy is stimulation of a strong immune response against the tumor cells that can result from expressing either the immune activator cytokines in the tumor area or gene-modified immune cells. Because of the problems of culturing and manipulating immune cells ex vivo, in recent years, embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC) have been used as new sources for generation of modified immune stimulatory cells. In this paper, we reviewed some of the progressions in iPSC technology for cancer immunotherapy. PMID:27019752

  18. 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.

  19. Taking up Cancer Immunotherapy Challenges: Bispecific Antibodies, the Path Forward?

    Directory of Open Access Journals (Sweden)

    Joanie Del Bano

    2015-12-01

    Full Text Available As evidenced by the recent approvals of Removab (EU, Trion Pharma in 2009 and of Blincyto (US, Amgen in 2014, the high potential of bispecific antibodies in the field of immuno-oncology is eliciting a renewed interest from pharmaceutical companies. Supported by rapid advances in antibody engineering and the development of several technological platforms such as Triomab or bispecific T cell engagers (BiTEs, the “bispecifics” market has increased significantly over the past decade and may occupy a pivotal space in the future. Over 30 bispecific molecules are currently in different stages of clinical trials and more than 70 in preclinical phase. This review focuses on the clinical potential of bispecific antibodies as immune effector cell engagers in the onco-immunotherapy field. We summarize current strategies targeting various immune cells and their clinical interests. Furthermore, perspectives of bispecific antibodies in future clinical developments are addressed.

  20. BCG immunotherapy of bladder cancer: inhibition of tumor recurrence and associated immune responses.

    Science.gov (United States)

    Lamm, D L; Thor, D E; Winters, W D; Stogdill, V D; Radwin, H M

    1981-07-01

    Fifty-one patients with confirmed bladder cancer have enrolled in a prospective evaluation of BCG immunotherapy. Following resection of existing tumors, patients were stratified according to tumor grade and number of previous recurrences and randomly assigned to control or BCG treatment groups. Immunotherapy consisted of six weekly administrations of Pasteur strain BCG using 120 mg intravesically and 5 mg percutaneously. Immunotherapy side effects were minimal and no patient required postponement of BCG treatments. Eleven control (46%) compared with five (22%) BCG-treated patients had tumor recurrence (P = 0.078, chi 2). Prolongation of the disease-free interval with BCG treatment was significantly at the P = 0.016 level by Wilcoxon analysis. Four control and two BCG-treated patients had multiple recurrences. Comparing total episodes of recurrence, nineteen of 79 (24%) control and eight of 85 (7%) BCG group cystoscopic examinations revealed tumor (P = 0.006, chi 2). Immunologic correlates of response to immunotherapy were not statistically significant since only five BCG-treated patients had tumor recurrence. However, four of these five patients evidenced impaired LIF response to PPD at the time of tumor recurrence, and impairment of skin test reactivity and BCG humoral antibody response were more commonly seen in this subgroup of patients. PMID:7016300

  1. Tumour Devitalization as a Tool for Cancer Immunotherapy Experiences from Animal Models

    Czech Academy of Sciences Publication Activity Database

    Horák, Vratislav; Vannucci, Luca; Morávková, Alena; Strnádel, Ján; Holubová, Monika; Hradecký, Jan; Klaudy, Jiří; Pokorná, Eva; Usvald, Dušan; Plánská, Daniela; Burócziová, Monika; Vure, Michal

    Indore: School of Biotechnology, 2009. s. 3-3. [5th World Congress of Cellular and Molecular Biology. 02.011.2009-06.11.2009, Indore] R&D Projects: GA MŠk 2B08063; GA ČR GA524/04/0102 Institutional research plan: CEZ:AV0Z50450515; CEZ:AV0Z50200510 Keywords : Devitalization * Cancer immunotherapy * Melanoma -bearing Libechov Minipig Subject RIV: EC - Immunology

  2. IMMUNOTHERAPY WITH VISCUM ALBUM EXTRACT IN THE TREATMENT OF ADVANCED COLORECTAL CANCER

    Directory of Open Access Journals (Sweden)

    T. Oniu

    2011-11-01

    Full Text Available Background: Most clinical trials using mistletoe to treat colorectal cancer are out-of-date and have major methodological weaknesses that raise doubts about their findings. Meanwhile, the arsenal of chemotherapy has much evolved over the last decade. Thus, the aim of this study was to determine the effectiveness of the total plant extract Isorel in association with modern chemotherapy in the treatment of colorectal cancer. Methods: After the surgical removal of the primary tumor, a total of 124 patients with advanced colorectal cancer (stage Dukes C and D, were randomly divided into the immunotherapy group (Isorel associated in most of the cases with chemotherapy, n=58 and the control group (most of which received chemotherapy. The chemotherapy regimens were based on 5-fluorouracil, irinotecan and oxaliplatin. Overall survival and adverse events were observed. Results: The addition of immunotherapy with Viscum album extract Isorel to 5FU-based chemotherapy significantly improved overall survival in Dukes stage C (5-year survival: 46% vs. 17%; median survival: 46 vs. 24 months, p=0.004 and D (median survival: 13,5 vs. 9,5 months, p=0.02; longest survival: 26 vs. 12 months. The addition of immunotherapy to oxaliplatin- and irinotecan-based chemotherapy further improved overall survival in Dukes stage C (5-year survival: 64% vs. 38%; median survival: 57,5 vs. 34 months, p=0.04 and D (median survival: 24 vs. 18 months, p=0.02; longest survival: 36 vs. 24 months. Inflammatory local reactions at the s.c. injection site occur frequently (83% of patients at the beginning of the treatment for 1 to 8 weeks. Conclusions: Immunotherapy with Viscum album extract Isorel, added to chemotherapy, improves the survival of the patients operated for advanced colorectal cancer compared with chemotherapy alone, whatever its type.

  3. Cytokine induced killer cell immunotherapy in cancer treatment: from bench to bedside

    Directory of Open Access Journals (Sweden)

    Arashar Arafar

    2014-02-01

    Full Text Available Cytokine-induced killer (CIK cells are T effector cells generated by monocytes cultured and stimulated by cytokines. CIK cells were studied for more than 20 years ago. They can cause lysis of tumor cells that of both autologous and allogeneic origins, so that they were used in cancer treatment. This review aimed to summarize advancements of CIK cells and their current clinical applications in cancer treatment. In general, CIK cells were widely clinically used for recent 5 years. They gave promising results in hepatocellular carcinoma, lung cancer, breast cancer, renal cancer, and treatment. Looking into the future, CIK cell based immunotherapy will become an important tool in cancer treatment. [Biomed Res Ther 2014; 1(2.000: 71-77

  4. Immunotherapy in gastrointestinal cancer: Recent results, current studies and future perspectives.

    Science.gov (United States)

    Moehler, Markus; Delic, Maike; Goepfert, Katrin; Aust, Daniela; Grabsch, Heike I; Halama, Niels; Heinrich, Bernd; Julie, Catherine; Lordick, Florian; Lutz, Manfred P; Mauer, Murielle; Alsina Maqueda, Maria; Schild, Hansjoerg; Schimanski, Carl C; Wagner, Anna-Dorothea; Roth, Arnaud; Ducreux, Michel

    2016-05-01

    The new therapeutic approach of using immune checkpoint inhibitors as anticancer agents is a landmark innovation. Early studies suggest that immune checkpoint inhibition might also be effective in patients with gastrointestinal cancer. To improve the efficacy of immunotherapy, different strategies are currently under evaluation. This review summarises the discussion during the European Organisation for Research and Treatment of Cancer Gastrointestinal Tract Cancer Translational Research Meeting in Mainz in November 2014 and provides an update on the most recent results of immune therapy in gastrointestinal cancers. Knowledge of potential relationships between tumour cells and their microenvironment including the immune system will be essential in gastrointestinal malignancies. In this context, the density of T cell infiltration within colorectal cancer metastases has been associated with response to chemotherapy, and a high expression of programmed cell death ligand 1 (PD-L1) in advanced gastric cancer has been related with poor prognosis. Effective targets might include neo-antigens encoded from genes carrying tumour-specific somatic mutations. Tailored immunotherapy based on such mutations could enable the effective targeting of an individual patient's tumour with vaccines produced on demand. Other strategies considering checkpoint inhibitors have shown efficacy by targeting cytotoxic T-lymphocyte-associated protein 4 and PD-1 or PD-L1. DNA mismatch repair-deficient tumours appear to be potentially the best candidates for these therapies. Finally, the combination of oncolytic viruses with immunotherapy might boost antitumour activity as well. Further evaluation of these promising immunological therapeutic approaches will require large prospective clinical studies. PMID:27039171

  5. Immunotherapy and therapeutic vaccines in prostate cancer: an update on current strategies and clinical implications

    Directory of Open Access Journals (Sweden)

    B Harpreet Singh

    2014-06-01

    Full Text Available In recent years, immunotherapy has emerged as a viable and attractive strategy for the treatment of prostate cancer. While there are multiple ways to target the immune system, therapeutic cancer vaccines and immune checkpoint inhibitors have been most successful in late-stage clinical trials. The landmark Food and Drug Administration approval of sipuleucel-T for asymptomatic or minimally symptomatic metastatic prostate cancer set the stage for ongoing phase III trials with the cancer vaccine PSA-TRICOM and the immune checkpoint inhibitor ipilimumab. A common feature of these immune-based therapies is the appearance of improved overall survival without short-term changes in disease progression. This class effect appears to be due to modulation of tumor growth rate kinetics, in which the activated immune system exerts constant immunologic pressure that slows net tumor growth. Emerging data suggest that the ideal population for clinical trials of cancer vaccines is patients with lower tumor volume and less aggressive disease. Combination strategies that combine immunotherapy with standard therapies have been shown to augment both immune response and clinical benefit.

  6. Recent advances in immunotherapy for non-small-cell lung cancer.

    Science.gov (United States)

    Suzuki, Hiroyuki; Owada, Yuki; Watanabe, Yuzuru; Inoue, Takuya; Fukuharav, Mitsuro; Yamaura, Takumi; Mutoh, Satoshi; Okabe, Naoyuki; Yaginuma, Hiroshi; Hasegawa, Takeo; Yonechi, Atsushi; Ohsugi, Jun; Hoshino, Mika; Higuchi, Mitsunori; Shio, Yutaka; Gotoh, Mitsukazu

    2014-01-01

    Despite of recent development in the field of molecular targeted therapies, lung cancer is a leading cause of cancer death in the world. Remarkable progress has been made recently in immunotherapy for patients with non-small-cell lung cancer (NSCLC), with several modalities, concepts, and treatment settings being investigated. In vaccine development, large-scale clinical trials such as those with L-BLP25, belagenpumatucel-L, TG4010, and talactoferrin are already ongoing and some results have been reported. A trial of a vaccine as adjuvant therapy for patients with completely resected NSCLC is also ongoing with one of the major cancer-testis antigens, melanoma-associated antigen (MAGE)-A3. More recently, the effectiveness of multiple peptide vaccines has also been shown. Recently developed unique treatment modalities are the immune checkpoint inhibitors, such as antibodies against PD-1 and PD-L1, which also show promise. However, although therapeutic cancer vaccines are generally thought to be safe, severe adverse events should be monitored carefully when using immune checkpoint inhibitors. Here, we discuss recent advances and future perspectives of immunotherapy for patients with NSCLC. PMID:24196313

  7. Immunotherapy and therapeutic vaccines in prostate cancer:an update on current strategies and clinical implications

    Institute of Scientific and Technical Information of China (English)

    B Harpreet Singh; James L Gulley

    2014-01-01

    In recent years, immunotherapy has emerged as a viable and attractive strategy for the treatment of prostate cancer. While there are multiple ways to target the immune system, therapeutic cancer vaccines and immune checkpoint inhibitors have been most successful in late-stage clinical trials. The landmark Food and Drug Administration approval of sipuleucel-T for asymptomatic or minimally symptomatic metastatic prostate cancer set the stage for ongoing phase III trials with the cancer vaccine PSA-TRICOM and the immune checkpoint inhibitor ipilimumab. A common feature of these immune-based therapies is the appearance of improved overall survival without short-term changes in disease progression. This class effect appears to be due to modulation of tumor growth rate kinetics, in which the activated immune system exerts constant immunologic pressure that slows net tumor growth. Emerging data suggest that the ideal population for clinical trials of cancer vaccines is patients with lower tumor volume and less aggressive disease. Combination strategies that combine immunotherapy with standard therapies have been shown to augment both immune response and clinical beneift.

  8. Therapeutic cancer vaccines and combination immunotherapies involving vaccination

    OpenAIRE

    Nguyen T; Urban J.; Kalinski P

    2014-01-01

    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 &...

  9. HLA ligandomics identifies histone deacetylase 1 as target for ovarian cancer immunotherapy

    Science.gov (United States)

    Peper, Janet Kerstin; Bösmüller, Hans-Christian; Schuster, Heiko; Gückel, Brigitte; Hörzer, Helen; Roehle, Kevin; Schäfer, Richard; Wagner, Philipp; Rammensee, Hans-Georg; Stevanović, Stefan; Fend, Falko; Staebler, Annette

    2016-01-01

    abstract The recent approval of clincially effective immune checkpoint inhibitors illustrates the potential of cancer immunotherapy. A challenging task remains the identification of specific targets guiding immunotherapy. Facilitated by technical advances, the direct identification of physiologically relevant targets is enabled by analyzing the HLA ligandome of cancer cells. Since recent publications demonstrate the immunogenicity of ovarian cancer (OvCa), immunotherapies, including peptide-based cancer vaccines, represent a promising treatment approach. To identify vaccine peptides, we employed a combined strategy of HLA ligandomics in high-grade serous OvCa samples and immunogenicity analysis. Only few proteins were naturally presented as HLA ligands on all samples analyzed, including histone deacetylase (HDAC) 1 and 2. In vitro priming of CD8+ T cells demonstrated that two HDAC1/2-derived HLA ligands can induce T-cell responses, capable of killing HLA-matched tumor cells. High HDAC1 expression shown by immunohistochemistry in 136 high-grade serous OvCa patients associated with significantly reduced overall survival (OS), whereas patients with high numbers of CD3+ tumor-infiltrating lymphocytes (TILs) in the tumor epithelium and CD8+ TILs in the tumor stroma showed improved OS. However, correlating HDAC1 expression with TILs, high levels of TILs abrogated the impact of HDAC1 on OS. This study strengthens the role of HDAC1/2 as an important tumor antigen in OvCa, demonstrating its impact on OS in a large cohort of OvCa patients. We further identified two immunogenic HDAC1-derived peptides, which frequently induce multi-functional T-cell responses in many donors, suitable for future multi-peptide vaccine trials in OvCa patients.

  10. Advances in immunotherapy for treatment of lung cancer

    International Nuclear Information System (INIS)

    Different approaches for treating lung cancer have been developed over time, including chemotherapy, radiotherapy and targeted therapies against activating mutations. Lately, better understanding of the role of the immunological system in tumor control has opened multiple doors to implement different strategies to enhance immune response against cancer cells. It is known that tumor cells elude immune response by several mechanisms. The development of monoclonal antibodies against the checkpoint inhibitor programmed cell death protein 1 (PD-1) and its ligand (PD-L1), on T cells, has led to high activity in cancer patients with long lasting responses. Nivolumab, an anti PD-1 inhibitor, has been recently approved for the treatment of squamous cell lung cancer patients, given the survival advantage demonstrated in a phase III trial. Pembrolizumab, another anti PD-1 antibody, has received FDA breakthrough therapy designation for treatment of non-small cell lung cancer (NSCLC), supported by data from a phase I trial. Clinical trials with anti PD-1/PD-L1 antibodies in NSCLC have demonstrated very good tolerability and activity, with response rates around 20% and a median duration of response of 18 months

  11. Advances in immunotherapy for treatment of lung cancer

    Institute of Scientific and Technical Information of China (English)

    Jean G Bustamante Alvarez; Mara Gonzlez-Cao; Niki Karachaliou; Mariacarmela Santarpia; Santiago Viteri; Cristina Teixid; Rafael Rosell

    2015-01-01

    Different approaches for treating lung cancer have been developed over time, including chemotherapy, radiotherapy and targeted therapies against activating mutations. Lately, better understanding of the role of the immunological system in tumor control has opened multiple doors to implement different strategies to enhance immune response against cancer cells. It is known that tumor cells elude immune response by several mechanisms. The development of monoclonal antibodies against the checkpoint inhibitor programmed cell death protein 1 (PD-1) and its ligand (PD-L1), on T cells, has led to high activity in cancer patients with long lasting responses. Nivolumab, an anti PD-1 inhibitor, has been recently approved for the treatment of squamous cell lung cancer patients, given the survival advantage demonstrated in a phase III trial. Pembrolizumab, another anti PD-1 antibody, has received FDA breakthrough therapy designation for treatment of non-small cell lung cancer (NSCLC), supported by data from a phase I trial. Clinical trials with anti PD-1/PD-L1 antibodies in NSCLC have demonstrated very good tolerability and activity, with response rates around 20% and a median duration of response of 18 months.

  12. Structure and Cancer Immunotherapy of the B7 Family Member B7x

    Directory of Open Access Journals (Sweden)

    Hyungjun Jeon

    2014-11-01

    Full Text Available B7x (B7-H4 or B7S1 is a member of the B7 family that can inhibit T cell function. B7x protein is absent in most normal human tissues and immune cells, but it is overexpressed in human cancers and often correlates with negative clinical outcome. The expression pattern and function of B7x suggest that it may be a potent immunosuppressive pathway in human cancers. Here, we determined the crystal structure of the human B7x immunoglobulin variable (IgV domain at 1.59 Å resolution and mapped the epitopes recognized by monoclonal antibodies. We developed an in vivo system to screen therapeutic monoclonal antibodies against B7x and found that the clone 1H3 significantly inhibited growth of B7x-expressing tumors in vivo via multiple mechanisms. Furthermore, the surviving mice given 1H3 treatment were resistant to tumor rechallenge. Our data suggest that targeting B7x on tumors is a promising cancer immunotherapy and humanized 1H3 may be efficacious for immunotherapy of human cancers.

  13. Cancer immunotherapy via combining oncolytic virotherapy with chemotherapy: recent advances

    Directory of Open Access Journals (Sweden)

    Simpson GR

    2016-01-01

    Full Text Available Guy R Simpson,1 Kate Relph,1 Kevin Harrington,2 Alan Melcher,3 Hardev Pandha1 1Department of Clinical and Experimental Medicine, Targeted Cancer Therapy, Faculty of Health and Medical Sciences, University of Surrey, Guildford, 2Targeted Therapy, The Institute of Cancer Research/The Royal Marsden NIHR Biomedical Research Centre, London, 3Targeted and Biological Therapies,Oncology and Clinical Research, Leeds Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, Leeds, UK Abstract: Oncolytic viruses are multifunctional anticancer agents with huge clinical potential, and have recently passed the randomized Phase III clinical trial hurdle. Both wild-type and engineered viruses have been selected for targeting of specific cancers, to elicit cytotoxicity, and also to generate antitumor immunity. Single-agent oncolytic virotherapy treatments have resulted in modest effects in the clinic. There is increasing interest in their combination with cytotoxic agents, radiotherapy and immune-checkpoint inhibitors. Similarly to oncolytic viruses, the benefits of chemotherapeutic agents may be that they induce systemic antitumor immunity through the induction of immunogenic cell death of cancer cells. Combining these two treatment modalities has to date resulted in significant potential in vitro and in vivo synergies through various mechanisms without any apparent additional toxicities. Chemotherapy has been and will continue to be integral to the management of advanced cancers. This review therefore focuses on the potential for a number of common cytotoxic agents to be combined with clinically relevant oncolytic viruses. In many cases, this combined approach has already advanced to the clinical trial arena. Keywords: oncolytic virotherapy, chemotherapy, immunogenic cell death

  14. Optimal control on bladder cancer growth model with BCG immunotherapy and chemotherapy

    Science.gov (United States)

    Dewi, C.; Trisilowati

    2015-03-01

    In this paper, an optimal control model of the growth of bladder cancer with BCG (Basil Calmate Guerin) immunotherapy and chemotherapy is discussed. The purpose of this optimal control is to determine the number of BCG vaccine and drug should be given during treatment such that the growth of bladder cancer cells can be suppressed. Optimal control is obtained by applying Pontryagin principle. Furthermore, the optimal control problem is solved numerically using Forward-Backward Sweep method. Numerical simulations show the effectiveness of the vaccine and drug in controlling the growth of cancer cells. Hence, it can reduce the number of cancer cells that is not infected with BCG as well as minimize the cost of the treatment.

  15. Targeting Foxp3+ regulatory T cells-related immunosuppression for cancer immunotherapy

    Institute of Scientific and Technical Information of China (English)

    FENG Li-li; WANG Xin

    2010-01-01

    Objective To review the current research into Foxp3+ regulatory T cells (Treg) cell surface molecules, plasticity of Treg cells and mechanisms of Treg cell suppression and to explore the possibilities to interfere in Treg cell suppression of anti-tumor immunity.Data sources A literature search of all English articles was performed on the online electronic PubMed database dated 1995 to 2010. The keywords searched included: CD4+CD25+Foxp3+ regulatory T lymphocytes, cancer, and immunotherapy. After finding relevant articles within these search limits, a manual search was conducted through the references from these articles.Study selection Articles regarding the role of Treg cells in tumor immunity and the utility of Treg cells in tumor immunotherapy.Results The results show that significant numbers of Treg cells are found in many tumors and it has been shown that the number of tumor infiltrating Treg cells correlates with adverse clinic outcomes. Treg cells are emerging as a key component of acquired tolerance to tumors.Conclusions Several mechanisms of immunosuppression can be mediated by Treg cell function. Distinct immunosuppressive molecules expressed by Treg cells or diverse molecules related to Treg induction or migration represent potential drug targets for caner immunotherapy.

  16. Lung cancer-associated tumor antigens and the present status of immunotherapy against non-small-cell lung cancer

    International Nuclear Information System (INIS)

    Despite recent advances in surgery, irradiation, and chemotherapy, the prognosis of patients with lung cancer is still poor. Therefore, the development and application of new therapeutic strategies are essential for improving the prognosis of this disease. Significant progress in our understanding of tumor immunology and molecular biology has allowed us to identify the tumor-associated antigens recognized by cytotoxic T lymphocytes. Immune responses and tumor-associated antigens against not only malignant melanoma but also lung cancer have been elucidated at the molecular level. In a theoretical sense, tumor eradication is considered possible through antigen-based immunotherapy against such diseases. However, many clinical trials of cancer vaccination with defined tumor antigens have resulted in objective clinical responses in only a small number of patients. Tumor escape mechanisms from host immune surveillance remain a major obstacle for cancer immunotherapy. A better understanding of the immune escape mechanisms employed by tumor cells is necessary before we can develop a more effective immunotherapeutic approach to lung cancer. We review recent studies regarding the identification of tumor antigens in lung cancer, tumor immune escape mechanisms, and clinical vaccine trials in lung cancer. (author)

  17. Rationale for a Multimodality Strategy to Enhance the Efficacy of Dendritic Cell-Based Cancer Immunotherapy.

    Science.gov (United States)

    Datta, Jashodeep; Berk, Erik; Cintolo, Jessica A; Xu, Shuwen; Roses, Robert E; Czerniecki, Brian J

    2015-01-01

    Dendritic cells (DC), master antigen-presenting cells that orchestrate interactions between the adaptive and innate immune arms, are increasingly utilized in cancer immunotherapy. Despite remarkable progress in our understanding of DC immunobiology, as well as several encouraging clinical applications - such as DC-based sipuleucel-T for metastatic castration-resistant prostate cancer - clinically effective DC-based immunotherapy as monotherapy for a majority of tumors remains a distant goal. The complex interplay between diverse molecular and immune processes that govern resistance to DC-based vaccination compels a multimodality approach, encompassing a growing arsenal of antitumor agents which target these distinct processes and synergistically enhance DC function. These include antibody-based targeted molecular therapies, immune checkpoint inhibitors, therapies that inhibit immunosuppressive cellular elements, conventional cytotoxic modalities, and immune potentiating adjuvants. It is likely that in the emerging era of "precision" cancer therapeutics, tangible clinical benefits will only be realized with a multifaceted - and personalized - approach combining DC-based vaccination with adjunctive strategies. PMID:26082780

  18. Rationale for a multimodality strategy to enhance the efficacy of dendritic cell-based cancer immunotherapy

    Directory of Open Access Journals (Sweden)

    Jashodeep eDatta

    2015-06-01

    Full Text Available Dendritic cells (DC, master antigen-presenting cells that orchestrate interactions between the adaptive and innate immune arms, are increasingly utilized in cancer immunotherapy. Despite remarkable progress in our understanding of DC immunobiology, as well as several encouraging clinical applications — such as DC-based sipuleucel-T for metastatic castration-resistant prostate cancer — clinically effective DC-based immunotherapy as monotherapy for a majority of tumors remains a distant goal. The complex interplay between diverse molecular and immune processes that govern resistance to DC-based vaccination compels a multimodality approach, encompassing a growing arsenal of antitumor agents which target these distinct processes and synergistically enhance DC function. These include antibody-based targeted molecular therapies, immune checkpoint inhibitors, therapies that inhibit immunosuppressive cellular elements, conventional cytotoxic modalities, and immune potentiating adjuvants. It is likely that in the emerging era of precision cancer therapeutics, tangible clinical benefits will only be realized with a multifaceted—and personalized—approach combining DC-based vaccination with adjunctive strategies.

  19. The rationale for combined chemo/immunotherapy using a Toll-like receptor 3 (TLR3) agonist and tumour-derived exosomes in advanced ovarian cancer.

    Science.gov (United States)

    Adams, M; Navabi, H; Croston, D; Coleman, S; Tabi, Z; Clayton, A; Jasani, B; Mason, M D

    2005-03-18

    A clinical trial employing an immunotherapeutic approach based on the use of a Toll-like receptor 3 (TLR3) agonist and tumour-derived exosomes carrying tumour-associated antigens is planned in advanced ovarian cancer in conjunction with conventional first line chemotherapy. Most patients with ovarian cancer present with advanced disease and despite high initial response rate to chemotherapy the majority will relapse within 2 years with poor overall survival. Tumour antigen-specific T cells are naturally occurring in ovarian cancer patients and T cell infiltration of the tumour is highly prognostic. Novel immunotherapy to expand and activate tumour antigen-specific T cells combined with adjuvant treatment to overcome tumour-induced immunosuppression is considered to be therapeutically beneficial. The rationale for adopting such a combined approach is discussed here. PMID:15755631

  20. Dendritic Cells as Vectors for Immunotherapy of Tumor and Its Application for Gastric Cancer Therapy

    Institute of Scientific and Technical Information of China (English)

    YugangWu; LiangWang; YanyunZhang

    2004-01-01

    Dendritic cells (DCs) are recognized as the most potent antigen-presenting cells (APCs) with the ability to stimulate naive resting T cells and initiate primary immune responses. DCs are poised to capture antigen (Ag),migrate to draining lymphoid organs, and, after a process of maturation, select Ag-specific lymphocytes to which they present the processed Ag, thereby inducing immune responses. Numerous studies indicated that immunotherapies utilizing DC-presenting tumor-associated antigens can safely be administered to cancer patients and induce significant immunologic and clinical responses. Moreover, it has been demonstrated that DCs are related to clinical stage, invasion, metastasis and prognosis of gastric cancer. DC-based tumor vaccines become a new effective immunoadjuvant therapy for gastric cancer. Cellular & Molecular Immunology. 2004;1(5):351-356.

  1. Effects of cyclophosphamide on laser immunotherapy for the treatment of metastatic cancer

    Science.gov (United States)

    Bahavar, Cody F.; Acquaviva, Joseph T.; Rabei, Sheyla; Sikes, Allie; Nordquist, Robert E.; Hode, Tomas; Liu, Hong; Chen, Wei R.

    2014-02-01

    Laser immunotherapy (LIT) is an innovative cancer modality that uses laser irradiation and immunological stimulation to treat late-stage, metastatic cancers. The current mode of operation in LIT is through interstitial laser irradiation. Although LIT is still in development, recent clinical trials have shown that it can be used to successfully treat patients with late-stage breast cancer and melanoma. Cyclophosphamide is a chemotherapy drug that suppresses regulatory T cells when used in low doses. In this study tumor-bearing rats were treated with LIT using an 805-nm laser with a power of 2.0 W and low-dose cyclophosphamide. Glycated chitosan was used as an immunological stimulant. The goal was to observe the effects of different doses of cyclophosphamide in addition to LIT on the survival of the tumor-bearing rats.

  2. Interferon Lambda: A New Sword in Cancer Immunotherapy

    Directory of Open Access Journals (Sweden)

    Ahmed Lasfar

    2011-01-01

    Full Text Available The discovery of the interferon-lambda (IFN-λ family has considerably contributed to our understanding of the role of interferon not only in viral infections but also in cancer. IFN-λ proteins belong to the new type III IFN group. Type III IFN is structurally similar to type II IFN (IFN-γ but functionally identical to type I IFN (IFN-α/β. However, in contrast to type I or type II IFNs, the response to type III IFN is highly cell-type specific. Only epithelial-like cells and to a lesser extent some immune cells respond to IFN-λ. This particular pattern of response is controlled by the differential expression of the IFN-λ receptor, which, in contrast to IFN-α, should result in limited side effects in patients. Recently, we and other groups have shown in several animal models a potent antitumor role of IFN-λ that will open a new challenging era for the current IFN therapy.

  3. Immunotherapy of murine bladder cancer by irradiated tumor vaccine

    Energy Technology Data Exchange (ETDEWEB)

    Lamm, D.L.; Riggs, D.R.; DeHaven, J.I.; Bryner, R.W. (West Virginia Univ. School of Medicine, Morgantown (USA))

    1991-01-01

    This investigation explored the efficacy of irradiated autologous mouse bladder tumor (Ir-MBT2) as an active specific immunotherapeutic agent and as adjuvant therapy with Bacillus Calmette-Guerin (BCG) against a subcutaneously transplanted murine bladder tumor. Tumor incidence was significantly reduced in groups receiving BCG (27%, p less than 0.005) or Ir-MBT2 with BCG (53%, p less than 0.025), compared to control (93%). Survival was significantly improved in groups treated with BCG (100%, p less than 0.005), 10(5) Ir-MBT2 with BCG (53%, p less than 0.01), or 10(7) Ir-MBT2 with BCG (47%, p less than 0.025) compared with control (13%). Surprisingly, Ir-MBT2 consistently reduced the efficacy of BCG alone. Ir-MBT2 alone (10(7)) appeared to enhance tumor growth. Autologous irradiated bladder tumor vaccine, alone or in combination with BCG, displayed no immunotherapeutic advantage. The use of irradiated tumor cell vaccine for bladder cancer therapy may reduce the results achievable with BCG alone.

  4. Immunotherapy of murine bladder cancer by irradiated tumor vaccine

    International Nuclear Information System (INIS)

    This investigation explored the efficacy of irradiated autologous mouse bladder tumor (Ir-MBT2) as an active specific immunotherapeutic agent and as adjuvant therapy with Bacillus Calmette-Guerin (BCG) against a subcutaneously transplanted murine bladder tumor. Tumor incidence was significantly reduced in groups receiving BCG (27%, p less than 0.005) or Ir-MBT2 with BCG (53%, p less than 0.025), compared to control (93%). Survival was significantly improved in groups treated with BCG (100%, p less than 0.005), 10(5) Ir-MBT2 with BCG (53%, p less than 0.01), or 10(7) Ir-MBT2 with BCG (47%, p less than 0.025) compared with control (13%). Surprisingly, Ir-MBT2 consistently reduced the efficacy of BCG alone. Ir-MBT2 alone (10(7)) appeared to enhance tumor growth. Autologous irradiated bladder tumor vaccine, alone or in combination with BCG, displayed no immunotherapeutic advantage. The use of irradiated tumor cell vaccine for bladder cancer therapy may reduce the results achievable with BCG alone

  5. Metastatic squamous cell non-small-cell lung cancer (NSCLC): disrupting the drug treatment paradigm with immunotherapies

    OpenAIRE

    Scarpace, Sarah L

    2015-01-01

    Lung cancer is the third most commonly diagnosed cancer and the leading cause of cancer-related death in the United States. Unlike non-squamous NSCLC, squamous NSCLC rarely harbor epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations for which there are directed therapies, and until the recent approval of immunotherapies for squamous NSCLC, a limited number of traditional cytotoxic chemotherapy drugs have been FDA-approved for use in the treatment of advanced ...

  6. Ribavirin in Cancer Immunotherapies: Controlling Nitric Oxide Augments Cytotoxic Lymphocyte Function

    Directory of Open Access Journals (Sweden)

    Richard E. Kast

    2003-01-01

    Full Text Available Either ribavirin (RBV or cyclophosphamide (CY can shift an immune response from Th2 toward a Thi cytokine profile. CY is used in this role in various current cancer immunotherapy attempts but with mixed success. More potent and reliable immunoadjuvants and Th1 response biasing methods are needed. RBV is used today mainly to augment interferon-alpha treatment of hepatitis C. RBV shifts an immune response from Th2 toward Th1 more effectively than CY and may be a safe and useful adjuvant for current cancer immunotherapeutic efforts. RBV is thought to act by inhibition of tetrahydrobiopterin synthesis. Tetrahydrobiopterin is an essential cofactor for all known isoforms of nitric oxide synthase. Lowered nitric oxide favors Th1 development as high levels favor Th2 weighting.

  7. Interdisciplinary critique of sipuleucel-T as immunotherapy in castration-resistant prostate cancer

    DEFF Research Database (Denmark)

    Huber, Marie L; Haynes, Laura; Parker, Chris;

    2012-01-01

    Sipuleucel-T was approved by the US Food and Drug Administration on April 29, 2010, as an immunotherapy for late-stage prostate cancer. To manufacture sipuleucel-T, mononuclear cells harvested from the patient are incubated with a recombinant prostatic acid phosphatase (PAP) antigen and reinfused...... 4-month survival benefit. Previously unpublished data from the sipuleucel-T trials show worse overall survival in older vs younger patients in the placebo groups, which have not been shown previously to be prognostic for survival in castration-resistant prostate cancer patients receiving...... chemotherapy. Because two-thirds of the cells harvested from placebo patients, but not from the sipuleucel-T arm, were frozen and not reinfused, a detrimental effect of this large repeated cell loss provides a potential alternative explanation for the survival "benefit." Patient safety depends on adequately...

  8. Sipuleucel-T: Autologous Cellular Immunotherapy for Men with Asymptomatic or Minimally Symptomatic Metastatic Castrate Resistant Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Robert B. Sims

    2011-01-01

    Full Text Available Sipuleucel T is an autologous cellular immunotherapy designed to stimulate an immune response in men diagnosed with asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory prostate cancer. Sipuleucel T improves overall survival and provides an additional treatment option for this patient population.

  9. Enhanced NK cell adoptive antitumor effects against breast cancer in vitro via blockade of the transforming growth factor-β signaling pathway

    Directory of Open Access Journals (Sweden)

    Zhao Y

    2015-06-01

    Full Text Available Yue Zhao,1,* Jinyue Hu,2,* Rongguo Li,1 Jian Song,1 Yujuan Kang,1 Si Liu,1 Dongwei Zhang1 1Department of General Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, 2Department of Breast and Thyroid Surgery, The Third Hospital of Zhengzhou, Zhengzhou, People’s Republic of China *These authors contributed equally to this work Abstract: Natural killer (NK cells have great potential for improving cancer immunotherapy. Adoptive NK cell transfer, an adoptive immunotherapy, represents a promising nontoxic anticancer therapy. However, existing data indicate that tumor cells can effectively escape NK cell-mediated apoptosis through immunosuppressive effects in the tumor microenvironment, and the therapeutic activity of adoptive NK cell transfer is not as efficient as anticipated. Transforming growth factor-beta (TGF-β is a potent immunosuppressant. Genetic and epigenetic events that occur during mammary tumorigenesis circumvent the tumor-suppressing activity of TGF-β, thereby permitting late-stage breast cancer cells to acquire an invasive and metastatic phenotype in response to TGF-β. To block the TGF-β signaling pathway, NK cells were genetically modified with a dominant-negative TGF-β type II receptor by optimizing electroporation using the Amaxa Nucleofector system. These genetically modified NK cells were insensitive to TGF-β and resisted the suppressive effect of TGF-β on MCF-7 breast cancer cells in vitro. Our results demonstrate that blocking the TGF-β signaling pathway to modulate the tumor microenvironment can improve the antitumor activity of adoptive NK cells in vitro, thereby providing a new rationale for the treatment of breast cancer. Keywords: transforming growth factor-beta, natural killer cells, breast cancer, adoptive immunotherapy

  10. NEW METHODS FOR PREDICTING THE SENSITIVITY OF RENAL CANCER TO IMMUNOTHERAPY ON THE BASIS OF ANALYSIS OF MOLECULAR GENETIC CHARACTERISTICS OF A TUMOR

    Directory of Open Access Journals (Sweden)

    M. T. Aivazov

    2014-07-01

    Full Text Available The paper reviews the literature on the treatment of renal cancer, mainly on postoperative immunotherapy. It outlines a role of cytokines in tumor-immune system interaction, the prognostic value of the level of expression of each cytokine for both survival rates and the efficiency of immunotherapy, as well as the use of this information to develop new therapeutic approaches.

  11. Proteogenomic-based discovery of minor histocompatibility antigens with suitable features for immunotherapy of hematologic cancers.

    Science.gov (United States)

    Granados, D P; Rodenbrock, A; Laverdure, J-P; Côté, C; Caron-Lizotte, O; Carli, C; Pearson, H; Janelle, V; Durette, C; Bonneil, E; Roy, D C; Delisle, J-S; Lemieux, S; Thibault, P; Perreault, C

    2016-06-01

    Pre-clinical studies have shown that injection of allogeneic T cells primed against a single minor histocompatibility antigen (MiHA) could cure hematologic cancers (HC) without causing any toxicity to the host. However, translation of this approach in humans has been hampered by the paucity of molecularly defined human MiHAs. Using a novel proteogenomic approach, we have analyzed cells from 13 volunteers and discovered a vast repertoire of MiHAs presented by the most common HLA haplotype in European Americans: HLA-A*02:01;B*44:03. Notably, out of >6000 MiHAs, we have identified a set of 39 MiHAs that share optimal features for immunotherapy of HCs. These 'optimal MiHAs' are coded by common alleles of genes that are preferentially expressed in hematopoietic cells. Bioinformatic modeling based on MiHA allelic frequencies showed that the 39 optimal MiHAs would enable MiHA-targeted immunotherapy of practically all HLA-A*02:01;B*44:03 patients. Further extension of this strategy to a few additional HLA haplotypes would allow treatment of almost all patients. PMID:26857467

  12. Combined treatment of syngeneic murine tumors and xenotransplanted human lung cancer by immunotherapy and radiotherapy

    International Nuclear Information System (INIS)

    The synergistic effect of nonspecific immunotherapy with cell-wall skeleton of BCG on radiotherapy against two syngeneic murine tumors, a methylcho-lanthrene-induced tumor (MCA) and a spontaneous well-differentiated mammary adenocarcinoma (Br-1), was studied in (+/+) BALB/c mice and (nu/nu) mice of BALB/c background. Single irradiation of tumors with a dose of 2000 rad induced complete shrinkage in about 18% of MCA and Br-1 tumors in (+/+) mice. Single irradiation did not induce complete shrinkage of tumors in (nu/nu) mice. When immunotherapy was combined with radiotherapy, the rates of complete shrinkage of MCA and Br-1 tumors increased to 82 and 61%, respectively. In contrast, such a strong synergistic effect was not observed in (nu/nu) mice. Moreover, human lung cancers (two squamous cell carcinomas and two small cell carcinomas) xenotransplanted to nude mice were treated with the combined therapy. The effect was stronger on squamous cell carcinomas than on small cell carcinomas. (author)

  13. Utilizing Cytokines to Function-Enable Human NK Cells for the Immunotherapy of Cancer

    Directory of Open Access Journals (Sweden)

    Rizwan Romee

    2014-01-01

    Full Text Available Natural killer (NK cells are innate lymphoid cells important for host defense against pathogens and mediate antitumor immunity. Cytokine receptors transduce important signals that regulate proliferation, survival, activation status, and trigger effector functions. Here, we review the roles of major cytokines that regulate human NK cell development, survival, and function, including IL-2, IL-12, IL-15, IL-18, and IL-21, and their translation to the clinic as immunotherapy agents. We highlight a recent development in NK cell biology, the identification of innate NK cell memory, and focus on cytokine-induced memory-like (CIML NK cells that result from a brief, combined activation with IL-12, IL-15, and IL-18. This activation results in long lived NK cells that exhibit enhanced functionality when they encounter a secondary stimulation and provides a new approach to enable NK cells for enhanced responsiveness to infection and cancer. An improved understanding of the cellular and molecular aspects of cytokine-cytokine receptor signals has led to a resurgence of interest in the clinical use of cytokines that sustain and/or activate NK cell antitumor potential. In the future, such strategies will be combined with negative regulatory signal blockade and enhanced recognition to comprehensively enhance NK cells for immunotherapy.

  14. 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.

  15. Sarcoma Immunotherapy

    International Nuclear Information System (INIS)

    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

  16. Adoptive T-cell Immunotherapy from third-party donors: Characterization of donors and set up of a T-cell donor registry

    Directory of Open Access Journals (Sweden)

    Britta eEiz-Vesper

    2013-01-01

    Full Text Available Infection with and reactivation of human cytomegalovirus (CMV, Epstein-Barr virus (EBV, and adenovirus (ADV are frequent and severe complications in immunocompromised recipients after hematopoietic stem cell transplantation (HSCT or solid organ transplantation (SOT. These serious adverse events are associated with significant morbidity and mortality. Donor lymphocyte infusions (DLIs are often used to treat both viral infections and leukemia relapses after transplantation but are associated with potentially life-threatening graft-versus-host disease (GvHD. Adoptive immunotherapy with virus-specific cytotoxic effector T cells (CTLs derived from seropositive donors can rapidly reconstitute antiviral immunity after HSCT and organ transplantation. Therefore, it can effectively prevent the clinical manifestation of these viruses with no significant acute toxicity or increased risk of GvHD. In conditions, where patients receiving an allogeneic cord blood transplant or a transplant from a virus-seronegative donor and since donor blood is generally not available for solid organ recipients, allogeneic third party T-cell donors would offer an alternative option. Recent studies showed that during granulocyte colony-stimulating factor (G-CSF mobilization, the functional activity of antiviral memory T cells is impaired for a long period. This finding suggests that even stem cell donors may not be the best source of T cells.Under these circumstances, partially human leukocyte antigen (HLA-matched virus-specific CTLs from healthy seropositive individuals may be a promising option. Therefore frequency assessments of virus-specific memory T cells in HLA-typed healthy donors as well as in HSCT/SOT donors using a high throughput T-cell assay were performed over a period of 4 years at Hannover Medical School. This chapter will address the relevance and potential of a third-party T-cell donor registry and will discuss its clinical implication for adoptive T

  17. Role of levamisole immunotherapy as an adjuvant to radiotherapy in oral cancer - Immune responses

    International Nuclear Information System (INIS)

    Investigations were carried out to assess the effect of levamisole immunotherapy as an adjuvant to radiotherapy, on the immune response of patients with squamous cell carcinoma of the oral cavity. Parameters assessed were leukocyte migration inhibition, response to PPD and oral cancer extract (OCA), lymphocyte transformation to PHA, circulating antibodies to OCA and circulating immune complexes (CIC). Comparisons were made between groups receiving levamisole, those receiving placebo and normal controls. The results of a thirty-month follow-up are presented. Radiotherapy resulted in a depression of cell-mediated functions, reduction in antibody titre also showed a gradual increase with time of follow-up. Levamisole, however, appeared to reduce the levels of CIC. (author). 2 figs., 1 tab., 38 refs

  18. New strategies in advanced cervical cancer: from angiogenesis blockade to immunotherapy.

    Science.gov (United States)

    Tewari, Krishnansu S; Monk, Bradley J

    2014-11-01

    Cervical cancer remains unique among solid tumor malignancies. Persistent infection with oncogenic subtypes of the human papillomavirus (HPV) results in carcinogenesis, predominantly occurring at the cervical transformation zone where endocervical columnar cells undergo metaplasia to a stratified squamous epithelium. The molecular cascade involving viral oncoproteins, E6 and E7 and their degradative interactions with cellular tumor suppressor gene products, p53 and pRb, respectively, has been precisely delineated. The precursor state of cervical neoplasia may last for years allowing for ready detection through successful screening programs in developed countries using cervical cytology and/or high-risk HPV DNA testing. Prophylactic HPV L1 capsid protein vaccines using virus-like-particle technology have been developed to prevent primary infection by the most common high-risk HPVs (16 and 18). Women who lack access to health care and those who undergo sporadic screening remain at risk. Although radical surgery (including fertility-sparing surgery) is available for patients with early-stage cancers, and chemoradiation plus high-dose-rate brachytherapy can cure the majority of those with locally advanced disease, patients with metastatic and nonoperable recurrent cervical cancer constitute a high-risk population with an unmet clinical need. On August 14, 2014, the FDA approved the antiangiogenesis drug bevacizumab for women with advanced cervical cancer. This review will highlight advances in translational science, antiangiogenesis therapy and immunotherapy for advanced disease. PMID:25104084

  19. Doxil Synergizes with Cancer Immunotherapies to Enhance Antitumor Responses in Syngeneic Mouse Models

    Directory of Open Access Journals (Sweden)

    Jonathan Rios-Doria

    2015-08-01

    Full Text Available Based on the previously described roles of doxorubicin in immunogenic cell death, both doxorubicin and liposomal doxorubicin (Doxil were evaluated for their ability to boost the antitumor response of different cancer immunotherapies including checkpoint blockers (anti–PD-L1, PD-1, and CTLA-4 mAbs and TNF receptor agonists (OX40 and GITR ligand fusion proteins in syngeneic mouse models. In a preventative CT26 mouse tumor model, both doxorubicin and Doxil synergized with anti–PD-1 and CTLA-4 mAbs. Doxil was active when CT26 tumors were grown in immunocompetent mice but not immunocompromised mice, demonstrating that Doxil activity is increased in the presence of a functional immune system. Using established tumors and maximally efficacious doses of Doxil and cancer immunotherapies in either CT26 or MCA205 tumor models, combination groups produced strong synergistic antitumor effects, a larger percentage of complete responders, and increased survival. In vivo pharmacodynamic studies showed that Doxil treatment decreased the percentage of tumor-infiltrating regulatory T cells and, in combination with anti–PD-L1, increased the percentage of tumor-infiltrating CD8+ T cells. In the tumor, Doxil administration increased CD80 expression on mature dendritic cells. CD80 expression was also increased on both monocytic and granulocytic myeloid cells, suggesting that Doxil may induce these tumor-infiltrating cells to elicit a costimulatory phenotype capable of activating an antitumor T-cell response. These results uncover a novel role for Doxil in immunomodulation and support the use of Doxil in combination with checkpoint blockade or TNFR agonists to increase response rates and antitumor activity.

  20. Deciphering CD137 (4-1BB) signaling in T-cell costimulation for translation into successful cancer immunotherapy.

    Science.gov (United States)

    Sanchez-Paulete, Alfonso R; Labiano, Sara; Rodriguez-Ruiz, Maria E; Azpilikueta, Arantza; Etxeberria, Iñaki; Bolaños, Elixabet; Lang, Valérie; Rodriguez, Manuel; Aznar, M Angela; Jure-Kunkel, Maria; Melero, Ignacio

    2016-03-01

    CD137 (4-1BB, TNF-receptor superfamily 9) is a surface glycoprotein of the TNFR family which can be induced on a variety of leukocyte subsets. On T and NK cells, CD137 is expressed following activation and, if ligated by its natural ligand (CD137L), conveys polyubiquitination-mediated signals via TNF receptor associated factor 2 that inhibit apoptosis, while enhancing proliferation and effector functions. CD137 thus behaves as a bona fide inducible costimulatory molecule. These functional properties of CD137 can be exploited in cancer immunotherapy by systemic administration of agonist monoclonal antibodies, which increase anticancer CTLs and enhance NK-cell-mediated antibody-dependent cell-mediated cytotoxicity. Reportedly, anti-CD137 mAb and adoptive T-cell therapy strongly synergize, since (i) CD137 expression can be used to select the T cells endowed with the best activities against the tumor, (ii) costimulation of the lymphocyte cultures to be used in adoptive T-cell therapy can be done with CD137 agonist antibodies or CD137L, and (iii) synergistic effects upon coadministration of T cells and antibodies are readily observed in mouse models. Furthermore, the signaling cytoplasmic tail of CD137 is a key component of anti-CD19 chimeric antigen receptors that are used to redirect T cells against leukemia and lymphoma in the clinic. Ongoing phase II clinical trials with agonist antibodies and the presence of CD137 sequence in these successful chimeric antigen receptors highlight the importance of CD137 in oncoimmunology. PMID:26773716

  1. Current status of immunotherapy for non-small-cell lung cancer.

    Science.gov (United States)

    Imbimbo, Martina; Lo Russo, Giuseppe; Blackhall, Fiona

    2016-08-01

    In the last few years, the introduction of novel immunotherapeutic agents has represented a treatment shift for a subset of patients with non-small-cell lung cancer (NSCLC). Checkpoint inhibitors have been demonstrated to improve survival in advanced stage disease with very good tolerability. This success follows many years of scientific effort to manipulate the human immune system to attack cancer cells. With a variety of approaches ranging from vaccines to administration of interleukin or interferon-γ, the results in NSCLC were unsuccessful, with the view that it is a scarcely immunogenic cancer, unlike melanoma or renal cell carcinoma. The step change has come from understanding of immune checkpoints-cell surface molecules that regulate immune system activation and mediate coinhibitory signaling pathways that physiologically protect the body from autoimmunity. These pathways play an important role in tumors, including NSCLC, and are a mechanism of escape from immune surveillance. Several monoclonal antibodies have been developed in order to inhibit these molecules and unleash the brakes of the immune system. Currently in NSCLC, 7 different checkpoint inhibitors are under investigation: 2 anti-cytotoxic T-lymphocyte-associated antigen 4, 2 anti-programmed death (PD)-1, and 3 anti-PD-ligand 1 antibodies. Here we review the progress to date in developing immunotherapy for NSCLC, summarize results from published trials, highlight ongoing trials, and discuss progress in the question of how best to select patients for this treatment. PMID:27443896

  2. IMRT reirradiation with concurrent cetuximab immunotherapy in recurrent head and neck cancer

    Energy Technology Data Exchange (ETDEWEB)

    Zwicker, Felix; Roeder, Falk; Thieke, Christian; Timke, Carmen; Huber, Peter E. [Heidelberg Univ. (Germany). Dept. of Radiation Oncology; Deutsches Krebsforschungszentrum (DKFZ), Heidelberg (Germany). Div. of Radiation Oncology; Muenter, Marc W.; Debus, Juergen [Heidelberg Univ. (Germany). Dept. of Radiation Oncology

    2011-01-15

    Purpose: In this retrospective investigation, the outcome and toxicity after reirradiation with concurrent cetuximab immunotherapy of recurrent head and neck cancer (HNC) in patients who had contraindications to platinum-based chemotherapy were analyzed. Materials and Methods: Ten patients with locally advanced recurrent HNC were retrospectively evaluated. In 9 cases, histology was squamous cell carcinoma, in one case adenoid cystic carcinoma. External beam radiotherapy was part of the initial treatment in all cases. Reirradiation was carried out using step-and-shoot intensity-modulated radiotherapy (IMRT) with a median dose of 50.4 Gy. Cetuximab was applied as loading dose (400 mg/m{sup 2}) 1 week prior to reirradiation and then weekly concurrently with radiotherapy (250 mg/m{sup 2}). Results: The median overall survival time after initiation of reirradiation was 7 months; the 1-year overall survival (OS) rate was 40%. Local failure was found in 3 patients, resulting in a 1-year local control (LC) rate of 61%. The 1-year locoregional control (LRC) rate was 44%, while the 1-year distant metastasis-free survival (DMFS) was 75%. Acute hematological toxicity was not observed in the group. Severe acute toxicity included one fatal infield arterial bleeding and one flap necrosis. Severe late toxicities were noted in 2 patients: fibrosis of the temporomandibular joint in 1 patient and stenosis of the cervical esophagus in another. Conclusions: IMRT reirradiation with concurrent cetuximab immunotherapy in recurrent HNC is feasible with acceptable acute toxicity. Further investigations are necessary to determine the clinical role of this therapy concept. (orig.)

  3. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. A systematic review and meta-analysis

    OpenAIRE

    Kawalec, Paweł; Paszulewicz, Anna; Holko, Przemysław; Pilc, Andrzej

    2012-01-01

    Introduction Sipuleucel-T is a novel active cellular immunotherapy for the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer (mCRPC). It is assumed to be associated with less adverse events than conventional docetaxel-based chemotherapy. Material and methods A systematic review of literature published between January, 1 1966 and February, 6 2012 was performed to assess the efficacy and safety of sipuleucel-T in patients with mCRPC. Databases were...

  4. Laser immunotherapy for treatment of patients with advanced breast cancer and melanoma

    Energy Technology Data Exchange (ETDEWEB)

    Li Xiaosong [Department of Oncology, the First Affiliated Hospital of Chinese PLA General Hospital, Beijing (China); Hode, Tomas; Guerra, Maria C [Immunophotonics Inc., 1601 South Providence Road, Columbia, Missouri 65211 (United States); Ferrel, Gabriela L [Hospital Nacional Edgardo Rebagliati Martins, Av. Edgardo Rebagliati 490 - Jesus Maria, Lima (Peru); Nordquist, Robert E [Wound Healing of Oklahoma, Inc., Oklahoma City, Oklahoma (United States); Chen, Wei R, E-mail: wchen@uco.edu [Department of Engineering and Physics, University of Central Oklahoma, Edmond, Oklahoma (United States)

    2011-02-01

    Laser immunotherapy (LIT) was developed for the treatment of metastatic tumors. It combines local selective photothermal interaction and active immunological stimulation to induce a long-term, systemic anti-tumor immunity. During the past sixteen years, LIT has been advanced from bench-top to bedside, with promising outcomes. In our pre-clinical and preliminary clinical studies, LIT has demonstrated the capability in inducing immunological responses, which not only can eradicate the treated primary tumors, but also can eliminate untreated metastases at distant sites. Specifically, LIT has been used to treat advanced melanoma and breast cancer patients during the past five years. LIT was shown to be effective in controlling both primary tumors and distant metastases in late-stage patients, who have failed conventional therapies such as surgery, chemotherapy, radiation, and other more advanced approaches. The methodology and the development of LIT are presented in this paper. The patients' responses to LIT are also reported in this paper. The preliminary results obtained in these studies indicated that LIT could be an effective modality for the treatment of patients with late-stage, metastatic cancers, who are facing severely limited options.

  5. Antitumor and Adjuvant Activity of λ-carrageenan by Stimulating Immune Response in Cancer Immunotherapy.

    Science.gov (United States)

    Luo, Min; Shao, Bin; Nie, Wen; Wei, Xia-Wei; Li, Yu-Li; Wang, Bi-Lan; He, Zhi-Yao; Liang, Xiao; Ye, Ting-Hong; Wei, Yu-Quan

    2015-01-01

    λ-Carrageenan is a seaweed polysaccharide which has been generally used as proinflammatory agent in the basic research, however, how the immunomodulating activity of λ-carrageenan affects tumor microenvironment remains unknown. In this study, we found that intratumoral injection of λ-carrageenan could inhibit tumor growth in B16-F10 and 4T1 bearing mice and enhance tumor immune response by increasing the number of tumor-infiltrating M1 macrophages, DCs and more activated CD4(+)CD8(+) T lymphocytes in spleen. In addition, λ-carrageenan could enhance the secretion of IL17A in spleen and significantly increase the level of TNF-α in tumor, most of which was secreted by infiltrating macrophages. Moreover, λ-carrageenan exhibited an efficient adjuvant effect in OVA-based preventative and therapeutic vaccine for cancer treatment, which significantly enhanced the production of anti-OVA antibody. The toxicity analysis suggested that λ-carrageenan was with a good safety profile. Thus, λ-carrageenan might be used both as a potent antitumor agent and an efficient adjuvant in cancer immunotherapy. PMID:26098663

  6. Laser immunotherapy for treatment of patients with advanced breast cancer and melanoma

    International Nuclear Information System (INIS)

    Laser immunotherapy (LIT) was developed for the treatment of metastatic tumors. It combines local selective photothermal interaction and active immunological stimulation to induce a long-term, systemic anti-tumor immunity. During the past sixteen years, LIT has been advanced from bench-top to bedside, with promising outcomes. In our pre-clinical and preliminary clinical studies, LIT has demonstrated the capability in inducing immunological responses, which not only can eradicate the treated primary tumors, but also can eliminate untreated metastases at distant sites. Specifically, LIT has been used to treat advanced melanoma and breast cancer patients during the past five years. LIT was shown to be effective in controlling both primary tumors and distant metastases in late-stage patients, who have failed conventional therapies such as surgery, chemotherapy, radiation, and other more advanced approaches. The methodology and the development of LIT are presented in this paper. The patients' responses to LIT are also reported in this paper. The preliminary results obtained in these studies indicated that LIT could be an effective modality for the treatment of patients with late-stage, metastatic cancers, who are facing severely limited options.

  7. Retrospective Comparative Study of the Effects of Dendritic Cell Vaccine and Cytokine-Induced Killer Cell Immunotherapy with that of Chemotherapy Alone and in Combination for Colorectal Cancer

    Directory of Open Access Journals (Sweden)

    Jingxiu Niu

    2014-01-01

    Full Text Available Purpose. This retrospective study determined the delayed-type hypersensitivity (DTH skin test and safety of dendritic cell (DC vaccine and cytokine-induced killer (CIK cell immunotherapy and the survival compared to chemotherapy in 239 colorectal cancer (CRC patients. Methods. DTH and safety of the immunotherapy were recorded. The overall survival (OS and disease free survival curves were compared according to the immunotherapy and/or chemotherapy received with Kaplan-Meier estimates. Results. Of the 70 patients who received immunotherapy, 62.86% had a positive DTH skin test, 38.57% developed fever, 47.14% developed insomnia, 38.57% developed anorexia, 4.29% developed joint soreness, and 11.43% developed skin rash. For 204 resectable CRC patients, median survival time (MST (198.00 days was significantly longer in patients with immunotherapy plus chemotherapy than with chemotherapy alone (106.00 days (P=0.02. For 35 patients with unresectable or postsurgery relapsed CRC and who were confirmed to be dead, no statistical difference was observed in the MST between the patients treated with immunotherapy and with chemotherapy (P=0.41. MST in the patients treated with chemotherapy plus immunotherapy was 154 days longer than that of patients treated with chemotherapy alone (P=0.41. Conclusions. DC vaccination and CIK immunotherapy did not cause severe adverse effects, induce immune response against CRC, and prolong OS.

  8. 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.

  9. Anticancer effects and mechanisms of polysaccharide-K (PSK): implications of cancer immunotherapy.

    Science.gov (United States)

    Fisher, Monte; Yang, Li-Xi

    2002-01-01

    Polysaccharide-K (polysaccharide-Kureha; PSK), also known as krestin, is a unique protein-bound polysaccharide, which has been used as a chemoimmunotherapy agent in the treatment of cancer in Asia for over 30 years. PSK and Polysaccharopeptide (PSP) are both protein-bound polysaccharides which are derived from the CM-101 and COV-1 strains of the fungus Coriolus versicolor by Japanese and Chinese researchers, respectively. Both polysaccharide preparations have documented anticancer activity in vitro, in vivo and in human clinical trials, though PSK has been researched longer and has therefore undergone more thorough laboratory, animal and clinical testing. Several randomized clinical trials have demonstrated that PSK has great potential as an adjuvant cancer therapy agent, with positive results seen in the adjuvant treatment of gastric, esophageal, colorectal, breast and lung cancers. These studies have suggested the efficacy of PSK as an immunotherapy or biological response modifier (BRM). BRMs potentially have the ability to improve the "host versus tumor response," thereby increasing the ability of the host to defend itself from tumor progression. The mechanisms of biological response modification by PSK have yet to be clearly and completely elucidated. Some studies suggest that PSK may act to increase leukocyte activation and response through up-regulation of key cytokines. Indeed, natural killer (NK) and lymphocyte-activated killer (LAK) cell activation has been demonstrated in vivo and in vitro, and recent genetic studies reveal increased expression of key immune cytokines in response to treatment with PSK. An antimetastatic action of PSK has also been demonstrated and is perhaps attributed to its potential to inhibit metalloproteinases and other enzymes involved in metastatic activity. PSK has also been shown to cause differentiation of leukemic cells in vitro, and this effect has been attributed to induction of differentiation cytokines. PSK has further been

  10. Combination Immunotherapy with 4-1BBL and CTLA-4 Blockade for the Treatment of Prostate Cancer

    OpenAIRE

    Kuang Youlin; Zhang Li; Weng Xiaodong; Liu Xiuheng; Zhu Hengchen

    2012-01-01

    Immune regulation has been shown to be involved in the progressive growth of some murine tumours. Interruption of immune regulatory pathways via activation of 4-1BB or cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) blockade appears to be a promising strategy for cancer immunotherapy. In this study, we examined the effectiveness of 4-1BBL-expressing tumor cell vaccine in combination with CTLA-4 blockade on rejection of murine prostate cancer RM-1. We found that the combination of both a ...

  11. Change in peripheral blood lymphocyte count in dogs following adoptive immunotherapy using lymphokine-activated T killer cells combined with palliative tumor resection.

    Science.gov (United States)

    Mie, Keiichiro; Shimada, Terumasa; Akiyoshi, Hideo; Hayashi, Akiyoshi; Ohashi, Fumihito

    2016-09-01

    We evaluated changes in peripheral blood lymphocyte (PBL) count in dogs following adoptive immunotherapy using lymphokine-activated T killer cells (T-LAK) in combination with surgery. Fifteen tumor-bearing dogs treated with T-LAK therapy combined with palliative resection of tumors were enrolled in the present study. T-LAK were generated from autologous peripheral blood mononuclear cells (PBMC) by culture with recombinant human interleukin -2 (rhIL-2) and solid phase anti-canine cluster of differentiation (CD)3 antibody. T-LAK were administrated intravenously at 2-4-week intervals. After the first administration of T-LAK, counts of PBL and T lymphocyte subsets (CD3(+), CD4(+) and CD8(+) cells) increased and the CD4/CD8 ratio decreased, with significant increases in CD8(+) cells (P<0.05). In 8 tumor-bearing dogs that were administered sequential T-LAK, available data on changes in PBL and T lymphocyte phenotypes until the fifth administration were also analyzed. In tumor-bearing dogs administered 5 rounds of T-LAK, CD8(+) cell counts were maintained high until the fifth administration of T-LAK. Moreover, the CD4/CD8 ratio remained low until the fifth administration of T-LAK. These results indicate that T-LAK therapy combined with surgery may increase peripheral blood T lymphocytes, particularly CD8(+) cells, in tumor-bearing dogs. PMID:27436446

  12. Structural Pathways of Cytokines May Illuminate Their Roles in Regulation of Cancer Development and Immunotherapy

    International Nuclear Information System (INIS)

    Cytokines are messengers between tissues and the immune system. They play essential roles in cancer initiation, promotion, metastasis, and immunotherapy. Structural pathways of cytokine signaling which contain their interactions can help understand their action in the tumor microenvironment. Here, our aim is to provide an overview of the role of cytokines in tumor development from a structural perspective. Atomic details of protein-protein interactions can help in understanding how an upstream signal is transduced; how higher-order oligomerization modes of proteins can influence their function; how mutations, inhibitors or antagonists can change cellular consequences; why the same protein can lead to distinct outcomes, and which alternative parallel pathways can take over. They also help to design drugs/inhibitors against proteins de novo or by mimicking natural antagonists as in the case of interferon-γ. Since the structural database (PDB) is limited, structural pathways are largely built from a series of predicted binary protein-protein interactions. Below, to illustrate how protein-protein interactions can help illuminate roles played by cytokines, we model some cytokine interaction complexes exploiting a powerful algorithm (PRotein Interactions by Structural Matching—PRISM)

  13. Structural Pathways of Cytokines May Illuminate Their Roles in Regulation of Cancer Development and Immunotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Guven-Maiorov, Emine; Acuner-Ozbabacan, Saliha Ece; Keskin, Ozlem; Gursoy, Attila [Center for Computational Biology and Bioinformatics and College of Engineering, Koc University, Rumelifeneri Yolu, 34450 Sariyer Istanbul (Turkey); Nussinov, Ruth, E-mail: nussinor@helix.nih.gov [Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD 21702 (United States); Sackler Institute of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978 (Israel)

    2014-03-25

    Cytokines are messengers between tissues and the immune system. They play essential roles in cancer initiation, promotion, metastasis, and immunotherapy. Structural pathways of cytokine signaling which contain their interactions can help understand their action in the tumor microenvironment. Here, our aim is to provide an overview of the role of cytokines in tumor development from a structural perspective. Atomic details of protein-protein interactions can help in understanding how an upstream signal is transduced; how higher-order oligomerization modes of proteins can influence their function; how mutations, inhibitors or antagonists can change cellular consequences; why the same protein can lead to distinct outcomes, and which alternative parallel pathways can take over. They also help to design drugs/inhibitors against proteins de novo or by mimicking natural antagonists as in the case of interferon-γ. Since the structural database (PDB) is limited, structural pathways are largely built from a series of predicted binary protein-protein interactions. Below, to illustrate how protein-protein interactions can help illuminate roles played by cytokines, we model some cytokine interaction complexes exploiting a powerful algorithm (PRotein Interactions by Structural Matching—PRISM)

  14. Immunotherapy for human papillomavirus-associated disease and cervical cancer: review of clinical and translational research.

    Science.gov (United States)

    Lee, Sung Jong; Yang, Andrew; Wu, T C; Hung, Chien Fu

    2016-09-01

    Cervical cancer is the fourth most lethal women's cancer worldwide. Current treatments against cervical cancer include surgery, radiotherapy, chemotherapy, and anti-angiogenic agents. However, despite the various treatments utilized for the treatment of cervical cancer, its disease burden remains a global issue. Persistent infection of human papillomavirus (HPV) has been identified as an essential step of pathogenesis of cervical cancer and many other cancers, and nation-wide HPV screening as well as preventative HPV vaccination program have been introduced globally. However, even though the commercially available prophylactic HPV vaccines, Gardasil (Merck) and Cervarix (GlaxoSmithKline), are effective in blocking the entry of HPV into the epithelium of cervix through generation of HPV-specific neutralizing antibodies, they cannot eliminate the pre-existing HPV infection. For these reason, other immunotherapeutic options against HPV-associated diseases, including therapeutic vaccines, have been continuously explored. Therapeutic HPV vaccines enhance cell-mediated immunity targeting HPV E6 and E7 antigens by modulating primarily dendritic cells and cytotoxic T lymphocyte. Our review will cover various therapeutic vaccines in development for the treatment of HPV-associated lesions and cancers. Furthermore, we will discuss the potential of immune checkpoint inhibitors that have recently been adopted and tested for their treatment efficacy against HPV-induced cervical cancer. PMID:27329199

  15. Maintenance treatment with chemotherapy and immunotherapy in non-small cell lung cancer:A case report.

    Directory of Open Access Journals (Sweden)

    Anabella eLlanos

    2012-10-01

    Full Text Available A 53-year-old woman was diagnosed with lung adenocarcinoma state IV (synchronous pleural involvement in April 2009. First-line systemic treatment included 6 cycles of Carboplatin, Paclitaxel, and Bevacizumab. Partial response was achieved. Maintenance therapy with Bevacizumab and Pemetrexed was given from September 2009 to February 2010. No response changes were observed. Immunotherapy was initiated, and then Pemetrexed was given with the same disease status. Both treatments were well tolerated. Immunotherapy toxicity included reaction at the site of injection grade 2. At present, the patient is still on this treatment. Given the poor prognosis of patients with advanced lung cancer, the combination of both treatments during the stable phase of the disease may improve progression-free survival.

  16. The role of human papilloma virus (HPV) infection in non-anogenital cancer and the promise of immunotherapy: a review.

    Science.gov (United States)

    Cobos, Chris; Figueroa, José A; Mirandola, Leonardo; Colombo, Michela; Summers, Gabby; Figueroa, Alejandro; Aulakh, Amardeep; Konala, Venu; Verma, Rashmi; Riaz, Jehanzeb; Wade, Raymond; Saadeh, Charles; Rahman, Rakhshanda L; Pandey, Apurva; Radhi, Saba; Nguyen, Diane D; Jenkins, Marjorie; Chiriva-Internati, Maurizio; Cobos, Everardo

    2014-10-01

    Over the past 30 years, human papilloma virus (HPV) has been shown to play a role in the development of various cancers. Most notably, HPV has been linked to malignant progression in neoplasms of the anogenital region. However, high-risk HPV has also been suggested to play a significant role in the development of cancers in other anatomic locations, such as the head and neck, lung, breast and bladder. In 2006, the first vaccine for HPV, Gardasil, was approved for the prevention of subtypes 6, 11, 16 and 18. A few years later, Cevarix was approved for the prevention of subtypes 16 and 18, the HPV subtypes most frequently implicated in malignant progression. Although increased awareness and vaccination could drastically decrease the incidence of HPV-positive cancers, these approaches do not benefit patients who have already contracted HPV and developed cancer as a result. For this reason, researchers need to continue developing treatment modalities, such as targeted immunotherapies, for HPV-positive lesions. Here, we review the potential evidence linking HPV infection with the development of non-anogenital cancers and the potential role of immunotherapy in the prevention and eradication of HPV infection and its oncogenic sequela. PMID:24811210

  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. Integrated cancer therapy combined radiotherapy and immunotherapy. The challenge of using Gc protein-derived macrophage activating factor (GcMAF) as a key molecule

    International Nuclear Information System (INIS)

    Radiation oncologists know the conflict between radiotherapy and immunotherapy, but now challenged trails of the integrative cancer therapies combined radiation therapy and various immunoreaction/immune therapies begin. We therefore review the recent results of basic research and clinical trial of the integrated cancer therapies which combined radiotherapy and various immune therapies/immunoreaction, and the challenged studies of combined use of radiotherapy and our developed cancer immunotherapy using serum GcMAF which is human serum containing Gc protein-derived macrophage activating factor (GcMAF). (author)

  19. 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

  20. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy.

    Science.gov (United States)

    Kranz, Lena M; Diken, Mustafa; Haas, Heinrich; Kreiter, Sebastian; Loquai, Carmen; Reuter, Kerstin C; Meng, Martin; Fritz, Daniel; Vascotto, Fulvia; Hefesha, Hossam; Grunwitz, Christian; Vormehr, Mathias; Hüsemann, Yves; Selmi, Abderraouf; Kuhn, Andreas N; Buck, Janina; Derhovanessian, Evelyna; Rae, Richard; Attig, Sebastian; Diekmann, Jan; Jabulowsky, Robert A; Heesch, Sandra; Hassel, Jessica; Langguth, Peter; Grabbe, Stephan; Huber, Christoph; Türeci, Özlem; Sahin, Ugur

    2016-06-16

    Lymphoid organs, in which antigen presenting cells (APCs) are in close proximity to T cells, are the ideal microenvironment for efficient priming and amplification of T-cell responses. However, the systemic delivery of vaccine antigens into dendritic cells (DCs) is hampered by various technical challenges. Here we show that DCs can be targeted precisely and effectively in vivo using intravenously administered RNA-lipoplexes (RNA-LPX) based on well-known lipid carriers by optimally adjusting net charge, without the need for functionalization of particles with molecular ligands. The LPX protects RNA from extracellular ribonucleases and mediates its efficient uptake and expression of the encoded antigen by DC populations and macrophages in various lymphoid compartments. RNA-LPX triggers interferon-α (IFNα) release by plasmacytoid DCs and macrophages. Consequently, DC maturation in situ and inflammatory immune mechanisms reminiscent of those in the early systemic phase of viral infection are activated. We show that RNA-LPX encoding viral or mutant neo-antigens or endogenous self-antigens induce strong effector and memory T-cell responses, and mediate potent IFNα-dependent rejection of progressive tumours. A phase I dose-escalation trial testing RNA-LPX that encode shared tumour antigens is ongoing. In the first three melanoma patients treated at a low-dose level, IFNα and strong antigen-specific T-cell responses were induced, supporting the identified mode of action and potency. As any polypeptide-based antigen can be encoded as RNA, RNA-LPX represent a universally applicable vaccine class for systemic DC targeting and synchronized induction of both highly potent adaptive as well as type-I-IFN-mediated innate immune mechanisms for cancer immunotherapy. PMID:27281205

  1. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy

    Science.gov (United States)

    Kranz, Lena M.; Diken, Mustafa; Haas, Heinrich; Kreiter, Sebastian; Loquai, Carmen; Reuter, Kerstin C.; Meng, Martin; Fritz, Daniel; Vascotto, Fulvia; Hefesha, Hossam; Grunwitz, Christian; Vormehr, Mathias; Hüsemann, Yves; Selmi, Abderraouf; Kuhn, Andreas N.; Buck, Janina; Derhovanessian, Evelyna; Rae, Richard; Attig, Sebastian; Diekmann, Jan; Jabulowsky, Robert A.; Heesch, Sandra; Hassel, Jessica; Langguth, Peter; Grabbe, Stephan; Huber, Christoph; Türeci, Özlem; Sahin, Ugur

    2016-06-01

    Lymphoid organs, in which antigen presenting cells (APCs) are in close proximity to T cells, are the ideal microenvironment for efficient priming and amplification of T-cell responses. However, the systemic delivery of vaccine antigens into dendritic cells (DCs) is hampered by various technical challenges. Here we show that DCs can be targeted precisely and effectively in vivo using intravenously administered RNA-lipoplexes (RNA-LPX) based on well-known lipid carriers by optimally adjusting net charge, without the need for functionalization of particles with molecular ligands. The LPX protects RNA from extracellular ribonucleases and mediates its efficient uptake and expression of the encoded antigen by DC populations and macrophages in various lymphoid compartments. RNA-LPX triggers interferon-α (IFNα) release by plasmacytoid DCs and macrophages. Consequently, DC maturation in situ and inflammatory immune mechanisms reminiscent of those in the early systemic phase of viral infection are activated. We show that RNA-LPX encoding viral or mutant neo-antigens or endogenous self-antigens induce strong effector and memory T-cell responses, and mediate potent IFNα-dependent rejection of progressive tumours. A phase I dose-escalation trial testing RNA-LPX that encode shared tumour antigens is ongoing. In the first three melanoma patients treated at a low-dose level, IFNα and strong antigen-specific T-cell responses were induced, supporting the identified mode of action and potency. As any polypeptide-based antigen can be encoded as RNA, RNA-LPX represent a universally applicable vaccine class for systemic DC targeting and synchronized induction of both highly potent adaptive as well as type-I-IFN-mediated innate immune mechanisms for cancer immunotherapy.

  2. Isolation and Characterization of an HLA-DPB1*04: 01-restricted MAGE-A3 T-Cell Receptor for Cancer Immunotherapy.

    Science.gov (United States)

    Yao, Xin; Lu, Yong-Chen; Parker, Linda L; Li, Yong F; El-Gamil, Mona; Black, Mary A; Xu, Hui; Feldman, Steven A; van der Bruggen, Pierre; Rosenberg, Steven A; Robbins, Paul F

    2016-06-01

    Long-term tumor regressions have been observed in patients following the adoptive transfer of autologous tumor-infiltrating lymphocytes or genetically modified T cells expressing MHC class I-restricted T-cell receptors (TCRs), but clinical trials have not evaluated responses to genetically modified T cells expressing antitumor MHC class II-restricted TCRs. As studies carried out in a murine tumor model system have demonstrated that the adoptive transfer of CD4 T cells could lead to the regression of established tumors, we plan to test the hypothesis that CD4 T cells can also induce tumor regressions in cancer patients. In this study, 2 MAGE-A3-specific TCRs were isolated from a regulatory T-cell clone (6F9) and an effector clone (R12C9), generated from the peripheral blood of 2 melanoma patients after MAGE-A3 vaccination. The results indicated that T cells transduced with 6F9 TCR mediated stronger effector functions than R12C9 TCR. The 6F9 TCR specifically recognized MAGE-A3 and the closely related MAGE-A6 gene product, but not other members of the MAGE-A family in the context of HLA-DPB1*04:01. To test the feasibility of a potential clinical trial using this TCR, a clinical-scale procedure was developed to obtain a large number of purified CD4 T cells transduced with 6F9 TCR. Because HLA-DPB1*04:01 is present in ∼60% of the Caucasian population and MAGE-A3 is frequently expressed in a variety of cancer types, this TCR immunotherapy could potentially be applicable for a significant portion of cancer patients. PMID:27163739

  3. Mechanistic insights into the oncolytic activity of vesicular stomatitis virus in cancer immunotherapy

    Directory of Open Access Journals (Sweden)

    Simovic B

    2015-10-01

    Full Text Available Boris Simovic, Scott R Walsh, Yonghong Wan Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada Abstract: Immunotherapy and oncolytic virotherapy have both shown anticancer efficacy in the clinic as monotherapies but the greatest promise lies in therapies that combine these approaches. Vesicular stomatitis virus is a prominent oncolytic virus with several features that promise synergy between oncolytic virotherapy and immunotherapy. This review will address the cytotoxicity of vesicular stomatitis virus in transformed cells and what this means for antitumor immunity and the virus' immunogenicity, as well as how it facilitates the breaking of tolerance within the tumor, and finally, we will outline how these features can be incorporated into the rational design of new treatment strategies in combination with immunotherapy. Keywords: virotherapy, rhabdovirus, anti-tumor immunity, t cell, natural killer cell, therapeutic vaccine

  4. MDSC-decreasing chemotherapy increases the efficacy of cytokine-induced killer cell immunotherapy in metastatic renal cell carcinoma and pancreatic cancer.

    Science.gov (United States)

    Wang, Zibing; Liu, Yuqing; Zhang, Yong; Shang, Yiman; Gao, Quanli

    2016-01-26

    Adoptive immunotherapy using cytokine-induced killer (CIK) cells is a promising cancer treatment, but its efficacy is restricted by various factors, including the accumulation of myeloid-derived suppressor cells (MDSCs). In this study, we determine whether chemotherapeutic drugs that reduce MDSC levels enhance the efficacy of CIK cell therapy in the treatment of solid tumors. Fifty-three patients were included in this study; 17 were diagnosed with metastatic renal cell carcinoma (MRCC), 10 with advanced pancreatic cancer (PC), and 26 with metastatic melanoma (MM). These patients were divided into two groups: CIK cell therapy alone and CIK cell therapy combined with chemotherapy. Combining CIK cell therapy and chemotherapy increased 1-year survival rates and median survival times in MRCC and PC patients, but not in MM patients. The disease control rate did not differ between treatment groups for MRCC or MM patients, but was higher in PC patients receiving combined treatment than CIK cell treatment alone. These data suggest that addition of MDSC-decreasing chemotherapy to CIK cell therapy improves survival in MRCC and PC patients. PMID:26716894

  5. Acquired resistance to immunotherapy and future challenges.

    Science.gov (United States)

    Restifo, Nicholas P; Smyth, Mark J; Snyder, Alexandra

    2016-02-01

    Advances in immunotherapy have resulted in remarkable clinical responses in some patients. However, one of the biggest challenges in cancer therapeutics is the development of resistant disease and disease progression on or after therapy. Given that many patients have now received various types of immunotherapy, we asked three scientists to give their views on the current evidence for whether acquired resistance to immunotherapy exists in patients and the future challenges posed by immunotherapy. PMID:26822578

  6. Cetuximab intensifies the ADCC activity of adoptive NK cells in a nude mouse colorectal cancer xenograft model

    Science.gov (United States)

    Chen, Shanshan; Li, Xuechun; Chen, Rongming; Yin, Mingang; Zheng, Qiuhong

    2016-01-01

    Natural killer (NK) cells, discovered ~40 years ago, are believed to be the most effective cytotoxic lymphocytes to counteract cancer; however, adoptive NK cell therapy in vivo has encountered certain limitations, including a lack of specificity. The drug cetuximab can mediate antibody dependent cell mediated cytotoxicity (ADCC) activity through NK cells in vivo, and has been approved for the first-line treatment of epidermal growth factor receptor (EGFR)-positive metastatic colorectal cancer (CRC). However, the ADCC activity of adoptive NK cells, induced by cetuximab in a nude mouse CRC xenograft model, has not been previously reported. The aim of the present study was to explore the ADCC activity of cetuximab combined with adoptive NK cells in CRC xenograft models with various EGFR expressions. The nude mouse xenograft models were established by subcutaneously injecting LOVO or SW620 cells. The mice were then randomly divided into 6 groups: Phosphate-buffered saline, cetuximab, human immunoglobulin G (hIgG), NK cells, hIgG plus NK cells and cetuximab plus NK cells. The ADCC antitumor activity was evaluated in these CRC models. The results indicated that the cetuximab plus NK cells group showed the greatest tumor inhibition effect compared with the NK cells group in LOVO xenograft tumor models with positive EGFR expression. However, the combination of cetuximab and NK cells did not show a stronger tumor inhibitory effect against the SW620 xenograft tumor models compared with the efficiency of NK cells. In conclusion, cetuximab could intensify the ADCC antitumor activity of adoptive NK cells towards CRC with an increased EGFR expression. The combination of cetuximab and NK cells may be a potential immunotherapy for metastatic CRC patients with positive EGFR expression. PMID:27602116

  7. A Functionally Superior Second-Generation Vector Expressing an Aurora Kinase-A-Specific T-Cell Receptor for Anti-Leukaemia Adoptive Immunotherapy.

    Science.gov (United States)

    Casey, Nicholas Paul; Fujiwara, Hiroshi; Tanimoto, Kazushi; Okamoto, Sachiko; Mineno, Junichi; Kuzushima, Kiyotaka; Shiku, Hiroshi; Yasukawa, Masaki

    2016-01-01

    Aurora Kinase A is a cancer-associated protein normally involved in the regulation of mitosis. Being over-expressed in a range of cancers, it is a suitable target for cell-based immunotherapy. Gene transfer of T-cell receptor sequences cognisant of HLA-A*0201-restricted Aurora Kinase A antigen has previously been shown to transfer specific immunoreactivity against the target peptide in a Human Lymphocyte Antigen-restricted manner. While T cell receptor gene-transfer has great potential in overcoming the difficulties of isolating and expanding tumour-reactive lymphocytes from a patient's own cells, one hurdle is potential mispairing and competition between exogenous and endogenous T cell receptor chains. We have used a retroviral vector design bearing a short-interfering RNA that downregulates endogenous T cell receptor chains, without affecting expression of the transgenic T cell receptor sequences. The T cell receptor expression cassette also includes a 2A self-cleaving peptide, resulting in equimolar expression of the T cell receptor alpha and beta chains, further enhancing formation of the desired T cell receptor. Via a simple, modular cloning method, we have cloned the alpha and beta chains of the anti-Aurora Kinase A-reactive T cell receptor into this 'siTCR' vector. We then compared the activity of this vector against the original, 'conventional' vector across a panel of assays. T cell receptors expressed from the siTCR-vector retained the cytotoxic functionality of the original vector, with evidence of reduced off-target reactivity. The rate of expression of correctly-formed T cell receptors was superior using the siTCR design, and this was achieved at lower vector copy numbers. Maintaining T cell receptor efficacy with a reduced vector copy number reduces the risk of genotoxicity. The siTCR design also reduces the risk of mispairing and cross-reactivity, while increasing the functional titre. Such improvements in the safety of T cell receptor gene

  8. A Functionally Superior Second-Generation Vector Expressing an Aurora Kinase-A-Specific T-Cell Receptor for Anti-Leukaemia Adoptive Immunotherapy.

    Directory of Open Access Journals (Sweden)

    Nicholas Paul Casey

    Full Text Available Aurora Kinase A is a cancer-associated protein normally involved in the regulation of mitosis. Being over-expressed in a range of cancers, it is a suitable target for cell-based immunotherapy. Gene transfer of T-cell receptor sequences cognisant of HLA-A*0201-restricted Aurora Kinase A antigen has previously been shown to transfer specific immunoreactivity against the target peptide in a Human Lymphocyte Antigen-restricted manner. While T cell receptor gene-transfer has great potential in overcoming the difficulties of isolating and expanding tumour-reactive lymphocytes from a patient's own cells, one hurdle is potential mispairing and competition between exogenous and endogenous T cell receptor chains. We have used a retroviral vector design bearing a short-interfering RNA that downregulates endogenous T cell receptor chains, without affecting expression of the transgenic T cell receptor sequences. The T cell receptor expression cassette also includes a 2A self-cleaving peptide, resulting in equimolar expression of the T cell receptor alpha and beta chains, further enhancing formation of the desired T cell receptor. Via a simple, modular cloning method, we have cloned the alpha and beta chains of the anti-Aurora Kinase A-reactive T cell receptor into this 'siTCR' vector. We then compared the activity of this vector against the original, 'conventional' vector across a panel of assays. T cell receptors expressed from the siTCR-vector retained the cytotoxic functionality of the original vector, with evidence of reduced off-target reactivity. The rate of expression of correctly-formed T cell receptors was superior using the siTCR design, and this was achieved at lower vector copy numbers. Maintaining T cell receptor efficacy with a reduced vector copy number reduces the risk of genotoxicity. The siTCR design also reduces the risk of mispairing and cross-reactivity, while increasing the functional titre. Such improvements in the safety of T cell

  9. miR-17-92 expression in differentiated T cells - implications for cancer immunotherapy

    Directory of Open Access Journals (Sweden)

    Martinson Jeremy

    2010-02-01

    tumor microenvironment induces the down-regulation of miR-17-92 expression in T cells, thereby diminishing the persistence of tumor-specific T cells and tumor control. Genetic engineering of T cells to express miR-17-92 may represent a promising approach for cancer immunotherapy.

  10. Nanomedicine for Cancer Immunotherapy: Tracking Cancer-Specific T-Cells in Vivo with Gold Nanoparticles and CT Imaging.

    Science.gov (United States)

    Meir, Rinat; Shamalov, Katerina; Betzer, Oshra; Motiei, Menachem; Horovitz-Fried, Miryam; Yehuda, Ronen; Popovtzer, Aron; Popovtzer, Rachela; Cohen, Cyrille J

    2015-06-23

    Application of immune cell-based therapy in routine clinical practice is challenging due to the poorly understood mechanisms underlying success or failure of treatment. Development of accurate and quantitative imaging techniques for noninvasive cell tracking can provide essential knowledge for elucidating these mechanisms. We designed a novel method for longitudinal and quantitative in vivo cell tracking, based on the superior visualization abilities of classical X-ray computed tomography (CT), combined with state-of-the-art nanotechnology. Herein, T-cells were transduced to express a melanoma-specific T-cell receptor and then labeled with gold nanoparticles (GNPs) as a CT contrast agent. The GNP-labeled T-cells were injected intravenously to mice bearing human melanoma xenografts, and whole-body CT imaging allowed examination of the distribution, migration, and kinetics of T-cells. Using CT, we found that transduced T-cells accumulated at the tumor site, as opposed to nontransduced cells. Labeling with gold nanoparticles did not affect T-cell function, as demonstrated both in vitro, by cytokine release and proliferation assays, and in vivo, as tumor regression was observed. Moreover, to validate the accuracy and reliability of the proposed cell tracking technique, T-cells were labeled both with green fluorescent protein for fluorescence imaging, and with GNPs for CT imaging. A remarkable correlation in signal intensity at the tumor site was observed between the two imaging modalities, at all time points examined, providing evidence for the accuracy of our CT cell tracking abilities. This new method for cell tracking with CT offers a valuable tool for research, and more importantly for clinical applications, to study the fate of immune cells in cancer immunotherapy. PMID:26039633

  11. Cellular immunotherapy directed against human cytomegalovirus as a novel approach for glioblastoma treatment

    OpenAIRE

    Schuessler, Andrea; Walker, David G.; Khanna, Rajiv

    2014-01-01

    Glioblastoma multiforme (GBM) has a very poor prognosis, despite multimodal therapy including surgery, radiation and chemotherapy. A novel adoptive immunotherapy that exploits the presence of cytomegalovirus antigens in malignant brain cancer cells has been shown to be safe and elicit potential clinical benefit for the treatment of recurrent GBM.

  12. CLINICAL EXPERIENCE OF CANCER IMMUNOTHERAPY INTEGRATED WITH OLEIC ACID COMPLEXED WITH DE-GLYCOSYLATED VITAMIN D BINDING PROTEIN

    Directory of Open Access Journals (Sweden)

    Emma Ward

    2014-01-01

    Full Text Available Proteins highly represented in milk such as α-lactalbumin and lactoferrin bind Oleic Acid (OA to form complexes with selective anti-tumor activity. A protein present in milk, colostrum and blood, vitamin D binding protein is the precursor of a potent Macrophage Activating Factor (GcMAF and in analogy with other OA-protein complexes, we proposed that OA-GcMAF could demonstrate a greater immunotherapeutic activity than that of GcMAF alone. We describe a preliminary experience treating patients with advanced cancers, often labelled as “incurable” with an integrative immunotherapy centred on OA-GcMAF. Patients with advanced cancer were treated at the Immuno Biotech Treatment Centre with OA-GcMAF-based integrative immunotherapy in combination with a very low carbohydrate, high protein diet, fermented milk products containing naturally produced GcMAF, vitamin D3 and low-dose acetylsalicylic acid. When the primary tumor or a metastasis could be measured by ultrasonographic techniques, we observed, on average, a decrease of tumor volume of approximately 25% in a week. We also observed a consistent increase in splenic blood flow that was interpreted in the context of generalised immune system activation and allowed to assess the degree of responsiveness of the individual patient. The results reported here are consistent with the results previously described in the experimental animal harbouring a human hepatocellular carcinoma as well as with the results reported for neoadjuvant chemotherapy. OA-protein complexes are bound to play a leading role in cancer therapy thanks to selectivity of antitumoral effects, absence of any side effects, safety and oral availability. We hypothesise that OA-GcMAF, combines the known anticancer effects OA-protein complexes with the well established immune stimulating effects of GcMAF.

  13. IR 820 dye encapsulated in polycaprolactone glycol chitosan: Poloxamer blend nanoparticles for photo immunotherapy for breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Kumar, Piyush; Srivastava, Rohit, E-mail: rsrivasta@iitb.ac.in

    2015-12-01

    In the present study, we have fabricated biocompatible and biodegradable monodisperse IR 820 encapsulated polycaprolactone (PCL) glycol chitosan (GC): Poloxamer blend nanoparticles (PP-IR NPs) for imaging and effective photo-immunotherapy. IR 820 has been used as an imaging and photothermal agent whereas glycol chitosan (GC) as an immunostimulatory agent. The combination of IR 820, poloxamer, and GC can be used effectively for photoimmunotherapy for cancer, drug-resistant and TNF-α resistant estrogen positive breast cancer. PP-IR NPs are stable in aqueous solution. The uniform size of 100–220 nm with a high zeta value of + 38 ± 2 mV led them to accumulate in cancer cells. Laser treatment did not affect the morphology of PP-IR NPs as observed under the transmission electron microscope (TEM). In vitro cytotoxicity studies on MCF-7 cells showed enhanced toxicity upon laser treatment. Further, we validated the cell death by reactive oxygen species (ROS) production. Our studies thus showed that PP-IR NPs are effective in suppressing metastatic cancer as the combinational therapy leads to the formation of apoptotic bodies in MCF-7 cells. - Highlights: • PPIR nanoparticles for photoimmunotherapy for cancer • IR 820/GC serves as theranostic and immunostimulatory. • Photoimmunotherapy enhances cytotoxicity by reactive oxygen species production.

  14. IR 820 dye encapsulated in polycaprolactone glycol chitosan: Poloxamer blend nanoparticles for photo immunotherapy for breast cancer

    International Nuclear Information System (INIS)

    In the present study, we have fabricated biocompatible and biodegradable monodisperse IR 820 encapsulated polycaprolactone (PCL) glycol chitosan (GC): Poloxamer blend nanoparticles (PP-IR NPs) for imaging and effective photo-immunotherapy. IR 820 has been used as an imaging and photothermal agent whereas glycol chitosan (GC) as an immunostimulatory agent. The combination of IR 820, poloxamer, and GC can be used effectively for photoimmunotherapy for cancer, drug-resistant and TNF-α resistant estrogen positive breast cancer. PP-IR NPs are stable in aqueous solution. The uniform size of 100–220 nm with a high zeta value of + 38 ± 2 mV led them to accumulate in cancer cells. Laser treatment did not affect the morphology of PP-IR NPs as observed under the transmission electron microscope (TEM). In vitro cytotoxicity studies on MCF-7 cells showed enhanced toxicity upon laser treatment. Further, we validated the cell death by reactive oxygen species (ROS) production. Our studies thus showed that PP-IR NPs are effective in suppressing metastatic cancer as the combinational therapy leads to the formation of apoptotic bodies in MCF-7 cells. - Highlights: • PPIR nanoparticles for photoimmunotherapy for cancer • IR 820/GC serves as theranostic and immunostimulatory. • Photoimmunotherapy enhances cytotoxicity by reactive oxygen species production

  15. Induction/Engineering, Detection, Selection, and Expansion of Clinical-Grade Human Antigen-Specific CD8+ Cytotoxic T Cell Clones for Adoptive Immunotherapy

    Directory of Open Access Journals (Sweden)

    Matjaž Jeras

    2010-01-01

    Full Text Available Adoptive transfer of effector antigen-specific immune cells is becoming a promising treatment option in allogeneic transplantation, infectious diseases, cancer, and autoimmune disorders. Within this context, the important role of CD8+ cytotoxic T cells (CTLs is objective of intensive studies directed to their in vivo and ex vivo induction, detection, selection, expansion, and therapeutic effectiveness. Additional questions that are being addressed by the scientific community are related to the establishment and maintenance of their longevity and memory state as well as to defining critical conditions underlying their transitions between discrete, but functionally different subtypes. In this article we review and comment latest approaches and techniques used for preparing large amounts of antigen-specific CTLs, suitable for clinical use.

  16. Immunotherapy in Sarcoma: Future Horizons.

    Science.gov (United States)

    Burgess, Melissa; Gorantla, Vikram; Weiss, Kurt; Tawbi, Hussein

    2015-11-01

    Immunologic approaches to cancer are over a century old. Over the years, the strategy has been fine-tuned from inciting infections in subjects to inhibiting negative regulatory signals from the innate immune system. Sarcomas are among the first tumors to be considered for immune interventions. From Coley's toxin to cytokine-based therapies to adoptive cell therapy, there have been numerous immunotherapeutic investigations in this patient population. A promising strategy includes adoptive T cell therapy which has been studied in small cohorts of synovial sarcoma, a subtype that is known to widely express the cancer testis antigen, NY-ESO-1. Additionally, recent data in metastatic melanoma and renal cell carcinoma demonstrate the utility and tremendous efficacy of immune checkpoint blockade with increased rates of durable responses compared to standard therapies. Responses in traditionally "non-immunogenic" tumors, such as lung and bladder cancers, provide ample rationale for the study of immune checkpoint inhibitors in sarcoma. While immunotherapy has induced some responses in sarcomas, further research will help clarify optimal patient selection for future clinical trials and new combinatorial immunotherapeutic strategies. PMID:26423769

  17. Doxorubicin Eliminates Myeloid-Derived Suppressor Cells and Enhances the Efficacy of Adoptive T Cell Transfer in Breast Cancer

    OpenAIRE

    Alizadeh, Darya; Trad, Malika; Hanke, Neale T.; Larmonier, Claire B.; Janikashvili, Nona; Bonnotte, Bernard; Katsanis, Emmanuel; Larmonier, Nicolas

    2013-01-01

    Myeloid-derived suppressor cells (MDSC) expand in tumor-bearing hosts and play a central role in cancer immune evasion by inhibiting adaptive and innate immunity. They therefore represent a major obstacle for successful cancer immunotherapy. Different strategies have thus been explored to deplete and/or inactivate MDSC in vivo. Using a murine mammary cancer model, we demonstrated that doxorubicin selectively eliminates MDSC in the spleen, blood and tumor beds. Furthermore, residual MDSC from ...

  18. Tumor-specific immunotherapy of murine bladder cancer with butanol-extracted antigens and ethylchlorformate polymerized tumor protein.

    Science.gov (United States)

    Rochester, M G; Sarosdy, M F; Pickett, S H; Stogdill, B J; Lamm, D L

    1988-09-01

    Successful treatment of superficial bladder cancer using nonspecific immunotherapy with Bacillus Calmette-Guerin (BCG) has been well documented. Investigation of two potential tumor-specific immunotherapeutic agents using a murine transitional-cell carcinoma model (MBT-2) is reported. The survival of mice immunized with tumor proteins obtained by treating tumor cells with either 1-butanol or ethylchlorformate was compared to the survival of animals immunized with BCG. Long-term immunity conferred by each of these agents was also assessed. Significant protection by both agents was noted in all treatment groups compared to controls. Long-term immunity was also found to result from treatment with both investigational agents as well as with BCG. Butanol-extracted antigens and ethylchlorformate polymerized tumor protein may be useful as immunotherapeutic alternatives to BCG. PMID:3411695

  19. Pathological Mobilization and Activities of Dendritic Cells in Tumor-Bearing Hosts: Challenges and Opportunities for Immunotherapy of Cancer

    Science.gov (United States)

    Tesone, Amelia J.; Svoronos, Nikolaos; Allegrezza, Michael J.; Conejo-Garcia, Jose R.

    2013-01-01

    A common characteristic of solid tumors is the pathological recruitment of immunosuppressive myeloid cells, which in certain tumors includes dendritic cells (DCs). DCs are of particular interest in the field of cancer immunotherapy because they induce potent and highly specific anti-tumor immune responses, particularly in the early phase of tumorigenesis. However, as tumors progress, these cells can be transformed into regulatory cells that contribute to an immunosuppressive microenvironment favoring tumor growth. Therefore, controlling DC phenotype has the potential to elicit effective anti-tumor responses while simultaneously weakening the tumor’s ability to protect itself from immune attack. This review focuses on the dual nature of DCs in the tumor microenvironment, the regulation of DC phenotype, and the prospect of modifying DCs in situ as a novel immunotherapeutic approach. PMID:24339824

  20. Effect of BCG cell-wall skeleton immunotherapy on the peripheral blood lymphocytes in patients with lung cancer after radiotherapy

    International Nuclear Information System (INIS)

    The effect of radiotherapy on peripheral blood lymphocytes (PBL) of lung cancer and the effect of BCG cell-wall skeleton (BCG-CWS) on recovery of impaired PBL were examined. A remarkable depression of the absolute number of E- or EAC-rosette cells and of the response of PBL to mitogens were observed immediately after radiotherapy, and these continued for several months. With BCG-CWS immunotherapy, the response of PBL to phytohemagglutinin recovered rapidly, compared with non-vaccinated patients. The response of PBL to pokeweed mitogen seemed to give similar results. These results suggested that BCG-CWS injection to the patient receiving radiotherapy was effective for recovery of T-cell response. (author)

  1. Class I histone deacetylase inhibitor entinostat suppresses regulatory T cells and enhances immunotherapies in renal and prostate cancer models.

    Directory of Open Access Journals (Sweden)

    Li Shen

    Full Text Available BACKGROUND: Immunosuppressive factors such as regulatory T cells (Tregs limit the efficacy of immunotherapies. Histone deacetylase (HDAC inhibitors have been reported to have antitumor activity in different malignancies and immunomodulatory effects. Herein, we report the Tregs-targeting and immune-promoting effect of a class I specific HDAC inhibitor, entinostat, in combination with either IL-2 in a murine renal cell carcinoma (RENCA model or a survivin-based vaccine therapy (SurVaxM in a castration resistant prostate cancer (CR Myc-CaP model. METHODS AND RESULTS: RENCA or CR Myc-CaP tumors were implanted orthotopically or subcutaneously, respectively. Inoculated mice were randomized into four treatment groups: vehicle, entinostat, cytokine or vaccine, and combination. Tregs in the blood were assessed by FACS analysis. Real time quantitative PCR and Western blot analysis of isolated T cell subpopulations from spleen were performed to determine Foxp3 gene and protein expression. The suppressive function of Tregs was tested by T cell proliferation assay. Low dose (5 mg/kg entinostat reduced Foxp3 levels in Tregs and this was associated with enhanced tumor growth inhibition in combination with either IL-2 or a SurVaxM vaccine. Entinostat down-regulated Foxp3 expression transcriptionally and blocked Tregs suppressive function without affecting T effector cells (Teffs. In vitro low dose entinostat (0.5 µM induced STAT3 acetylation and a specific inhibitor of STAT3 partially rescued entinostat-induced down-regulation of Foxp3, suggesting that STAT3 signaling is involved in Foxp3 down-regulation by entinostat. CONCLUSIONS: These results demonstrate a novel immunomodulatory effect of class I HDAC inhibition and provide a rationale for the clinical testing of entinostat to enhance cancer immunotherapy.

  2. Mouse Models of Tumor Immunotherapy.

    Science.gov (United States)

    Ngiow, Shin Foong; Loi, Sherene; Thomas, David; Smyth, Mark J

    2016-01-01

    Immunotherapy is now evolving into a major therapeutic option for cancer patients. Such clinical advances also promote massive interest in the search for novel immunotherapy targets, and to understand the mechanism of action of current drugs. It is projected that a series of novel immunotherapy agents will be developed and assessed for their therapeutic activity. In light of this, in vivo experimental mouse models that recapitulate human malignancies serve as valuable tools to validate the efficacy and safety profile of immunotherapy agents, before their transition into clinical trials. In this review, we will discuss the major classes of experimental mouse models of cancer commonly used for immunotherapy assessment and provide examples to guide the selection of appropriate models. We present some new data concerning the utility of a carcinogen-induced tumor model for comparing immunotherapies and combining immunotherapy with chemotherapy. We will also highlight some recent advances in experimental modeling of human malignancies in mice that are leading towards personalized therapy in patients. PMID:26922998

  3. Breast cancer research in Asia : Adopt or adapt Western knowledge?

    NARCIS (Netherlands)

    Bhoo-Pathy, Nirmala; Yip, Cheng-Har; Hartman, Mikael; Uiterwaal, Cuno S. P. M.; Devi, Beena C. R.; Peeters, Petra H. M.; Taib, Nur Aishah; van Gils, Carla H.; Verkooijen, Helena M.

    2013-01-01

    The incidence and mortality of breast cancer continues to rise rapidly in Asian countries. However, most of our current knowledge on breast cancer has been generated in Western populations. As the socio-economic profile, life style and culture of Asian and Western women are substantially different,

  4. Review of Cancer Immunotherapy: Application of Chimeric Antigen Receptor T Cells and Programmed Death 1/Programmed Death-ligand 1 Antibodies

    Directory of Open Access Journals (Sweden)

    Tengfei Zhang

    2015-01-01

    Full Text Available Cancer immunotherapy strategies based on chimeric antigen receptor (CAR transduced T cells or antibodies against immune checkpoints, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4 and programmed death 1 (PD-1, achieved significant successes from bench to clinic in the past 2 years. CARs are artificial engineered receptors that can specifically target tumor cell surface antigen, activate T cell and further enhance T cell function, independent of major histocompatibility complex. CAR T cells have shown promising outcomes in cancers, especially in hematologic malignancies. CTLA-4 and PD-1 are two important immune checkpoints negatively regulating T cell activation. Clinical benefits of CTLA-4/PD-1 antibodies are significant in melanoma and other solid tumors. PD-1 is predicted to have fewer side effects and greater antitumor activity than CTLA-4. In this review, we will summarize current immunotherapies based on CAR T cells and PD-1.

  5. 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.

  6. Immunotherapy for prostate cancer: lessons from responses to tumor-associated antigens

    NARCIS (Netherlands)

    Westdorp, H.; Skold, A.; Snijer, B.A.; Franik, S.; Mulder, S.F.; Major, P.P.; Foley, R.; Gerritsen, W.R.; Vries, I.J.M. de

    2014-01-01

    Prostate cancer (PCa) is the most common cancer in men and the second most common cause of cancer-related death in men. In recent years, novel therapeutic options for PCa have been developed and studied extensively in clinical trials. Sipuleucel-T is the first cell-based immunotherapeutic vaccine fo

  7. Immunotherapy of childhood Sarcomas

    Directory of Open Access Journals (Sweden)

    Stephen S Roberts

    2015-08-01

    Full Text Available Pediatric sarcomas are a heterogeneous group of malignant tumors of bone and soft tissue origin. Although more than 100 different histologic subtypes have been described, the majority of pediatric cases belong to the Ewing’s family of tumors, rhabdomyosarcoma and osteosarcoma. Most patients that present with localized stage are curable with surgery and/or chemotherapy; however, those with metastatic disease at diagnosis or those who experience a relapse continue to have a very poor prognosis. New therapies for these patients are urgently needed. Immunotherapy is an established treatment modality for both liquid and solid tumors, and in pediatrics, most notably for neuroblastoma and osteosarcoma. In the past, immunomodulatory agents such as interferon, interleukin-2, and Liposomal-muramyl  tripeptide phosphatidyl-ethanolamine (L-MTP have been tried, with some activity seen in subsets of patients; additionally, various cancer vaccines have been studied with possible benefit. Monoclonal antibody therapies against tumor antigens such as disialoganglioside GD2 or immune checkpoint targets such as CTLA4 and PD-1 are being actively explored in pediatric sarcomas. Building on the success of adoptive T cell therapy for EBV-related lymphoma, strategies to redirect T cells using chimeric antigen receptors and bispecific antibodies are rapidly evolving with potential for the treatment of sarcomas. This review will focus on recent preclinical and clinical developments in targeted agents for pediatric sarcomas with emphasis on the immunobiology of immune checkpoints, immunoediting, tumor microenvironment, antibody engineering, cell engineering, and tumor vaccines. The future integration of antibody based and cell based therapies into an overall treatment strategy of sarcoma will be discussed.

  8. Immunotherapy of Childhood Sarcomas.

    Science.gov (United States)

    Roberts, Stephen S; Chou, Alexander J; Cheung, Nai-Kong V

    2015-01-01

    Pediatric sarcomas are a heterogeneous group of malignant tumors of bone and soft tissue origin. Although more than 100 different histologic subtypes have been described, the majority of pediatric cases belong to the Ewing's family of tumors, rhabdomyosarcoma and osteosarcoma. Most patients that present with localized stage are curable with surgery and/or chemotherapy; however, those with metastatic disease at diagnosis or those who experience a relapse continue to have a very poor prognosis. New therapies for these patients are urgently needed. Immunotherapy is an established treatment modality for both liquid and solid tumors, and in pediatrics, most notably for neuroblastoma and osteosarcoma. In the past, immunomodulatory agents such as interferon, interleukin-2, and liposomal-muramyl tripeptide phosphatidyl-ethanolamine have been tried, with some activity seen in subsets of patients; additionally, various cancer vaccines have been studied with possible benefit. Monoclonal antibody therapies against tumor antigens such as disialoganglioside GD2 or immune checkpoint targets such as CTLA-4 and PD-1 are being actively explored in pediatric sarcomas. Building on the success of adoptive T cell therapy for EBV-related lymphoma, strategies to redirect T cells using chimeric antigen receptors and bispecific antibodies are rapidly evolving with potential for the treatment of sarcomas. This review will focus on recent preclinical and clinical developments in targeted agents for pediatric sarcomas with emphasis on the immunobiology of immune checkpoints, immunoediting, tumor microenvironment, antibody engineering, cell engineering, and tumor vaccines. The future integration of antibody-based and cell-based therapies into an overall treatment strategy of sarcoma will be discussed. PMID:26301204

  9. Adjuvant for vaccine immunotherapy of cancer--focusing on Toll-like receptor 2 and 3 agonists for safely enhancing antitumor immunity.

    Science.gov (United States)

    Seya, Tsukasa; Shime, Hiroaki; Takeda, Yohei; Tatematsu, Megumi; Takashima, Ken; Matsumoto, Misako

    2015-12-01

    Immune-enhancing adjuvants usually targets antigen (Ag)-presenting cells to tune up cellular and humoral immunity. CD141(+) dendritic cells (DC) represent the professional Ag-presenting cells in humans. In response to microbial pattern molecules, these DCs upgrade the maturation stage sufficient to improve cross-presentation of exogenous Ag, and upregulation of MHC and costimulators, allowing CD4/CD8 T cells to proliferate and liberating cytokines/chemokines that support lymphocyte attraction and survival. These DCs also facilitate natural killer-mediated cell damage. Toll-like receptors (TLRs) and their signaling pathways in DCs play a pivotal role in DC maturation. Therefore, providing adjuvants in addition to Ag is indispensable for successful vaccine immunotherapy for cancer, which has been approved in comparison with antimicrobial vaccines. Mouse CD8α(+) DCs express TLR7 and TLR9 in addition to the TLR2 family (TLR1, 2, and 6) and TLR3, whereas human CD141(+) DCs exclusively express the TLR2 family and TLR3. Although human and mouse plasmacytoid DCs commonly express TLR7/9 to respond to their agonists, the results on mouse adjuvant studies using TLR7/9 agonists cannot be simply extrapolated to human adjuvant immunotherapy. In contrast, TLR2 and TLR3 are similarly expressed in both human and mouse Ag-presenting DCs. Bacillus Calmette-Guerin peptidoglycan and polyinosinic-polycytidylic acid are representative agonists for TLR2 and TLR3, respectively, although they additionally stimulate cytoplasmic sensors: their functional specificities may not be limited to the relevant TLRs. These adjuvants have been posted up to a certain achievement in immunotherapy in some cancers. We herein summarize the history and perspectives of TLR2 and TLR3 agonists in vaccine-adjuvant immunotherapy for cancer. PMID:26395101

  10. Immunotherapy: A useful strategy to help combat multidrug resistance

    OpenAIRE

    Curiel, Tyler J.

    2012-01-01

    Multidrug resistance (MDR) renders cancer cells relatively invulnerable to treatment with many standard cytotoxic anti-cancer agents. Cancer immunotherapy could be an important adjunct other strategies to treat MDR positive cancers, as resistance to immunotherapy generally is unrelated to mechanisms of resistance to cytotoxic agents. Immunotherapy to combat MDR positive tumors could use any of the following strategies: direct immune attack against MDR positive cells, using MDR as an immune ta...

  11. Cellular immunotherapy using irradiated lung cancer cell vaccine co-expressing GM-CSF and IL-18 can induce significant antitumor effects

    International Nuclear Information System (INIS)

    Although the whole tumor cell vaccine can provide the best source of immunizing antigens, there is still a limitation that most tumors are not naturally immunogenic. Tumor cells genetically modified to secrete immune activating cytokines have been proved to be more immunogenic. IL-18 could augment proliferation of T cells and cytotoxicity of NK cells. GM-CSF could stimulate dendritic cells, macrophages and enhance presentation of tumor antigens. In our study, we used mouse GM-CSF combined with IL-18 to modify Lewis lung cancer LL/2, then investigated whether vaccination could suppress tumor growth and promote survival. The Lewis lung cancer LL/2 was transfected with co-expressing mouse GM-CSF and IL-18 plasmid by cationic liposome, then irradiated with a sublethal dose X ray (100 Gy) to prepare vaccines. Mice were subcutaneously immunized with this inactivated vaccine and then inoculated with autologous LL/2 to estimate the antitumor efficacy. The studies reported here showed that LL/2 tumor cell vaccine modified by a co-expressing mouse GM-CSF and IL-18 plasmid could significantly inhibit tumor growth and increased survival of the mice bearing LL/2 tumor whether prophylactic or adoptive immunotherapy in vivo. A significant reduction of proliferation and increase of apoptosis were also observed in the tumor treated with vaccine of co-expressing GM-CSF and IL-18. The potent antitumor effect correlated with higher secretion levels of pro-inflammatory cytokines such as IL-18, GM-CSF, interferon-γ in serum, the proliferation of CD4+ IFN-γ+, CD8+ IFN-γ+ T lymphocytes in spleen and the infiltration of CD4+, CD8+ T in tumor. Furthermore, the mechanism of tumor-specific immune response was further proved by 51Cr cytotoxicity assay in vitro and depletion of CD4, CD8, NK immune cell subsets in vivo. The results suggested that the antitumor mechanism was mainly depended on CD4+, CD8+ T lymphocytes. These results provide a new insight into therapeutic mechanisms of IL-18

  12. Immunotherapy of metastatic and autochthonous liver cancer with IL-15/IL-15Rα fusion protein

    OpenAIRE

    Cheng, Liang; Du, Xuexiang; Su, Lishan; Wang, Shengdian

    2014-01-01

    Liver cancer has a poor prognosis. Our recent study demonstrates that hyper-IL-15, composed of IL-15 and the sushi domain of IL-15 receptor α chain, provides an effective therapy against well-established metastatic and autochthonous liver cancers in mouse models by triggering activation and expansion of hepatic CD8+ T cells.

  13. CYTOTOXIC T-LYMPHOCYTE IMMUNOTHERAPY FOR OVARIAN CANCER: A PILOT STUDY

    OpenAIRE

    Wright, Stephen E.; Rewers-Felkins, Kathleen A.; Quinlin, Imelda S.; Phillips, Catherine A.; Townsend, Mary; Philip, Ramila; Dobrzanski, Mark J.; Lockwood-Cooke, Pamela R.; Robinson, William

    2012-01-01

    The objective was to evaluate the toxicity and feasibility of intraperitoneal (IP) infusion of tumor-specific cytotoxic T-lymphocytes (CTL) as therapy for recurrent ovarian cancer, and to determine if repetitive cycles of CTL generation and infusion measurably increases the host’s ovarian cancer immune response.

  14. Dynamic contrast enhanced MRI detects early response to adoptive NK cellular immunotherapy targeting the NG2 proteoglycan in a rat model of glioblastoma.

    Directory of Open Access Journals (Sweden)

    Cecilie Brekke Rygh

    Full Text Available There are currently no established radiological parameters that predict response to immunotherapy. We hypothesised that multiparametric, longitudinal magnetic resonance imaging (MRI of physiological parameters and pharmacokinetic models might detect early biological responses to immunotherapy for glioblastoma targeting NG2/CSPG4 with mAb9.2.27 combined with natural killer (NK cells. Contrast enhanced conventional T1-weighted MRI at 7±1 and 17±2 days post-treatment failed to detect differences in tumour size between the treatment groups, whereas, follow-up scans at 3 months demonstrated diminished signal intensity and tumour volume in the surviving NK+mAb9.2.27 treated animals. Notably, interstitial volume fraction (ve, was significantly increased in the NK+mAb9.2.27 combination therapy group compared mAb9.2.27 and NK cell monotherapy groups (p = 0.002 and p = 0.017 respectively in cohort 1 animals treated with 1 million NK cells. ve was reproducibly increased in the combination NK+mAb9.2.27 compared to NK cell monotherapy in cohort 2 treated with increased dose of 2 million NK cells (p<0.0001, indicating greater cell death induced by NK+mAb9.2.27 treatment. The interstitial volume fraction in the NK monotherapy group was significantly reduced compared to mAb9.2.27 monotherapy (p<0.0001 and untreated controls (p = 0.014 in the cohort 2 animals. NK cells in monotherapy were unable to kill the U87MG cells that highly expressed class I human leucocyte antigens, and diminished stress ligands for activating receptors. A significant association between apparent diffusion coefficient (ADC of water and ve in combination NK+mAb9.2.27 and NK monotherapy treated tumours was evident, where increased ADC corresponded to reduced ve in both cases. Collectively, these data support histological measures at end-stage demonstrating diminished tumour cell proliferation and pronounced apoptosis in the NK+mAb9.2.27 treated tumours compared to the other

  15. Dynamic Contrast Enhanced MRI Detects Early Response to Adoptive NK Cellular Immunotherapy Targeting the NG2 Proteoglycan in a Rat Model of Glioblastoma

    Science.gov (United States)

    Thuen, Marte; Gras Navarro, Andrea; Huuse, Else Marie; Thorsen, Frits; Poli, Aurelie; Zimmer, Jacques; Haraldseth, Olav; Lie, Stein Atle; Enger, Per Øyvind; Chekenya, Martha

    2014-01-01

    There are currently no established radiological parameters that predict response to immunotherapy. We hypothesised that multiparametric, longitudinal magnetic resonance imaging (MRI) of physiological parameters and pharmacokinetic models might detect early biological responses to immunotherapy for glioblastoma targeting NG2/CSPG4 with mAb9.2.27 combined with natural killer (NK) cells. Contrast enhanced conventional T1-weighted MRI at 7±1 and 17±2 days post-treatment failed to detect differences in tumour size between the treatment groups, whereas, follow-up scans at 3 months demonstrated diminished signal intensity and tumour volume in the surviving NK+mAb9.2.27 treated animals. Notably, interstitial volume fraction (ve), was significantly increased in the NK+mAb9.2.27 combination therapy group compared mAb9.2.27 and NK cell monotherapy groups (p = 0.002 and p = 0.017 respectively) in cohort 1 animals treated with 1 million NK cells. ve was reproducibly increased in the combination NK+mAb9.2.27 compared to NK cell monotherapy in cohort 2 treated with increased dose of 2 million NK cells (p<0.0001), indicating greater cell death induced by NK+mAb9.2.27 treatment. The interstitial volume fraction in the NK monotherapy group was significantly reduced compared to mAb9.2.27 monotherapy (p<0.0001) and untreated controls (p = 0.014) in the cohort 2 animals. NK cells in monotherapy were unable to kill the U87MG cells that highly expressed class I human leucocyte antigens, and diminished stress ligands for activating receptors. A significant association between apparent diffusion coefficient (ADC) of water and ve in combination NK+mAb9.2.27 and NK monotherapy treated tumours was evident, where increased ADC corresponded to reduced ve in both cases. Collectively, these data support histological measures at end-stage demonstrating diminished tumour cell proliferation and pronounced apoptosis in the NK+mAb9.2.27 treated tumours compared to the other groups. In

  16. Complications of bacillus Calmette-Guerin immunotherapy in 1,278 patients with bladder cancer.

    Science.gov (United States)

    Lamm, D L; Stogdill, V D; Stogdill, B J; Crispen, R G

    1986-02-01

    Our series of 195 patients, plus 134 reported on in the literature and 949 reviewed by various physicians provide 1,278 patients for review of bacillus Calmette-Guerin therapy complications. Cystitis occurred in 91 per cent of the patients. Complications identified included fever more than 103F in 50 patients (3.9 per cent), granulomatous prostatitis in 17 (1.3 per cent), bacillus Calmette-Guerin pneumonitis or hepatitis in 12 (0.9 per cent), arthritis or arthralgia in 6 (0.5 per cent), hematuria requiring catheterization or transfusion in 6 (0.5 per cent), skin rash in 5 (0.4 per cent), skin abscess in 5 (0.4 per cent), ureteral obstruction in 4 (0.3 per cent), epididymo-orchitis in 2 (0.2 per cent), bladder contracture in 2 (0.2 per cent), hypotension in 1 (0.1 per cent) and cytopenia in 1 (0.1 per cent). Most of the severe irritative side effects and subsequent systemic complications can be prevented with prophylactic isoniazid given for 3 days, beginning the morning of treatment. Patients with life-threatening systemic bacillus Calmette-Guerin infection or anaphylaxis should receive 500 mg. cycloserine twice daily for 3 days in addition to combination antituberculous therapy because the rapid action of this drug may be life-saving. Direct intralesional bacillus Calmette-Guerin immunotherapy can produce sepsis and death, and should be avoided but intravesical bacillus Calmette-Guerin generally is well tolerated and has produced no complication in more than 95 per cent of the patients treated. PMID:3511286

  17. Virus-based immunotherapy of cancer: what do we know and where are we going?

    DEFF Research Database (Denmark)

    Sørensen, Maria Rathmann; Thomsen, Allan Randrup

    2007-01-01

    mechanisms. This review aims to evaluate selected cancer vaccination approaches using virus-based cancer vaccines. These seem promising based on their capacity to mimic natural infection and hence to efficiently trigger the innate immune system and in turn a potent cellular immune response towards the...... tumours. However, even when a potent immune response has been induced, this is often not sufficient to eliminate the tumour completely before the cancer cells have had time to evolve new escape mechanisms as a result of the selection pressure from the initial immune response directed towards them...

  18. Cancer immunotherapy employing an innovative strategy to enhance CD4+ T cell help in the tumor microenvironment.

    Directory of Open Access Journals (Sweden)

    Liwen Song

    Full Text Available Chemotherapy and/or radiation therapy are widely used as cancer treatments, but the antitumor effects they produce can be enhanced when combined with immunotherapies. Chemotherapy kills tumor cells, but it also releases tumor antigen and allows the cross-presentation of the tumor antigen to trigger antigen-specific cell-mediated immune responses. Promoting CD4+ T helper cell immune responses can be used to enhance the cross-presentation of the tumor antigen following chemotherapy. The pan HLA-DR binding epitope (PADRE peptide is capable of generating antigen-specific CD4+ T cells that bind various MHC class II molecules with high affinity and has been widely used in conjunction with vaccines to improve their potency by enhancing CD4+ T cell responses. Here, we investigated whether intratumoral injection of PADRE and the adjuvant CpG into HPV16 E7-expressing TC-1 tumors following cisplatin chemotherapy could lead to potent antitumor effects and antigen-specific cell-mediated immune responses. We observed that treatment with all three agents produced the most potent antitumor effects compared to pairwise combinations. Moreover, treatment with cisplatin, CpG and PADRE was able to control tumors at a distant site, indicating that our approach is able to induce cross-presentation of the tumor antigen. Treatment with cisplatin, CpG and PADRE also enhanced the generation of PADRE-specific CD4+ T cells and E7-specific CD8+ T cells and decreased the number of MDSCs in tumor loci. The treatment regimen presented here represents a universal approach to cancer control.

  19. IMMUNOTHERAPY WITH VISCUM ALBUM EXTRACT IN THE TREATMENT OF ADVANCED COLORECTAL CANCER

    OpenAIRE

    T. Oniu; M. CAZACU; Muntean, V.; Melania Oniu; Anca Mihailov; C. Lungoci

    2011-01-01

    Background: Most clinical trials using mistletoe to treat colorectal cancer are out-of-date and have major methodological weaknesses that raise doubts about their findings. Meanwhile, the arsenal of chemotherapy has much evolved over the last decade. Thus, the aim of this study was to determine the effectiveness of the total plant extract Isorel in association with modern chemotherapy in the treatment of colorectal cancer. Methods: After the surgical removal of the primary tumor, a total of 1...

  20. MOUSE MODEL FOR PRE-CLINICAL STUDY OF HUMAN CANCER IMMUNOTHERAPY

    Science.gov (United States)

    Ya, Zhiya; Hailemichael, Yared; Overwijk, Willem; Restifo, Nicholas

    2015-01-01

    This unit describes protocols for developing tumors in mice including subcutaneous growth, pulmonary metastases of B16 melanoma, and spontaneous melanoma in B-Raf V600E/PTEN deletion transgenic mouse models. Two immunization methods to prevent B16 tumor growth are described using B16.GM-CSF and recombinant vaccinia virus. A therapeutic approach is also included that uses adoptive transfer of tumor antigen-specific T cells. Methods including CTL induction, isolation, testing, and genetic modification of mouse T cells for adoptive transfer by using retrovirus expressing genes of interest are provided. Additional sections, including growing B16 melanoma, enumerating pulmonary metastases, tumor imaging technique and use of recombinant viruses for vaccination, are discussed together with safety concerns. PMID:25640991

  1. MOUSE MODEL FOR PRE-CLINICAL STUDY OF HUMAN CANCER IMMUNOTHERAPY

    OpenAIRE

    Ya, Zhiya; Hailemichael, Yared; Overwijk, Willem; Restifo, Nicholas

    2015-01-01

    This unit describes protocols for developing tumors in mice including subcutaneous growth, pulmonary metastases of B16 melanoma, and spontaneous melanoma in B-Raf V600E/PTEN deletion transgenic mouse models. Two immunization methods to prevent B16 tumor growth are described using B16.GM-CSF and recombinant vaccinia virus. A therapeutic approach is also included that uses adoptive transfer of tumor antigen-specific T cells. Methods including CTL induction, isolation, testing, and genetic modif...

  2. The feasibility research of galactosyl-anti-mouse CD3 monoclonal antibody being used as carrier of immunotherapy after surgical operation of liver cancer

    International Nuclear Information System (INIS)

    Objective: To probe into the feasibility of galactosyl-anti-mouse CD3 monoclonal antibody (Gal-Ant-CD3 McAb) being used as carrier of immunotherapy after surgical operation of liver cancer. Methods: Gal-Ant-CD3 McAb was prepared by the covalent coupling of anti-mouse CD3 monoclonal antibody (Ant-CD3 McAb) with a bifunctional reagent, 2-imino-2-methoxyethyl-1-thio-galactose. After Gal-Ant-CD3 McAb and Ant-CD3 McAb were labelled with 131I or 125I, the data of biodistribution in mice, and of imaging in rabbit were obtained. After tumour infiltrating lymphocytes (TIL) and Gal-Ant-CD3 McAb were coupled into Gal-Ant-CD3 McAb-TIL, its liver taxis and cytotoxic activity against autologous cancer cells were measured in vitro. Results: Gal-Ant-CD3 McAb had remarkable livertaxis and its uptake in per gram liver was (59.0 +- 2.1)% that was more than two-fold higher than that of Ant-CD3 McAb. Gal-Ant-CD3 McAb-TIL had an obvious liver taxis and cytotoxic activity against autologous cancer cells in vitro. Conclusion: Gal-Ant-CD3 McAb can be used as the carrier of immunotherapy after surgical operation of liver cancer

  3. Identification of a microRNA signature in dendritic cell vaccines for cancer immunotherapy

    DEFF Research Database (Denmark)

    Holmstrøm, Kim; Pedersen, Ayako Wakatsuki; Claesson, Mogens Helweg;

    2010-01-01

    Dendritic cells (DCs) exposed to tumor antigens followed by treatment with T(h)1-polarizing differentiation signals have paved the way for the development of DC-based cancer vaccines. Critical parameters for assessment of the optimal functional state of DCs and prediction of the vaccine potency of...

  4. 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. PMID:18633461

  5. Sub-lethal radiation enhances anti-tumor immunotherapy in a transgenic mouse model of pancreatic cancer

    International Nuclear Information System (INIS)

    It is not uncommon to observe circulating tumor antigen-specific T lymphocytes in cancer patients despite a lack of significant infiltration and destruction of their tumors. Thus, an important goal for tumor immunotherapy is to identify ways to modulate in vivo anti-tumor immunity to achieve clinical efficacy. We investigate this proposition in a spontaneous mouse tumor model, Rip1-Tag2. Experimental therapies were carried out in two distinctive trial designs, intended to either intervene in the explosive growth of small tumors, or regress bulky end-stage tumors. Rip1-Tag2 mice received a single transfer of splenocytes from Tag-specific, CD4+ T cell receptor transgenic mice, a single sub-lethal radiation, or a combination therapy in which the lymphocyte transfer was preceded by the sub-lethal radiation. Tumor burden, the extent of lymphocyte infiltration into solid tumors and host survival were used to assess the efficacy of these therapeutic approaches. In either intervention or regression, the transfer of Tag-specific T cells alone did not result in significant lymphocyte infiltration into solid tumors, not did it affect tumor growth or host survival. In contrast, the combination therapy resulted in significant reduction in tumor burden, increase in lymphocyte infiltration into solid tumors, and extension of survival. The results indicate that certain types of solid tumors may be intrinsically resistant to infiltration and destruction by tumor-specific T lymphocytes. Our data suggest that such resistance can be disrupted by sub-lethal radiation. The combinatorial approach presented here merits consideration in the design of clinical trials aimed to achieve T cell-mediated anti-tumor immunity

  6. Route of administration of the TLR9 agonist CpG critically determines the efficacy of cancer immunotherapy in mice.

    Directory of Open Access Journals (Sweden)

    Stefan Nierkens

    Full Text Available BACKGROUND: The TLR9 agonist CpG is increasingly applied in preclinical and clinical studies as a therapeutic modality to enhance tumor immunity. The clinical application of CpG appears, however, less successful than would be predicted from animal studies. One reason might be the different administration routes applied in most mouse studies and clinical trials. We studied whether the efficacy of CpG as an adjuvant in cancer immunotherapy is dependent on the route of CpG administration, in particular when the tumor is destructed in situ. METHODOLOGY/PRINCIPAL FINDINGS: In situ tumor destruction techniques are minimally invasive therapeutic alternatives for the treatment of (nonresectable solid tumors. In contrast to surgical resection, tumor destruction leads to the induction of weak but tumor-specific immunity that can be enhanced by coapplication of CpG. As in situ tumor destruction by cryosurgery creates an instant local release of antigens, we applied this model to study the efficacy of CpG to enhance antitumor immunity when administrated via different routes: peritumoral, intravenous, and subcutaneous but distant from the tumor. We show that peritumoral administration is superior in the activation of dendritic cells, induction of tumor-specific CTL, and long-lasting tumor protection. Although the intravenous and subcutaneous (at distant site exposures are commonly used in clinical trials, they only provided partial protection or even failed to enhance antitumor responses as induced by cryosurgery alone. CONCLUSIONS/SIGNIFICANCE: CpG administration greatly enhances the efficacy of in situ tumor destruction techniques, provided that CpG is administered in close proximity of the released antigens. Hence, this study helps to provide directions to fully benefit from CpG as immune stimulant in a clinical setting.

  7. The Local Influence of Pioneer Investigators on Technology Adoption: Evidence from New Cancer Drugs

    OpenAIRE

    Leila Agha; David Molitor

    2015-01-01

    Local opinion leaders may play a key role in easing information frictions associated with technology adoption. This paper analyzes the influence of physician investigators who lead pivotal clinical trials for new cancer drugs. By comparing diffusion patterns across many drugs, we separate correlated regional demand for new technology from information spillovers. Using original data on clinical trial study authors for 21 new cancer drugs along with Medicare claims data from 1998-2008, we find ...

  8. Development of molecularly targeted agents and immunotherapies in small cell lung cancer.

    Science.gov (United States)

    Sharp, Adam; Bhosle, Jaishree; Abdelraouf, Fatma; Popat, Sanjay; O'Brien, Mary; Yap, Timothy A

    2016-06-01

    Small cell lung cancer (SCLC) is a smoking-induced malignancy with multiple toxin-associated mutations, which accounts for 15% of all lung cancers. It remains a clinical challenge with a rapid doubling time, early dissemination and poor prognosis. Despite multiple clinical trials in SCLC, platinum-based chemotherapy remains the mainstay of treatment in the first line advanced disease setting; good initial responses are nevertheless inevitably followed by disease relapse and survival ultimately remains poor. There are currently no molecularly targeted agents licenced for use in SCLC. Advances in sequencing the cancer genome and other high-throughput profiling technologies have identified aberrant pathways and mechanisms implicated in SCLC development and progression. Novel anti-tumour therapeutics that impact these putative targets are now being developed and investigated in SCLC. In this review, we discuss novel anti-tumour agents assessed in SCLC with reference to the complex molecular mechanisms implicated in SCLC development and progression. We focus on novel DNA damage response inhibitors, immune checkpoint modulators and antibody-drug conjugates that have shown promise in SCLC, and which may potentially transform treatment strategies in this disease. Finally, we envision the future management of SCLC and propose a biomarker-driven translational treatment paradigm for SCLC that incorporates next generation sequencing studies with patient tumours, circulating plasma DNA and functional imaging. Such modern strategies have the potential to transform the management and improve patient outcomes in SCLC. PMID:27060747

  9. Combination immunotherapy and active-specific tumor cell vaccination augments anti-cancer immunity in a mouse model of gastric cancer

    Directory of Open Access Journals (Sweden)

    van den Engel Natasja K

    2011-08-01

    Full Text Available Abstract Background Active-specific immunotherapy used as an adjuvant therapeutic strategy is rather unexplored for cancers with poorly characterized tumor antigens like gastric cancer. The aim of this study was to augment a therapeutic immune response to a low immunogenic tumor cell line derived from a spontaneous gastric tumor of a CEA424-SV40 large T antigen (CEA424-SV40 TAg transgenic mouse. Methods Mice were treated with a lymphodepleting dose of cyclophosphamide prior to reconstitution with syngeneic spleen cells and vaccination with a whole tumor cell vaccine combined with GM-CSF (a treatment strategy abbreviated as LRAST. Anti-tumor activity to subcutaneous tumor challenge was examined in a prophylactic as well as a therapeutic setting and compared to corresponding controls. Results LRAST enhances tumor-specific T cell responses and efficiently inhibits growth of subsequent transplanted tumor cells. In addition, LRAST tended to slow down growth of established tumors. The improved anti-tumor immune response was accompanied by a transient decrease in the frequency and absolute number of CD4+CD25+FoxP3+ T cells (Tregs. Conclusions Our data support the concept that whole tumor cell vaccination in a lymphodepleted and reconstituted host in combination with GM-CSF induces therapeutic tumor-specific T cells. However, the long-term efficacy of the treatment may be dampened by the recurrence of Tregs. Strategies to counteract suppressive immune mechanisms are required to further evaluate this therapeutic vaccination protocol.

  10. Substantially Modified Ratios of Effector to Regulatory T Cells During Chemotherapy in Ovarian Cancer Patients Return to Pre-Treatment Levels at Completion: Implications for Immunotherapy

    International Nuclear Information System (INIS)

    Ovarian cancer is the leading cause of death from gynaecological malignancy. Despite improved detection and treatment options, relapse rates remain high. Combining immunotherapy with the current standard treatments may provide an improved prognosis, however, little is known about how standard chemotherapy affects immune potential (particularly T cells) over time, and hence, when to optimally combine it with immunotherapy (e.g., vaccines). Herein, we assess the frequency and ratio of CD8+ central memory and effector T cells as well as CD4+ effector and regulatory T cells (Tregs) during the first 18 weeks of standard chemotherapy for ovarian cancer patients. In this pilot study, we observed increased levels of recently activated Tregs with tumor migrating ability (CD4+CD25hiFoxp3+CD127−CCR4+CD38+ cells) in patients when compared to controls. Although frequency changes of Tregs as well as the ratio of effector T cells to Tregs were observed during treatment, the Tregs consistently returned to pre-chemotherapy levels at the end of treatment. These results indicate T cell subset distributions associated with recurrence may be largely resistant to being “re-set” to healthy control homeostatic levels following standard treatments. However, it may be possible to enhance T effector to Treg ratios transiently during chemotherapy. These results suggest personalized immune monitoring maybe beneficial when combining novel immuno-therapeutics with standard treatment for ovarian cancer patients

  11. Substantially Modified Ratios of Effector to Regulatory T Cells During Chemotherapy in Ovarian Cancer Patients Return to Pre-Treatment Levels at Completion: Implications for Immunotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Park, Anthony; Govindaraj, Chindu; Xiang, Sue D., E-mail: Sue.Xiang@monash.edu [Department of Immunology, Central Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Victoria 3004 (Australia); Halo, Julene; Quinn, Michael [Department of Oncology, Royal Women’s Hospital, Melbourne, Victoria 3052 (Australia); Scalzo-Inguanti, Karen; Plebanski, Magdalena, E-mail: Sue.Xiang@monash.edu [Department of Immunology, Central Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Victoria 3004 (Australia)

    2012-06-18

    Ovarian cancer is the leading cause of death from gynaecological malignancy. Despite improved detection and treatment options, relapse rates remain high. Combining immunotherapy with the current standard treatments may provide an improved prognosis, however, little is known about how standard chemotherapy affects immune potential (particularly T cells) over time, and hence, when to optimally combine it with immunotherapy (e.g., vaccines). Herein, we assess the frequency and ratio of CD8+ central memory and effector T cells as well as CD4+ effector and regulatory T cells (Tregs) during the first 18 weeks of standard chemotherapy for ovarian cancer patients. In this pilot study, we observed increased levels of recently activated Tregs with tumor migrating ability (CD4+CD25{sup hi}Foxp3+CD127−CCR4+CD38+ cells) in patients when compared to controls. Although frequency changes of Tregs as well as the ratio of effector T cells to Tregs were observed during treatment, the Tregs consistently returned to pre-chemotherapy levels at the end of treatment. These results indicate T cell subset distributions associated with recurrence may be largely resistant to being “re-set” to healthy control homeostatic levels following standard treatments. However, it may be possible to enhance T effector to Treg ratios transiently during chemotherapy. These results suggest personalized immune monitoring maybe beneficial when combining novel immuno-therapeutics with standard treatment for ovarian cancer patients.

  12. Mucin 1-specific immunotherapy in a mouse model of spontaneous breast cancer.

    Science.gov (United States)

    Mukherjee, Pinku; Madsen, Cathy S; Ginardi, Amelia R; Tinder, Teresa L; Jacobs, Fred; Parker, Joanne; Agrawal, Babita; Longenecker, B Michael; Gendler, Sandra J

    2003-01-01

    Human mucin 1 (MUC1) is an epithelial mucin glycoprotein that is overexpressed in 90% of all adenocarcinomas including breast, lung, pancreas, prostate, stomach, colon, and ovary. MUC1 is a target for immune intervention, because, in patients with solid adenocarcinomas, low-level cellular and humoral immune responses to MUC1 have been observed, which are not sufficiently strong to eradicate the growing tumor. The hypothesis for this study is that enhancing MUC1-specific immunity will result in antitumor immunity. To test this, the authors have developed a clinically relevant breast cancer model that demonstrates peripheral and central tolerance to MUC1 and develops spontaneous tumors of the mammary gland. In these mice, the authors tested a vaccine formulation comprised of liposomal-MUC1 lipopeptide and human recombinant interleukin-2. Results indicate that when compared with untreated mice, immunized mice develop T cells that express intracellular IFN-gamma, are reactive with MHC class I H-2Db/MUC1 tetramer, and are cytotoxic against MUC1-expressing tumor cells in vitro. The presence of MUC1-specific CTL did not translate into a clinical response as measured by time of tumor onset, tumor burden, and survival. The authors demonstrate that some of the immune-evasion mechanisms used by the tumor cells include downregulation of MHC-class I molecule, expression of TGF-beta2, and decrease in IFN-gamma -expressing effector T cells as tumors progress. Finally, utilizing an injectable breast cancer model, the authors show that targeting a single tumor antigen may not be an effective antitumor treatment, but that immunization with dendritic cells fed with whole tumor lysate is effective in breaking tolerance and protecting mice from subsequent tumor challenge. A physiologically relevant spontaneous breast cancer model has been developed to test improved immunotherapeutic approaches. PMID:12514429

  13. Identification of cell surface proteins as potential immunotherapy targets in twelve pediatric cancers

    Directory of Open Access Journals (Sweden)

    RimasJOrentas

    2012-12-01

    Full Text Available Technological advances now allow us to rapidly produce CARs and other antibody-derived therapeutics targeting cell surface receptors. To maximize the potential of these new technologies, relevant extracellular targets must be identified. The Pediatric Oncology Branch of the NCI curates a freely accessible database of gene expression data for both pediatric cancers and normal tissues, through which we have defined discrete sets of over-expressed transcripts in twelve pediatric cancer subtypes as compared to normal tissues. We coupled gene expression profiles to current annotation databases (i.e., Affymetrix, Gene Ontology, Entrez Gene, in order to categorize transcripts by their subcellular location. In this manner we generated a list of potential immune targets expressed on the cell surface, ranked by their difference from normal tissue. Global differences from normal between each of the pediatric tumor types studied varied, indicating that some malignancies expressed transcript sets that were more highly diverged from normal tissues than others. The validity of our approach is seen by our findings for pre-B cell ALL, where targets currently in clinical trials were top-ranked hits (CD19, CD22. For some cancers, reagents already in development could potentially be applied to a new disease class, as exemplified by CD30 expression on sarcomas. Moreover, several potential new targets shared among several pediatric solid tumors are herein identified, such as MCAM (MUC18, MTDH (metadherin, and GPC2 (glypican-2. These targets have been identified at the mRNA level and are yet to be validated at the protein level. The safety of targeting these antigens has yet to be demonstrated and therefore the identified transcripts should be considered preliminary candidates for new CAR and therapeutic antibody targets. Prospective candidate targets will be evaluated by proteomic analysis including Westerns and immunohistochemistry of normal and tumor tissues.

  14. Sinks, suppressors and antigen presenters: how lymphodepletion enhances T cell-mediated tumor immunotherapy

    OpenAIRE

    Klebanoff, Christopher A.; Khong, Hung T.; Antony, Paul A.; Douglas C Palmer; Restifo, Nicholas P

    2005-01-01

    Lymphodepletion followed by adoptive cell transfer (ACT) of autologous, tumor-reactive T cells boosts antitumor immunotherapeutic activity in mouse and in humans. In the most recent clinical trials, lymphodepletion together with ACT has an objective response rate of 50% in patients with solid metastatic tumors. The mechanisms underlying this recent advance in cancer immunotherapy are beginning to be elucidated and include: the elimination of cellular cytokine ‘sinks’ for homeostatic γC-cytoki...

  15. Sialoglyco proteins trypanosome cruz i. Possible to use for specific active immunotherapy strategies in colon cancer?

    International Nuclear Information System (INIS)

    Introduction: The sialyl-Tn structure (SAa2-6GalNAcaSer / Thr) is expressed in cancer colon and not in normal colon tissue, with an intermediate expression in premalignant lesions. Dimethylhydrazine (DMH) induced colon cancer in rats with similar morphology carcinomas human colorectal and express sialyl-Tn similarly. It has been observed that infection of rats the flagellated protozoan Trypanosoma cruzi is associated with a lower incidence colon cancer in this experimental model. There is still no explanation this phenomenon. Recently, our group demonstrated the presence of antigen sialyl-Tn in T. cruzi. Objectives: To evaluate the antitumor effect of immunobiological extracts of T. cruzi in the model of colon carcinogenesis induced by DMH, determining the role of the glycoproteins expressing sialyl Tn. Methodology: was induced colonic carcinogenesis in 16 Wistar rats by injection weekly DMH (15 mg / Kg). The animals were divided into four groups: (A) only treated with the carcinogen; (B) Simultaneous immunization carcinogenesis with extracts of T. cruzi (epimastigotes); (C) Simultaneous immunization carcinogenesis with extracts of T. cruzi I deglycosylated (m-periodate 80 mM); and (D) Carcinogenesis Simultaneous immunization with ovine submaxillary mucin (OSM), rich in antigen sialyl-Tn. After five immunizations (weeks 0, 4, 8, 10 and 12) the animals were sacrificed at week 24 and the colon was evaluated istopathologically. Results: compatible with carcinomas of colon, macroscopic lesions were observed in 3/4 rats from group A, group B in fourth in 4/4 in group C and group D. When 0/4 microscopic analysis, the animals in groups A and C showed lesions more invasive than the lesions observed in animals of group B. Conclusions: These Preliminary results suggest that immunization with T. cruzi extracts can have a protective effect against the development of colon cancer, where the epitopes Carb may be responsible for this effect. He is currently in course further

  16. Checkpoint inhibitors in cancer immunotherapy: Cross reactivity of a CTLA-4 antibody and IDO-inhibitor L-1MT in pigs

    DEFF Research Database (Denmark)

    Al-Shatrawi, Zina Adil; Frøsig, Thomas Mørch; Jungersen, Gregers

    Blockade of checkpoint inhibitors has recently shown very convincing results in the treatment of cancer. One key target is CTLA-4, which has been demonstrated to be a potent negative regulator of lymphocyte activation. The treatment with the FDA-approved fully human CTLA-4 monoclonal antibody...... a non-specific activation of porcine T cells. This will be further investigated to provide the basis for in vivo studies investigating checkpoint inhibitor blockade in combination with other cancer immunotherapies. Eventually our goal is to establish pigs as an alternative large animal model...... Ipilimumab increases anticancer T-cell reactivity and overall survival of metastatic cancer patients. Indole-amine 2,3-dioxygenase (IDO) is another checkpoint inhibitor which suppresses T-cell immunity by the depletion of tryptophan in the T-cell microenvironment, and also inhibition of IDO by L-1...

  17. Adoption of Hypofractionated Whole-Breast Irradiation for Early-Stage Breast Cancer: A National Cancer Data Base Analysis

    International Nuclear Information System (INIS)

    Purpose: To evaluate the relationship of patient, hospital, and cancer characteristics with the adoption of hypofractionation in a national sample of patients diagnosed with early-stage breast cancer. Methods and Materials: We performed a retrospective study of breast cancer patients in the National Cancer Data Base from 2004-2011 who were treated with radiation therapy and met eligibility criteria for hypofractionation. We used logistic regression to identify factors associated with receipt of hypofractionation (vs conventional fractionation). Results: We identified 13,271 women (11.7%) and 99,996 women (88.3%) with early-stage breast cancer who were treated with hypofractionation and conventional fractionation, respectively. The use of hypofractionation increased significantly, with 5.4% of patients receiving it in 2004 compared with 22.8% in 2011 (P<.001 for trend). Patients living ≥50 miles from the cancer reporting facility had increased odds of receiving hypofractionation (odds ratio 1.57 [95% confidence interval 1.44-1.72], P<.001). Adoption of hypofractionation was associated with treatment at an academic center (P<.001) and living in an area with high median income (P<.001). Hypofractionation was less likely to be used in patients with high-risk disease, such as increased tumor size (P<.001) or poorly differentiated histologic grade (P<.001). Conclusions: The use of hypofractionation is rising and is associated with increased travel distance and treatment at an academic center. Further adoption of hypofractionation may be tempered by both clinical and nonclinical concerns

  18. Adoption of Hypofractionated Whole-Breast Irradiation for Early-Stage Breast Cancer: A National Cancer Data Base Analysis

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Elyn H. [Yale School of Medicine, Yale School of Medicine, New Haven, Connecticut (United States); Mougalian, Sarah S. [Yale School of Medicine, Yale School of Medicine, New Haven, Connecticut (United States); Department of Medical Oncology, Yale School of Medicine, New Haven, Connecticut (United States); Cancer Outcomes, Public Policy, and Effectiveness Research Center at Yale, New Haven, Connecticut (United States); Soulos, Pamela R. [Yale School of Medicine, Yale School of Medicine, New Haven, Connecticut (United States); Cancer Outcomes, Public Policy, and Effectiveness Research Center at Yale, New Haven, Connecticut (United States); Rutter, Charles E.; Evans, Suzanne B. [Yale School of Medicine, Yale School of Medicine, New Haven, Connecticut (United States); Cancer Outcomes, Public Policy, and Effectiveness Research Center at Yale, New Haven, Connecticut (United States); Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut (United States); Haffty, Bruce G. [Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey and Robert Wood Johnson Medical School, New Brunswick, New Jersey (United States); Gross, Cary P. [Yale School of Medicine, Yale School of Medicine, New Haven, Connecticut (United States); Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey and Robert Wood Johnson Medical School, New Brunswick, New Jersey (United States); Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut (United States); Yu, James B., E-mail: james.b.yu@yale.edu [Yale School of Medicine, Yale School of Medicine, New Haven, Connecticut (United States); Cancer Outcomes, Public Policy, and Effectiveness Research Center at Yale, New Haven, Connecticut (United States); Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut (United States)

    2014-12-01

    Purpose: To evaluate the relationship of patient, hospital, and cancer characteristics with the adoption of hypofractionation in a national sample of patients diagnosed with early-stage breast cancer. Methods and Materials: We performed a retrospective study of breast cancer patients in the National Cancer Data Base from 2004-2011 who were treated with radiation therapy and met eligibility criteria for hypofractionation. We used logistic regression to identify factors associated with receipt of hypofractionation (vs conventional fractionation). Results: We identified 13,271 women (11.7%) and 99,996 women (88.3%) with early-stage breast cancer who were treated with hypofractionation and conventional fractionation, respectively. The use of hypofractionation increased significantly, with 5.4% of patients receiving it in 2004 compared with 22.8% in 2011 (P<.001 for trend). Patients living ≥50 miles from the cancer reporting facility had increased odds of receiving hypofractionation (odds ratio 1.57 [95% confidence interval 1.44-1.72], P<.001). Adoption of hypofractionation was associated with treatment at an academic center (P<.001) and living in an area with high median income (P<.001). Hypofractionation was less likely to be used in patients with high-risk disease, such as increased tumor size (P<.001) or poorly differentiated histologic grade (P<.001). Conclusions: The use of hypofractionation is rising and is associated with increased travel distance and treatment at an academic center. Further adoption of hypofractionation may be tempered by both clinical and nonclinical concerns.

  19. Synergistic effects of laser and adjuvant therapies for cancer: progress in the development of novel cancer treatment methods using combinations of photothermal, photochemical, immunotherapy, and chemotherapy

    Science.gov (United States)

    Chen, Wei R.; Bartels, Kenneth E.; Korbelik, Mladen; Liu, Hong; Nordquist, Robert E.

    2005-04-01

    Combination therapy has been commonly used in chemotherapy, taking advantage of different effects of different chemotherapeutic agents. The treatment effects are often synergistic. The same approach has been investigated in laser phototherapy. Specifically, different combinations of laser photothermal interaction, laser photochemical interaction, immunotherapy and chemotherapy have been used in the treatment of tumors. These novel approaches showed promise in cancer treatment, particularly against metastatic tumors. The recent development in this area is discussed in this paper. Furthermore, a specific combination of photodynamic therapy (PDT) with a novel immunoadjuvant, glycated chitosan (GC), has shown to be effective in the treatment mammary tumors and lung tumors in mice. In the treatment of EMT6 tumor-bearing mice, the Photofrin-based PDT and GC has significantly increased the survival rates from 37.5% with PDT alone to 62.5% when a 0.1-ml 0.5% GC was peritumoral injected immediately after PDT treatment. The survival rate was further increased to 75.0% when GC of higher concentration was used. In comparison, the individual components of the PDT-GC treatment showed either no effect or very limited effects. In the treatment of a poorly immunogenic tumor model, Line 1 lung tumors in mice, the combination of PDT and GC resulted in a 37.5% survival rate, while no survival mice were observed with PDT alone.

  20. Identification of new tumor associated antigens and their usage for new therapeutic strategies based on the combination of chemotherapy and immunotherapy for colorectal cancer patients

    International Nuclear Information System (INIS)

    The main general objective of this project was to characterize a new colorectal carcinoma (CRC) tumor-associated antigen (TAA) and validate a new therapeutic strategy combining chemotherapy and tumor vaccination for the treatment of cancer patients. To this purpose a strategic interaction between Drs. Proietti/Maccali at the ISS and the group of Drs. Rosenberg/Robbins at the NIH was established. A stage of Dr. Maccalli at the NIH allowed to carry out the first steps for the identification and the initial characterization of the CRC TAA named COA-1. A laboratory meeting with Dr. Robbins has been planned on May 24-25 2006 at the ISS, during the International Meeting on Immunotherapy of Cancer: Challenges and Needs, for discussing results and perspectives of this research project

  1. Imaging Biomarkers in Immunotherapy

    Science.gov (United States)

    Juergens, Rosalyn A.; Zukotynski, Katherine A.; Singnurkar, Amit; Snider, Denis P.; Valliant, John F.; Gulenchyn, Karen Y.

    2016-01-01

    Immune-based therapies have been in use for decades but recent work with immune checkpoint inhibitors has now changed the landscape of cancer treatment as a whole. While these advances are encouraging, clinicians still do not have a consistent biomarker they can rely on that can accurately select patients or monitor response. Molecular imaging technology provides a noninvasive mechanism to evaluate tumors and may be an ideal candidate for these purposes. This review provides an overview of the mechanism of action of varied immunotherapies and the current strategies for monitoring patients with imaging. We then describe some of the key researches in the preclinical and clinical literature on the current uses of molecular imaging of the immune system and cancer. PMID:26949344

  2. Classification of current anticancer immunotherapies

    Science.gov (United States)

    Vacchelli, Erika; Pedro, José-Manuel Bravo-San; Buqué, Aitziber; Senovilla, Laura; Baracco, Elisa Elena; Bloy, Norma; Castoldi, Francesca; Abastado, Jean-Pierre; Agostinis, Patrizia; Apte, Ron N.; Aranda, Fernando; Ayyoub, Maha; Beckhove, Philipp; Blay, Jean-Yves; Bracci, Laura; Caignard, Anne; Castelli, Chiara; Cavallo, Federica; Celis, Estaban; Cerundolo, Vincenzo; Clayton, Aled; Colombo, Mario P.; Coussens, Lisa; Dhodapkar, Madhav V.; Eggermont, Alexander M.; Fearon, Douglas T.; Fridman, Wolf H.; Fučíková, Jitka; Gabrilovich, Dmitry I.; Galon, Jérôme; Garg, Abhishek; Ghiringhelli, François; Giaccone, Giuseppe; Gilboa, Eli; Gnjatic, Sacha; Hoos, Axel; Hosmalin, Anne; Jäger, Dirk; Kalinski, Pawel; Kärre, Klas; Kepp, Oliver; Kiessling, Rolf; Kirkwood, John M.; Klein, Eva; Knuth, Alexander; Lewis, Claire E.; Liblau, Roland; Lotze, Michael T.; Lugli, Enrico; Mach, Jean-Pierre; Mattei, Fabrizio; Mavilio, Domenico; Melero, Ignacio; Melief, Cornelis J.; Mittendorf, Elizabeth A.; Moretta, Lorenzo; Odunsi, Adekunke; Okada, Hideho; Palucka, Anna Karolina; Peter, Marcus E.; Pienta, Kenneth J.; Porgador, Angel; Prendergast, George C.; Rabinovich, Gabriel A.; Restifo, Nicholas P.; Rizvi, Naiyer; Sautès-Fridman, Catherine; Schreiber, Hans; Seliger, Barbara; Shiku, Hiroshi; Silva-Santos, Bruno; Smyth, Mark J.; Speiser, Daniel E.; Spisek, Radek; Srivastava, Pramod K.; Talmadge, James E.; Tartour, Eric; Van Der Burg, Sjoerd H.; Van Den Eynde, Benoît J.; Vile, Richard; Wagner, Hermann; Weber, Jeffrey S.; Whiteside, Theresa L.; Wolchok, Jedd D.; Zitvogel, Laurence; Zou, Weiping

    2014-01-01

    During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into “passive” and “active” based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification does not properly reflect the complexity of the drug-host-tumor interaction. Alternatively, anticancer immunotherapeutics can be classified according to their antigen specificity. While some immunotherapies specifically target one (or a few) defined tumor-associated antigen(s), others operate in a relatively non-specific manner and boost natural or therapy-elicited anticancer immune responses of unknown and often broad specificity. Here, we propose a critical, integrated classification of anticancer immunotherapies and discuss the clinical relevance of these approaches. PMID:25537519

  3. Immunotherapy of Metastases Enhances Subsequent Chemotherapy

    Science.gov (United States)

    Hanna, Michael G.; Key, Marc E.

    1982-07-01

    In many multimodal therapies of cancer, postsurgical chemotherapy is administered before immunotherapy for treatment of micrometastatic disease. This sequence may not be the most efficacious. Experiments in which strain 2 guinea pigs bearing syngeneic L10 hepatocarcinomas were given immunotherapy showed that infiltrating immune effector cells not only were tumoricidal but disrupted the characteristically compact structure of metastatic foci. When cytotoxic drugs were administered at the peak of this inflammatory response, the survival rate of the guinea pigs increased significantly. We conclude that postsurgical immunotherapy can enhance the effect of cytotoxic drugs administered subsequently.

  4. Feasibility of capecitabine immunotherapy in a taxane-refractory metastatic breast cancer patient: A rural cancer hospital experience

    Directory of Open Access Journals (Sweden)

    Vivek Tiwari

    2014-05-01

    Full Text Available To manage a metastatic cancer patient in a rural setting is a daunting task owing to the lack of resources and infrastructure. Intravenous chemotherapy (CT, with its debilitating side effects, often causes a decrease in the quality of life (QOL of the patient. When the treatment is of palliative intent, efforts should be made to provide maximum symptom relief to the patient, striking a balance between the patient’s wishes and a sound scientific rationale. We describe our experience with a patient with extensively metastatic breast cancer treated in our rural center with single-agent oral capecitabine, without development of any severe toxicity and with a significant improvement in disease process and patient’s performance status (PS.

  5. Potential utility of the pan-Bcl-2 inhibitor GX15–070 (obatoclax) in cancer immunotherapy

    OpenAIRE

    Kim, Peter S.; Schlom, Jeffrey

    2014-01-01

    An exploration of the immunotherapeutic potential of the pan-Bcl-2 inhibitor GX15–070 (GX15) has revealed that early-activated T cells derived from human peripheral blood are more sensitive to GX15 than are prolonged-activated T cells. Furthermore, non-memory and regulatory T cells also exhibit higher sensitivity to GX15. The implication of these prior findings suggests that GX15 may enhance the efficacy of immunotherapies in clinical settings.

  6. Towards antibody-mediated targeting of dendritic cells for cancer immunotherapy with multivalent polymer-antigen conjugates

    OpenAIRE

    Reuter, Anika

    2013-01-01

    Der Fokus dieser Arbeit lag auf der definierten Synthese multifunktioneller Polymer-Konjugate zur Anwendung in der Krebs-Immunotherapie. Durch gezielte Variation der Kon-jugationsbedingungen wurde Zusammensetzung, Größe und Aggregationsverhalten in Zell-medium sowie in humanem Serum untersucht. Nach definierter physikalisch-chemischer Charakterisierung wurde dann die induzierte Antigen-Präsentation zur Aktivierung der T-Zellproliferation analysiert.rnDafür wurden zwei verschiedene polymere Ca...

  7. Tumor genotype and immune microenvironment in POLE-ultramutated and MSI-hypermutated Endometrial Cancers: New candidates for checkpoint blockade immunotherapy?

    Science.gov (United States)

    Gargiulo, Piera; Della Pepa, Chiara; Berardi, Simona; Califano, Daniela; Scala, Stefania; Buonaguro, Luigi; Ciliberto, Gennaro; Brauchli, Peter; Pignata, Sandro

    2016-07-01

    Endometrial Cancer (EC) is still a challenge for gynecological oncologists because the treatment of the advanced disease remains an unmet need for patients. The Cancer Genome Atlas Research Network (TCGA) recently provided a comprehensive genomic and transcriptomic analysis of EC, offering a new classification of the disease, based on genetic features, which defines four subgroups of cancer rather than the two traditionally recognized. In the molecular classification two types of EC, the polymerase epsilon (POLE)-ultramutated and the microsatellite instability (MSI)-hypermutated, seem to present an enhanced immune microenvironment and a high mutation burden. The blockade of the immune checkpoints is an innovative approach that has largely demonstrated to be effective in solid malignancies, such as lung, renal and melanoma; it acts by reducing the cancer-induced immune-suppression through inhibition of the PD-1/PD-L1 (Programmed Death and PD-Ligand) axis. All available evidence supporting an over-expression of the PD-1/PD-L1 pathway in EC has been reviewed. In particular in the POLE and MSI ECs an up-regulation of this pathway was found, aiming to suggest a rationale for testing the PD-1/PD-L1 immunotherapy in these cancer subgroups. PMID:27362548

  8. IL-12 enhances efficacy and shortens enrichment time in cytokine-induced killer cell immunotherapy

    Science.gov (United States)

    Helms, Mike W.; Prescher, Jennifer A.; Cao, Yu-An; Schaffert, Steven

    2016-01-01

    Cytokine-induced killer (CIK) cells are T cell derived ex vivo expanded cells with both NK and T cell properties. They exhibit potent anti-tumor efficacy against various malignancies in preclinical models and have proven safe and effective in clinical studies. We combined CIK cell adoptive immunotherapy with IL-12 cytokine immunotherapy in an immunocompetent preclinical breast cancer model. Combining CIK cells with IL-12 increased anti-tumor efficacy in vivo compared to either therapy alone. Combination led to full tumor remission and long-term protection in 75% of animals. IL-12 treatment sharply increased the anti-tumor efficacy of short-term cultured CIK cells that exhibited no therapeutic effect alone. Bioluminescence imaging based in vitro cytotoxicity and in vivo homing assays revealed that short-term cultured CIK cells exhibit full cytotoxicity in vitro, but display different tumor homing properties than fully expanded CIK cells in vivo. Our data suggest that short-term cultured CIK cells can be “educated” in vivo, producing fully expanded CIK cells upon IL-12 administration with anti-tumor efficacy in a mouse model. Our findings demonstrate the potential to improve current CIK cell-based immunotherapy by increasing efficacy and shortening ex vivo expansion time. This holds promise for a highly efficacious cancer therapy utilizing synergistic effects of cytokine and cellular immunotherapy. PMID:20532883

  9. Regulatory and effector functions of gamma-delta (γδ) T cells and their therapeutic potential in adoptive cellular therapy for cancer.

    Science.gov (United States)

    Paul, Sourav; Lal, Girdhari

    2016-09-01

    γδ T cells are an important innate immune component of the tumor microenvironment and are known to affect the immune response in a wide variety of tumors. Unlike αβ T cells, γδ T cells are capable of spontaneous secretion of IL-17A and IFN-γ without undergoing clonal expansion. Although γδ T cells do not require self-MHC-restricted priming, they can distinguish "foreign" or transformed cells from healthy self-cells by using activating and inhibitory killer Ig-like receptors. γδ T cells were used in several clinical trials to treat cancer patient due to their MHC-unrestricted cytotoxicity, ability to distinguish transformed cells from normal cells, the capacity to secrete inflammatory cytokines and also their ability to enhance the generation of antigen-specific CD8(+) and CD4(+) T cell response. In this review, we discuss the effector and regulatory function of γδ T cells in the tumor microenvironment with special emphasis on the potential for their use in adoptive cellular immunotherapy. PMID:27012367

  10. Brother of the regulator of the imprinted site (BORIS) variant subfamily 6 is involved in cervical cancer stemness and can be a target of immunotherapy.

    Science.gov (United States)

    Asano, Takuya; Hirohashi, Yoshihiko; Torigoe, Toshihiko; Mariya, Tasuku; Horibe, Ryota; Kuroda, Takafumi; Tabuchi, Yuta; Saijo, Hiroshi; Yasuda, Kazuyo; Mizuuchi, Masahito; Takahashi, Akari; Asanuma, Hiroko; Hasegawa, Tadashi; Saito, Tsuyoshi; Sato, Noriyuki

    2016-03-01

    Cervical cancer is a major cause of cancer death in females worldwide. Cervical cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are resistant to conventional radiotherapy and chemotherapy, and CSCs/CICs are thought to be responsible for recurrence. Eradication of CSCs/CICs is thus essential to cure cervical cancer. In this study, we isolated cervical CSCs/CICs by sphere culture, and we identified a cancer testis (CT) antigen, CTCFL/BORIS, that is expressed in cervical CSCs/CICs. BORIS has 23 mRNA isoform variants classified by 6 subfamilies (sfs), and they encode 17 different BORIS peptides. BORIS sf1 and sf4 are expressed in both CSCs/CICs and non-CSCs/CICs, whereas BORIS sf6 is expressed only in CSCs/CICs. Overexpression of BORIS sf6 in cervical cancer cells increased sphere formation and tumor-initiating ability compared with those in control cells, whereas overexpression of BORIS sf1 and BORIS sf4 resulted in only slight increases. Thus, BORIS sf6 is a cervical CSC/CIC-specific subfamily and has a role in the maintenance of cervical CSCs/CICs. BORIS sf6 contains a specific c-terminal domain (C34), and we identified a human leukocyte antigen (HLA)-A2-restricted antigenic peptide, BORIS C34_24(9) encoded by BORIS sf6. A BORIS C34_24(9)-specific cytotoxic T cell (CTL) clone showed cytotoxicity for BORIS sf6-overexpressing cervical cancer cells. Furthermore, the CTL clone significantly suppressed sphere formation of CaSki cells. Taken together, the results indicate that the CT antigen BORIS sf6 is specifically expressed in cervical CSCs/CICs, that BORIS sf6 has a role in the maintenance of CSCs/CICs, and that BORIS C34_24(9) peptide is a promising candidate for cervical CSC/CIC-targeting immunotherapy. PMID:26849232

  11. A Phase I/II Trial of DCVac/IR Dendritic Cell Immunotherapy Combined with Irradiation in Cases of Refractory Colorectal Cancer with Multiple Liver Metastases

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Young-Min; Lee, Hyung-Sik; Kwon, Hyuk-Chan; Han, Sang-Young; Choi, Jong-Cheol [Donga Univ. School of Medicine, Busan (Korea, Republic of); Chung, Ju-Seop; Kim, Chang-Won; Kim, Dong-Won; Kang, Chi-Duk [Busan National University College of Medicine, Busan (Korea, Republic of)

    2008-06-15

    To assess the toxicity and tumor response induced by DCVac/IR dendritic cell (DC) immunotherapy combined with irradiation for refractory colorectal cancer patients with multiple liver metastases. Between May 2004 and November 2006, applicants from a pool of refractory colorectal cancer patients with multiple liver metastases were enrolled. The patients were registered after having signed the informed consent form, which had been approved by the Institutional Review Board from the Dong-A University and Busan National University Hospital. DCs were obtained from peripheral blood of each patient, and then cultured in vitro. A total of 6x10{sup 6} DCs were packed into a vial (DCVac/IR, 0.5 ml) at the convenience of each patient's schedule. On the day before and on the day of each vaccination, each patient received a 4 Gy radiation dose to the target tumor. On the day of vaccination, the indicated dose of autologous DCs was injected into the irradiated tumor using ultrasound-guided needle injection procedures. A total of four vaccinations were scheduled at three 2-week intervals and one 4 week interval at the Dong-A University and Busan National University Hospital. If the tumor status was deemed to be stable or responding to therapy, an additional vaccination dose or two was approved at 4 week intervals beyond the fourth immunization. A tolerance test for DCs was conducted by injecting a range of doses (3x10{sup 6} to 12x10{sup 6} DCs) after the 3rd injection. Moreover, the maximal tolerable dose was applied to additional patients. Treatment safety was evaluated in all patients who had at least one injection. Treatment feasibility was evaluated by the 10th week by assessing the response of patients having at least 4 injections. For systemic toxicities, the evaluation was performed using the National Cancer Institute Common Toxicity Criteria, whereas adverse effects were recorded using common WHO toxicity criteria. Of the 24 registered patients, 22 received the DCs

  12. A Phase I/II Trial of DCVac/IR Dendritic Cell Immunotherapy Combined with Irradiation in Cases of Refractory Colorectal Cancer with Multiple Liver Metastases

    International Nuclear Information System (INIS)

    To assess the toxicity and tumor response induced by DCVac/IR dendritic cell (DC) immunotherapy combined with irradiation for refractory colorectal cancer patients with multiple liver metastases. Between May 2004 and November 2006, applicants from a pool of refractory colorectal cancer patients with multiple liver metastases were enrolled. The patients were registered after having signed the informed consent form, which had been approved by the Institutional Review Board from the Dong-A University and Busan National University Hospital. DCs were obtained from peripheral blood of each patient, and then cultured in vitro. A total of 6x106 DCs were packed into a vial (DCVac/IR, 0.5 ml) at the convenience of each patient's schedule. On the day before and on the day of each vaccination, each patient received a 4 Gy radiation dose to the target tumor. On the day of vaccination, the indicated dose of autologous DCs was injected into the irradiated tumor using ultrasound-guided needle injection procedures. A total of four vaccinations were scheduled at three 2-week intervals and one 4 week interval at the Dong-A University and Busan National University Hospital. If the tumor status was deemed to be stable or responding to therapy, an additional vaccination dose or two was approved at 4 week intervals beyond the fourth immunization. A tolerance test for DCs was conducted by injecting a range of doses (3x106 to 12x106 DCs) after the 3rd injection. Moreover, the maximal tolerable dose was applied to additional patients. Treatment safety was evaluated in all patients who had at least one injection. Treatment feasibility was evaluated by the 10th week by assessing the response of patients having at least 4 injections. For systemic toxicities, the evaluation was performed using the National Cancer Institute Common Toxicity Criteria, whereas adverse effects were recorded using common WHO toxicity criteria. Of the 24 registered patients, 22 received the DCs injections. Moreover

  13. Adoption of Intensity Modulated Radiation Therapy For Early-Stage Breast Cancer From 2004 Through 2011

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Elyn H. [Yale School of Medicine, New Haven, Connecticut (United States); Mougalian, Sarah S. [Yale School of Medicine, New Haven, Connecticut (United States); Yale Cancer Center, New Haven, Connecticut (United States); Cancer Outcomes, Public Policy, and Effectiveness Research Center at Yale, New Haven, Connecticut (United States); Soulos, Pamela R. [Yale School of Medicine, New Haven, Connecticut (United States); Cancer Outcomes, Public Policy, and Effectiveness Research Center at Yale, New Haven, Connecticut (United States); Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut (United States); Smith, Benjamin D. [Department of Radiation Oncology, MD Anderson Cancer Center, Houston, Texas (United States); Haffty, Bruce G. [Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey (United States); Gross, Cary P. [Yale School of Medicine, New Haven, Connecticut (United States); Cancer Outcomes, Public Policy, and Effectiveness Research Center at Yale, New Haven, Connecticut (United States); Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut (United States); Yu, James B., E-mail: james.b.yu@yale.edu [Yale School of Medicine, New Haven, Connecticut (United States); Cancer Outcomes, Public Policy, and Effectiveness Research Center at Yale, New Haven, Connecticut (United States); Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut (United States)

    2015-02-01

    Purpose: Intensity modulated radiation therapy (IMRT) is a newer method of radiation therapy (RT) that has been increasingly adopted as an adjuvant treatment after breast-conserving surgery (BCS). IMRT may result in improved cosmesis compared to standard RT, although at greater expense. To investigate the adoption of IMRT, we examined trends and factors associated with IMRT in women under the age of 65 with early stage breast cancer. Methods and Materials: We performed a retrospective study of early stage breast cancer patients treated with BCS followed by whole-breast irradiation (WBI) who were ≤65 years old in the National Cancer Data Base from 2004 to 2011. We used logistic regression to identify factors associated with receipt of IMRT (vs standard RT). Results: We identified 11,089 women with early breast cancer (9.6%) who were treated with IMRT and 104,448 (90.4%) who were treated with standard RT, after BCS. The proportion of WBI patients receiving IMRT increased yearly from 2004 to 2009, with 5.3% of WBI patients receiving IMRT in 2004 and 11.6% receiving IMRT in 2009. Further use of IMRT declined afterward, with the proportion remaining steady at 11.0% and 10.7% in 2010 and 2011, respectively. Patients treated in nonacademic community centers were more likely to receive IMRT (odds ratio [OR], 1.36; 95% confidence interval [CI], 1.30-1.43 for nonacademic vs academic center). Compared to privately insured patients, the uninsured patients (OR, 0.81; 95% CI, 0.70-0.95) and those with Medicaid insurance (OR, 0.87; 95% CI, 0.79-0.95) were less likely to receive IMRT. Conclusions: The use of IMRT rose from 2004 to 2009 and then stabilized. Important nonclinical factors associated with IMRT use included facility type and insurance status.

  14. Adoption of Intensity Modulated Radiation Therapy For Early-Stage Breast Cancer From 2004 Through 2011

    International Nuclear Information System (INIS)

    Purpose: Intensity modulated radiation therapy (IMRT) is a newer method of radiation therapy (RT) that has been increasingly adopted as an adjuvant treatment after breast-conserving surgery (BCS). IMRT may result in improved cosmesis compared to standard RT, although at greater expense. To investigate the adoption of IMRT, we examined trends and factors associated with IMRT in women under the age of 65 with early stage breast cancer. Methods and Materials: We performed a retrospective study of early stage breast cancer patients treated with BCS followed by whole-breast irradiation (WBI) who were ≤65 years old in the National Cancer Data Base from 2004 to 2011. We used logistic regression to identify factors associated with receipt of IMRT (vs standard RT). Results: We identified 11,089 women with early breast cancer (9.6%) who were treated with IMRT and 104,448 (90.4%) who were treated with standard RT, after BCS. The proportion of WBI patients receiving IMRT increased yearly from 2004 to 2009, with 5.3% of WBI patients receiving IMRT in 2004 and 11.6% receiving IMRT in 2009. Further use of IMRT declined afterward, with the proportion remaining steady at 11.0% and 10.7% in 2010 and 2011, respectively. Patients treated in nonacademic community centers were more likely to receive IMRT (odds ratio [OR], 1.36; 95% confidence interval [CI], 1.30-1.43 for nonacademic vs academic center). Compared to privately insured patients, the uninsured patients (OR, 0.81; 95% CI, 0.70-0.95) and those with Medicaid insurance (OR, 0.87; 95% CI, 0.79-0.95) were less likely to receive IMRT. Conclusions: The use of IMRT rose from 2004 to 2009 and then stabilized. Important nonclinical factors associated with IMRT use included facility type and insurance status

  15. Targeted Therapies for Kidney Cancer

    Science.gov (United States)

    ... for kidney cancer Targeted therapies for kidney cancer Biologic therapy (immunotherapy) for kidney cancer Chemotherapy for kidney cancer Pain control for kidney cancer Treatment choices by stage for ...

  16. 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.

  17. Emerging immunotherapy in pediatric lymphoma.

    Science.gov (United States)

    Erker, Craig; Harker-Murray, Paul; Burke, Michael J

    2016-01-01

    Hodgkin and non-Hodgkin lymphoma collectively are the third most common cancer diagnosed in children each year. For children who relapse or have refractory disease, outcomes remain poor. Immunotherapy has recently emerged as a novel approach to treat hematologic malignancies. The field has been rapidly expanding over the past few years broadening its armamentarium which now includes monoclonal antibodies, antibody-drug conjugates and cellular therapies including bispecific T-cell engagers and chimeric antigen receptor-engineered T cells. Many of these agents are in their infancy stages and only beginning to make their mark on lymphoma treatment while others have begun to show promising efficacy in relapsed disease. In this review, the authors provide an overview of current and emerging immunotherapies in the field of pediatric lymphoma. PMID:26616565

  18. Oncogenic cancer/testis antigens

    DEFF Research Database (Denmark)

    Gjerstorff, Morten F; Andersen, Mads H; Ditzel, Henrik J

    2015-01-01

    Recent developments have set the stage for immunotherapy as a supplement to conventional cancer treatment. Consequently, a significant effort is required to further improve efficacy and specificity, particularly the identification of optimal therapeutic targets for clinical testing. Cancer....../testis antigens are immunogenic, highly cancer-specific, and frequently expressed in various types of cancer, which make them promising candidate targets for cancer immunotherapy, including cancer vaccination and adoptive T-cell transfer with chimeric T-cell receptors. Our current understanding of tumor...... immunology and immune escape suggests that targeting oncogenic antigens may be beneficial, meaning that identification of cancer/testis antigens with oncogenic properties is of high priority. Recent work from our lab and others provide evidence that many cancer/testis antigens, in fact, have oncogenic...

  19. Measuring Health Belief Model components in adopting preventive behaviors of cervical cancer

    Directory of Open Access Journals (Sweden)

    Azam Namdar

    2012-06-01

    Full Text Available Background & Objective: Cervical cancer is the second prevalent women cancer in the world. This cancer is found preventable because of having the prolong time before the appearance, its complications and the available proper screening program and possibility of the primary lesion treatment. Since the Health Belief Model is one of the applicable praxeology model in health education to prevent and control of diseases. Therefore, this study was aimed to determine the Health Belief Model components in adopting preventive behaviors in cervical cancer in women. Materials & Methods: This descriptive-analytical study was carried out on 213 married 20-65 year-old women selected by a two-stage sampling method. The data was collected by a valid and reliable questionnaire and interview. This questionnaire based on health belief model correlation (components Perceived Susceptibility and Severity, Perceived Barriers and Benefits, Self-efficacy with behavior survey. The data were analyzed by using descriptive statistics and Mann-Whhitney test, Kruskal-wallis test, and Regression by SPSS software. Results: The mean age of the study group was 40.6 ± 12.1. The results show that 32.5% of them had at least one time examined for Pap smear test out of which only 7.9% of them had this test on a regular interval. Only 12% of them had an adequate knowledge about the cervical cancer and its preventive measure. 90% of them had inappropriate behavior. The average score of knowledge was 6.73± 2.97 which considered as moderate. Regression analysis showed the knowledge (P=0.009, job (P=0.005, perceived barriers (P<0.001 and perceived severity (P=0.036 determine as predictors in the final behavior. Conclusion: Perceived barriers and knowledge behind the strongest predictor of behavior. Educational programs are recommended based on the health belief model with emphasis on reducing barriers and increasing awareness to improve behavior.

  20. Factors Affecting Cervical Cancer Screening Behaviors Based on the Precaution Adoption Process Model: A Qualitative Study

    Science.gov (United States)

    Bahmani, Afshin; Baghianimoghadam, Mohammad Hossein; Enjezab, Behnaz; Mahmoodabad, Seyed Saeed Mazloomy; Askarshahi, Mohsen

    2016-01-01

    One of the most preventable cancers in women is cervical cancer. Pap smear test is an effective screening program; however, it is not conducted very frequently. The aim of this study is explaining the determinants affecting women’s participation in the Pap smear test based on precaution adoption process model with a qualitative approach. This study was a qualitative approach using a Directed Content Analysis methodology which was conducted in 2014. Participants were 30 rural women who participated in this study voluntarily in sarvabad, Iran. Purposive sampling was initiated and continued until data saturation. Semi-structured interviews were the primary method of data collection. Data were analyzed using qualitative content analysis and continuous comparisons. Women`s information and awareness about cervical cancer and Pap smear is insufficient and most of them believed that they were not at risk; however, they perceived the severity of the disease. Some of them had no adequate understanding of the test benefits. They pointed to the lack of time, financial difficulties, fear of test result and lack of awareness as the main barriers against the Pap smear test; however, they did not say that they were not willing to do the test. Findings could help health policy makers to find the right area and purpose to facilitate the participation of women in the Pap smear test. PMID:26755465

  1. γδ T LYMPHOCYTES AS A FIRST LINE OF IMMUNE DEFENSE: OLD AND NEW WAYS OF ANTIGEN RECOGNITION AND IMPLICATIONS FOR CANCER IMMUNOTHERAPY.

    Directory of Open Access Journals (Sweden)

    Maria Raffaella eZocchi

    2014-11-01

    Full Text Available Among γδT cells, the Vδ1 subset, resident in epithelial tissues, is implied in the defense against viruses, fungi and certain hematological malignancies, while the circulating Vδ2 subpopulation mainly respond to mycobacteria and solid tumors. Both subsets can be activated by stress-induced molecules (MIC-A, MIC-B, ULBPs to produce pro-inflammatory cytokines and lytic enzymes and destroy bacteria or damaged cells. γδT lymphocytes can also recognize lipids, as those associated to M. tuberculosis, presented by the CD1 molecule, or phosphoantigens (P-Ag, either autologous, which accumulates in virus-infected cells, or microbial produced by prokaryotes and parasites. In cancer cells P-Ag accumulate due to alterations in the mevalonate pathway; recently, butyrophilin 3A1 has been shown to be the presenting molecule for P-Ag. Of interest, aminobisphosphonates indirectly activate Vδ2 T cells inducing the accumulation of P-Ag. Based on these data, γδT lymphocytes are attractive effectors for cancer immunotherapy. However, the results obtained in clinical trials so far have been disappointing: this review will focus on the possible reasons of this failure as well as on suggestions for implementation of the therapeutic strategies.

  2. Targeting inhibition of Foxp3 by a CD28 2'-Fluro oligonucleotide aptamer conjugated to P60-peptide enhances active cancer immunotherapy.

    Science.gov (United States)

    Lozano, Teresa; Soldevilla, Mario Martínez; Casares, Noelia; Villanueva, Helena; Bendandi, Maurizio; Lasarte, Juan Jose; Pastor, Fernando

    2016-06-01

    The specific inhibition of Treg function has long been a major technical challenge in cancer immunotherapy. So far no single cell-surface marker has been identified that could be used to distinguish Treg cells from other lymphocytes. The only available specific marker mostly expressed in Treg is Foxp3, which is an intracellular transcription factor. A targeting molecule able to penetrate the membrane and inhibit Foxp3 within the cell is needed. P60-peptide is able to do that, but due to lack of target specificity, the doses are extremely high. In this study we have shown as a proof of concept that P60 Foxp3 inhibitor peptide can be conjugated with a CD28 targeting aptamer to deliver the peptide to CD28-expressing cells. The AptCD28-P60 construct is a clinically feasible reagent that improves the efficacy of the unconjugated P60 peptide very significantly. This approach was used to inhibit Treg function in a vaccination context, and it has shown a significant improvement in the induced immune response, entailing a lower tumor load in an antigen-specific cancer vaccine protocol. PMID:26999456

  3. Novel immunotherapies in lymphoid malignancies.

    Science.gov (United States)

    Batlevi, Connie Lee; Matsuki, Eri; Brentjens, Renier J; Younes, Anas

    2016-01-01

    The success of the anti-CD20 monoclonal antibody rituximab in the treatment of lymphoid malignancies provided proof-of-principle for exploiting the immune system therapeutically. Since the FDA approval of rituximab in 1997, several novel strategies that harness the ability of T cells to target cancer cells have emerged. Reflecting on the promising clinical efficacy of these novel immunotherapy approaches, the FDA has recently granted 'breakthrough' designation to three novel treatments with distinct mechanisms. First, chimeric antigen receptor (CAR)-T-cell therapy is promising for the treatment of adult and paediatric relapsed and/or refractory acute lymphoblastic leukaemia (ALL). Second, blinatumomab, a bispecific T-cell engager (BiTE(®)) antibody, is now approved for the treatment of adults with Philadelphia-chromosome-negative relapsed and/or refractory B-precursor ALL. Finally, the monoclonal antibody nivolumab, which targets the PD-1 immune-checkpoint receptor with high affinity, is used for the treatment of Hodgkin lymphoma following treatment failure with autologous-stem-cell transplantation and brentuximab vedotin. Herein, we review the background and development of these three distinct immunotherapy platforms, address the scientific advances in understanding the mechanism of action of each therapy, and assess the current clinical knowledge of their efficacy and safety. We also discuss future strategies to improve these immunotherapies through enhanced engineering, biomarker selection, and mechanism-based combination regimens. PMID:26525683

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

    OpenAIRE

    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 pu...

  5. Genetic Variant as a Selection Marker for Anti–Prostate Stem Cell Antigen Immunotherapy of Bladder Cancer

    OpenAIRE

    Kohaar, Indu; Porter-Gill, Patricia; Lenz, Petra; Fu, Yi-Ping; Mumy, Adam; Tang, Wei; Apolo, Andrea B.; Rothman, Nathaniel; Baris, Dalsu; Schned, Alan R.; Ylaya, Kris; Schwenn, Molly; Johnson, Alison; Jones, Michael; Kida, Masatoshi

    2012-01-01

    A monoclonal antibody against prostate stem cell antigen (PSCA) has emerged as a novel cancer therapy currently being tested in clinical trials for prostate and pancreatic cancers, but this treatment is likely to be efficient only in patients with PSCA-expressing tumors. The present study demonstrates that a genetic variant (rs2294008) discovered by bladder cancer genome-wide association studies is a strong predictor of PSCA protein expression in bladder tumors, as measured by two-sided multi...

  6. Selective expression and immunogenicity of the cancer/testis antigens SP17, AKAP4 and PTTG1 in non-small cell lung cancer: new candidates for active immunotherapy.

    Science.gov (United States)

    Chiriva-Internati, Maurizio; Mirandola, Leonardo; Figueroa, Jose A; Yu, Yuefei; Grizzi, Fabio; Kim, Minji; Jenkins, Marjorie; Cobos, Everardo; Jumper, Cynthia; Alalawi, Raed

    2014-05-01

    ABSTRACT BACKGROUND. Lung cancer is the leading cause of cancer deaths in both genders worldwide, with an incidence only second to prostate cancer in men and breast cancer in women. The lethality of the disease highlights the urgent need for innovative therapeutic options. Immunotherapy can afford efficient and specific targeting of tumor cells, improving efficacy and reducing the side effects of current therapies. We have previously reported the aberrant expression of cancer/testis antigens (CTAs) in tumors of unrelated histological origin. In this study we investigated the expression and immunogenicity of the cancer/testis antigens (CTAs) Sperm Protein 17 (SP17), A-kinase anchor protein 4 (AKAP4) and Pituitary Tumor Transforming Gene 1 (PTTG1) in human non-small cell lung cancer (NSCLC) cell lines and primary tumors. METHODS. We used RT-PCR, immunofluorescence, flow cytometry, ELISA and cytotoxicity assays to determine the expression levels and immunogenicity of SP17, AKAP4 and PTTG1 in human NSCLC cell lines and primary tumors. RESULTS. We found that SP17, AKAP4 and PTTG1 are aberrantly expressed in NSCLC cancer cell lines and primary tumor tissues from patients, compared to normal lung cell lines and tissues. We established the immunogenicity of these CTAs by measuring CTA-specific autoantibodies in patients' sera and generating CTA-specific autologous cytotoxic lymphocytes (CTLs) from patients' peripheral blood mononuclear cells (PBMCs). CONCLUSIONS. Our results provide proof of principle that the CTAs SP17/AKAP4/PTTG1 are expressed in both human NSCLC cell lines and primary tumors and can elicit an immunogenic response in NSCLC patients. Based on our findings, further studies are warranted to explore the feasibility of developing CTA-specific immunotherapeutic strategies for NSCLC patients. PMID:24811938

  7. A pilot study to assess the level of depression and the coping strategies adopted by cancer patients receiving treatment in Mizoram State Cancer Institute, Aizawl

    Directory of Open Access Journals (Sweden)

    Gitumoni Konwar

    2015-01-01

    Full Text Available Background: Cancer, the second most common cause of death, has become a major health problem. Depression is the most common psychological problem encountered in patients with cancer. The coping skills adopted may affect the mental health of patients. Therefore, this research is undertaken to assess the level of depression and coping strategy adopted by the patients diagnosed with cancer. Materials and methods: A descriptive study to assess the level of depression and coping strategy adopted by cancer patients receiving treatment in Mizoram State Cancer Institute, Aizawl was carried out from April to May 2014 with 30 convenient samples. Depression was assessed by using Hospital Anxiety and Depression Scale (HADS developed by Zigmond and Snaith in 1983. Coping strategy adopted by patients were assessed by revised version of the Ways of Coping Checklist developed by Folkman and Lazarus in 1985. Results: Findings of the study showed that depression was universal to all the cancer patients. Majority of cancer patients (66.5% had moderate depression while 13.26% of the cancer patients had severe depression, and only 6.7% of them reported to have low depression. The most effective coping strategy adopted was reappraisal, followed by distancing. There is significant correlation between depression and reappraisal (r=-0.538, p<0.002, and also with depression and acceptance (r=-0.415, p<0.022 strategies. Conclusion: As depression is universal to all cancer patients, use of appropriate coping strategy is very essential to improve their quality of life. The recognition of coping strategies by health team may enable appropriate information and interventions to be provided at optimal times for each individual.

  8. Current Studies of Immunotherapy on Glioblastoma.

    Science.gov (United States)

    Agrawal, Neena Stephanie; Miller, Rickey; Lal, Richa; Mahanti, Harshini; Dixon-Mah, Yaenette N; DeCandio, Michele L; Vandergrift, W Alex; Varma, Abhay K; Patel, Sunil J; Banik, Naren L; Lindhorst, Scott M; Giglio, Pierre; Das, Arabinda

    2014-04-01

    Glioblastoma is a form of brain tumor with a very high morbidity and mortality. Despite decades of research, the best treatments currently in clinical practice only extend survival by a number of months. A promising alternative to conventional treatment for glioblastomas is immunotherapy. Although proposed over a century ago, the field of cancer immunotherapy has historically struggled to translate it into effective clinical treatments. Better understanding is needed of the various regulatory and co-stimulatory factors in the glioblastoma patient for more efficient immunotherapy treatments. The tumor microenvironment is anatomically shielded from normal immune-surveillance by the blood-brain barrier, irregular lymphatic drainage system, and it's in a potently immunosuppressive environment. Immunotherapy can potentially manipulate these forces effectively to enhance anti-tumor immune response and clinical benefit. New treatments utilizing the immune system show promise in terms of targeting and efficacy. This review article attempts to discuss current practices in glioblastoma treatment, the theory behind immunotherapy, and current research into various clinical trials. PMID:25346943

  9. Improved Methods for the Clinical Manufacture of Proteins Used In Cancer Immunotherapy | NCI Technology Transfer Center | TTC

    Science.gov (United States)

    Interleukin-15 (IL-15) is an immune system modulating protein (cytokine) that stimulates the proliferation and differentiation of T- lymphocytes.  In the clinical context, IL-15 is being investigated for use in the treatment of diseases such as cancer.  Manufacture of IL-15 for clinical use can be problematic. The National Cancer Institute seeks partners to co-develop or license methods that facilitate pharmaceutical purification and processing of Interleukin-15 (IL-15).

  10. 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. PMID:18058096

  11. Adoption of Hypofractionated Radiation Therapy for Breast Cancer After Publication of Randomized Trials

    International Nuclear Information System (INIS)

    Purpose: Large randomized trials have established the noninferiority of shorter courses of “hypofractionated” radiation therapy (RT) to the whole breast compared to conventional courses using smaller daily doses in the adjuvant treatment of selected breast cancer patients undergoing lumpectomy. Hypofractionation is more convenient and less costly. Therefore, we sought to determine uptake of hypofractionated breast RT over time. Methods and Materials: In the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database, we identified 16,096 women with node-negative breast cancer and 4269 with ductal carcinoma in situ (DCIS) who received lumpectomy followed by more than 12 fractions of RT between 2004 and 2010. Based on Medicare claims, we determined the number of RT treatments given and grouped patients into those receiving hypofractionation (13-24) or those receiving conventional fractionation (≥25). We also determined RT technique (intensity modulated RT or not) using Medicare claims. We evaluated patterns and correlates of hypofractionation receipt using bivariate and multivariable analyses. Results: Hypofractionation use was similar in patients with DCIS and those with invasive disease. Overall, the use of hypofractionation increased from 3.8% in 2006 to 5.4% in 2007, to 9.4% in 2008, and to 13.6% in 2009 and 2010. Multivariable analysis showed increased use of hypofractionation in recent years and in patients with older age, smaller tumors, increased comorbidity, higher regional education, and Western SEER regions. However, even in patients over the age of 80, the hypofractionation rate in 2009 to 2010 was only 25%. Use of intensity modulated RT (IMRT) also increased over time (from 9.4% in 2004 to 22.7% in 2009-2010) and did not vary significantly between patients receiving hypofractionation and those receiving traditional fractionation. Conclusions: Hypofractionation use increased among low-risk older US breast cancer patients with

  12. Adoption of Hypofractionated Radiation Therapy for Breast Cancer After Publication of Randomized Trials

    Energy Technology Data Exchange (ETDEWEB)

    Jagsi, Reshma, E-mail: rjagsi@med.umich.edu [Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, Michigan (United States); Falchook, Aaron D.; Hendrix, Laura H. [Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (United States); Curry, Heather [Radiation Oncology, Eviti, Inc, Philadelphia, Pennsylvania (United States); Chen, Ronald C. [Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (United States)

    2014-12-01

    Purpose: Large randomized trials have established the noninferiority of shorter courses of “hypofractionated” radiation therapy (RT) to the whole breast compared to conventional courses using smaller daily doses in the adjuvant treatment of selected breast cancer patients undergoing lumpectomy. Hypofractionation is more convenient and less costly. Therefore, we sought to determine uptake of hypofractionated breast RT over time. Methods and Materials: In the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database, we identified 16,096 women with node-negative breast cancer and 4269 with ductal carcinoma in situ (DCIS) who received lumpectomy followed by more than 12 fractions of RT between 2004 and 2010. Based on Medicare claims, we determined the number of RT treatments given and grouped patients into those receiving hypofractionation (13-24) or those receiving conventional fractionation (≥25). We also determined RT technique (intensity modulated RT or not) using Medicare claims. We evaluated patterns and correlates of hypofractionation receipt using bivariate and multivariable analyses. Results: Hypofractionation use was similar in patients with DCIS and those with invasive disease. Overall, the use of hypofractionation increased from 3.8% in 2006 to 5.4% in 2007, to 9.4% in 2008, and to 13.6% in 2009 and 2010. Multivariable analysis showed increased use of hypofractionation in recent years and in patients with older age, smaller tumors, increased comorbidity, higher regional education, and Western SEER regions. However, even in patients over the age of 80, the hypofractionation rate in 2009 to 2010 was only 25%. Use of intensity modulated RT (IMRT) also increased over time (from 9.4% in 2004 to 22.7% in 2009-2010) and did not vary significantly between patients receiving hypofractionation and those receiving traditional fractionation. Conclusions: Hypofractionation use increased among low-risk older US breast cancer patients with

  13. Phenotypic profile of dendritic and T cells in the lymph node of Balb/C mice with breast cancer submitted to dendritic cells immunotherapy.

    Science.gov (United States)

    da Cunha, Alessandra; Antoniazi Michelin, Marcia; Cândido Murta, Eddie Fernando

    2016-09-01

    Breast cancer (BC) is the most common malignant neoplasm and the cause of death by cancer among women worldwide. Its development influenced by various mutations that occur in the tumor cell and by the immune system's status, which has a direct influence on the tumor microenvironment and, consequently, on interactions with non-tumor cells involved in the immunological response. Strategies using dendritic cells (DCs) or antigen-presenting cells (APCs), therapeutic mode, in cancer have been developed for some time. The proper interaction between DCs and T cells upon antigen presentation is of greatest importance for an antitumor immune response activation. Thus, various receptors on the surface of T cells must be able to recognize ligands that are located on the surface of APCs. However, little is known about the real behavior and interaction forms of CDs and T cells after vaccination. Due to the crucial importance of DCs in an effective anti-tumor immune response activation and the search for compliant results in inducing this response by immunotherapies with DCs, the phenotypic profile of DCs and T cells in lymph nodes obtained from female Balb/C mice with breast cancer induced by 4T1 cells and DCs treated with vaccines was investigated. We evaluated through flow cytometry based on the surface and intracellular molecules marking; as well as the presence of cytokines and chemokines, IL-2, IL-4, IL-10, IL-12, IFN-γ, TNF-α and TGF-β in the supernatant of the culture of Balb/C lymph nodes by ELISA. The results show that the vaccination with DCs, in the maturation parameters used in this study, was able to stimulate the secretion of cytokines such as IFN-γ and IL-12 and inhibit the secretion of TGF-β and IL-10 in nodal lymph infiltrates, as well as co-stimulatory activating (CD86) and adhesion molecules in DCs and T cells LFA-1/ICAM-1 and inhibit the secretion of CTLA-4 present in lymph nodes. Facts that led to aTh1 profile polarization, immuno competent in relation

  14. 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

  15. Playing in three makes it simpler: Mapping the cognitive figure-ground framework onto cancer-immunology and immunotherapy (Review)

    Czech Academy of Sciences Publication Activity Database

    Gidron, Y.; Vannucci, Luca

    2010-01-01

    Roč. 36, č. 5 (2010), s. 1061-1065. ISSN 1019-6439 R&D Projects: GA AV ČR IAA500200917 Institutional research plan: CEZ:AV0Z50200510 Keywords : immune system * cancer development * tumour escape Subject RIV: EC - Immunology Impact factor: 2.571, year: 2010

  16. Activated human gammadelta T cells as stimulators of specific CD8+ T-cell responses to subdominant Epstein Barr virus epitopes: potential for immunotherapy of cancer.

    Science.gov (United States)

    Landmeier, Silke; Altvater, Bianca; Pscherer, Sibylle; Juergens, Heribert; Varnholt, Lena; Hansmeier, Anna; Bollard, Catherine M; Moosmann, Andreas; Bisping, Guido; Rossig, Claudia

    2009-04-01

    The efficacy of current cancer vaccines is limited by the functional heterogeneity and poor availability and expansion of professional antigen-presenting cells (APCs). Besides their potent innate effector properties, gammadelta T cells have been suggested to be involved in the initiation and maintenance of adaptive immune responses. Here, we investigated the capacity of human gammadelta T cells to induce expansion of virus-specific T cells to Epstein Barr virus (EBV) antigens. Aminobisphosphonate-stimulated human peripheral blood-derived gammadelta T cells (Vgamma2+Vdelta2+) acquired a dual phenotype characteristic for both APCs and effector memory T cells. Coincubation of activated gammadelta T cells pulsed with human leukocyte antigen-restricted epitopes of either the highly stimulatory EBV lytic cycle antigen Bam H1 Z fragment leftward open reading frame or the tumor-associated latent EBV antigen latent membrane protein 2a (LMP2a) with autologous peripheral blood lymphocytes induced selective expansion of peptide-specific, fully functional CD3CD8 cytolytic effector memory T cells. Furthermore, gammadelta T APCs efficiently processed and presented endogenous antigen, as demonstrated by the capacity of LMP2a gene-transduced gammadelta T cells to induce expansion of T cells with broad specificity for various LMP2a peptides. The capacity of autologous gammadelta T cells to induce LMP2a-specific autologous cytotoxic T lymphocytes was confirmed in 2 patients with Hodgkin lymphoma. In summary, bisphosphonate-activated human gammadelta T cells stimulate expansion of cytotoxic effector T cells specific for both subdominant and dominant viral epitopes and thus show promise as a novel source of efficient APCs for immunotherapy of viral and malignant disease. PMID:19242369

  17. Activated human γδ T cells as stimulators of specific CD8+ T cell responses to subdominant Epstein Barr virus (EBV) epitopes: Potential for immunotherapy of cancer

    Science.gov (United States)

    Landmeier, Silke; Altvater, Bianca; Pscherer, Sibylle; Juergens, Heribert; Varnholt, Lena; Hansmeier, Anna; Bollard, Catherine M.; Moosmann, Andreas; Bisping, Guido; Rossig, Claudia

    2011-01-01

    The efficacy of current cancer vaccines is limited by the functional heterogeneity and poor availability and expansion of professional antigen-presenting cells (APCs). Besides their potent innate effector properties, γδ T cells have been suggested to be involved in the initiation and maintenance of adaptive immune responses. Here, we investigated the capacity of human γδ T cells to induce expansion of virus-specific T cells to Epstein Barr virus (EBV) antigens. Aminobisphosphonate-stimulated human peripheral blood-derived γδ T cells (Vγ9+Vδ2+) acquired a dual phenotype characteristic for both APCs and effector memory T cells. Coincubation of activated γδ T cells pulsed with HLA-restricted epitopes of either the highly stimulatory EBV lytic cycle antigen BZLF-1 or the tumor-associated latent EBV antigen LMP2a with autologous peripheral blood lymphocytes induced selective expansion of peptide-specific, fully functional CD3+CD8+ cytolytic effector memory T cells. Furthermore, γδ T-APCs efficiently processed and presented endogenous antigen, as demonstrated by the capacity of LMP2a gene-transduced γδ T cells to induce expansion of T cells with broad specificity for various LMP2a peptides. The capacity of autologous γδ T cells to induce LMP2a-specific autologous CTLs was confirmed in two patients with Hodgkin lymphoma. In summary, bisphosphonate-activated human γδ T cells stimulate expansion of cytotoxic effector T cells specific for both subdominant and dominant viral epitopes and thus show promise as a novel source of efficient APCs for immunotherapy of viral and malignant disease. PMID:19242369

  18. An Approach to Breast Cancer Immunotherapy: The Apoptotic Activity of Recombinant Anti-Interleukin-6 Monoclonal Antibodies in Intact Tumour Microenvironment of Breast Carcinoma.

    Science.gov (United States)

    Abou-Shousha, S; Moaaz, M; Sheta, M; Motawea, M A

    2016-06-01

    Current work is one of our comprehensive preclinical studies, a new approach to breast cancer (BC) immunotherapy through induction of tumour cell apoptosis. Tumour growth is not just a result of uncontrolled cell proliferation but also of reduced apoptosis. High levels of interleukin-6 (IL-6) are associated with metastatic BC and correlated with poor survival as it promotes growth of tumour-initiating cells during early tumorigenesis protecting these cells from apoptosis. Therefore, this study aims at investigating the potential of anti-IL-6 monoclonal antibodies to suppress IL-6 proliferative/anti-apoptotic activities in intact tumour microenvironment of BC. Fresh sterile tumour and normal breast tissue specimens were taken from 50 female Egyptian patients with BC undergoing radical mastectomy. A unique tissue culture system designed to provide cells of each intact tumour/normal tissue sample with its proper microenvironment either supplemented or not with anti-IL-6 monoclonal antibodies. To evaluate the apoptotic activity of anti-IL-6 as a novel candidate for BC treatment strategy, we compared its effects with those obtained using tumour necrosis-related apoptosis-inducing ligand TRAIL as an established apoptotic agent. Our results revealed that levels of either anti-IL-6- or TRAIL-induced apoptosis in the tumour or normal tissue cultures were significantly higher than those in their corresponding untreated ones (P Recombinant anti-IL-6 monoclonal antibodies could represent a novel effective element of immunotherapeutic treatment strategy for BC. The selectivity and anti-apoptotic potential of anti-IL-6 is highly hopeful in IL-6- abundant BC tumour microenvironment. PMID:26971879

  19. Mucin 1-specific active cancer immunotherapy with tecemotide (L-BLP25) in patients with multiple myeloma: An exploratory study

    OpenAIRE

    Rossmann, Eva; Österborg, Anders; Löfvenberg, Eva; Choudhury, Aniruddha; Forssmann, Ulf; von Heydebreck, Anja; Schröder, Andreas; Mellstedt, Håkan

    2014-01-01

    Patients (n = 34) with previously untreated, slowly progressive asymptomatic stage I/II multiple myeloma or with stage II/III multiple myeloma in stable response/plateau phase following conventional anti-tumor therapy were immunized repeatedly with the antigen-specific cancer immunotherapeutic agent tecemotide (L-BLP25). Additionally, patients were randomly allocated to either single or multiple low doses of cyclophosphamide to inhibit regulatory T cells (Treg). Immunization with tecemotide r...

  20. Autoimmunity and the Immunotherapy of Cancer: Targeting the “Self” to Destroy the “Other”

    OpenAIRE

    Overwijk, Willem W.; Restifo, Nicholas P

    2000-01-01

    It is increasingly clear that immunity to “self”-antigens may result in tumor destruction in mouse and man. But which antigens should be targeted with therapeutic cancer vaccines? In the case of melanoma, recognition of melanocyte differentiation antigens (MDA) can be associated with autoimmune depigmentation (vitiligo). We propose that intersection of protein transport to melanosomes and endosomes allows for the loading of MDA-derived peptides on MHC class II molecules, resulting in the acti...

  1. Ablation and Other Local Therapy for Kidney Cancer

    Science.gov (United States)

    ... for kidney cancer Targeted therapies for kidney cancer Biologic therapy (immunotherapy) for kidney cancer Chemotherapy for kidney cancer Pain control for kidney cancer Treatment choices by stage for ...

  2. Vγ9Vδ2 T cells as a promising innovative tool for immunotherapy of hematologic malignancies

    Directory of Open Access Journals (Sweden)

    Serena Meraviglia

    2011-12-01

    Full Text Available The potent anti-tumor activities of γδ T cells, their ability to produce pro-inflammatory cytokines, and their strong cytolytic activity have prompted the development of protocols in which γδ agonists or ex vivo-expanded γδ cells are administered to tumor patients. γδ T cells can be selectively activated by either synthetic phosphoantigens or by drugs that enhance their accumulation into stressed cells as aminobisphosphonates, thus offering new avenues for the development of γδ T cell-based immunotherapies. The recent development of small drugs selectively activating Vγ9Vδ2 T lymphocytes, which upregulate the endogenous phosphoantigens, has enabled the investigators to design the experimental approaches of cancer immunotherapies; several ongoing phase I and II clinical trials are focused on the role of the direct bioactivity of drugs and of adoptive cell therapies involving phosphoantigen- or aminobisphosphonate-activated Vγ9Vδ2 T lymphocytes in humans. In this review, we focus on the recent advances in the activation/expansion of γδ T cells in vitro and in vivo that may represent a promising target for the design of novel and highly innovative immunotherapy in patients with hematologic malignancies.

  3. 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. PMID:17935130

  4. Targeted Vaccination against Human α-Lactalbumin for Immunotherapy and Primary Immunoprevention of Triple Negative Breast Cancer

    OpenAIRE

    Tuohy, Vincent K; Ritika Jaini; Johnson, Justin M.; Matthew G. Loya; Dennis Wilk; Erinn Downs-Kelly; Suparna Mazumder

    2016-01-01

    We have proposed that safe and effective protection against the development of adult onset cancers may be achieved by vaccination against tissue-specific self-proteins that are “retired” from expression at immunogenic levels in normal tissues as we age, but are overexpressed in emerging tumors. α-Lactalbumin is an example of a “retired” self-protein because its expression in normal tissues is confined exclusively to the breast during late pregnancy and lactation, but is also expressed in the ...

  5. Photo-nano immunotherapy for metastatic breast cancer using synergistic single-walled carbon nanotubes and glycated chitosan

    Science.gov (United States)

    Zhou, Feifan; Hasanjee, Aamr; Doughty, Austin; West, Connor; Liu, Hong; Chen, Wei R.

    2015-03-01

    In our previous work, we constructed a multifunctional nano system, using single-walled carbon nanotube (SWNT) and glycated chitosan (GC), which can synergize photothermal and immunological effects. To further confirm the therapy efficacy, with a metastatic mouse mammary tumor model (4T1), we investigate the therapy effects and immune response induced by SWNT-GC, under laser irradiation. Laser+SWNT-GC treatment not only suppressed the prime tumor, but also induced antitumor immune response. It could be developed into a promising treatment modality for the metastatic breast cancer.

  6. [News about targeted therapies in non-small-cell lung cancer in 2015 (except immuno-therapy)].

    Science.gov (United States)

    Hamard, Cécile; Ruppert, Anne-Marie; Lavole, Armelle; Rozensztajn, Nathalie; Antoine, Martine; Cadranel, Jacques; Wislez, Marie

    2016-01-01

    Recently, developments of therapies that target abnormally activated signaling pathways are increasing for patients with non-small cell lung cancer. EGFR mutations are found in about 10% of lung cancers, especially in adenocarcinoma, women and non-smokers. Three EGFR inhibitors (erlotinib, gefitinib and afatinib) received a European marketing authorization for up to first line treatment of EGFR mutated NSCLC. Effectiveness of EGFR inhibitors is higher than conventional chemotherapy. Third generation EGFR inhibitors (rociletinib, AZD9291) are effective for patients who develop a resistance mutation such as T790M resistance mutation; they obtained temporary authorization for use in France in 2015. The EML4-ALK translocation is found in about 5% of NSCLC and more particularly in adenocarcinoma of young non-smoking patients. Crizotinib is a new therapeutic standard in ALK translocated NSCLC in second line. Ceritinib is a 2nd generation ALK inhibitor which received a European marketing authorization for up to treatment of ALK translocated NSCLC after progression with crizotinib. INCA supports ACSé program evaluating the efficacy of crizotinib in NSCLC amplified for MET or translocated for ROS1 and ACSé program evaluating the efficacy of vemurafenib in tumors non melanoma mutated V600E BRAF. The role of other biomarkers such as KRAS, BRAF, HER2 and PI3KCA mutations remains to be defined in NSCLC. PMID:26775573

  7. Therapeutic cancer vaccines: are we there yet?

    OpenAIRE

    Klebanoff, Christopher A.; Acquavella, Nicholas; Yu, Zhiya; Restifo, Nicholas P

    2011-01-01

    Enthusiasm for therapeutic cancer vaccines has been rejuvenated with the recent completion of several large, randomized phase III clinical trials that in some cases have reported an improvement in progression free or overall survival. However, an honest appraisal of their efficacy reveals modest clinical benefit and a frequent requirement for patients with relatively indolent cancers and minimal or no measurable disease. Experience with adoptive cell transfer-based immunotherapies unequivocal...

  8. Evaluation of the potential role of the new Cancer-Testis Antigen BORIS for the development of novel strategies of immunotherapy of cancer

    International Nuclear Information System (INIS)

    BORIS/CTCFL (for brother of the regulator of imprinted sites), a paralogue of the transcription factor CTCF, is a recently described novel member of the cancer-testis (CT) antigen family (Loukinov D, et al. Proc Natl Acad Sci USA 2002;99:6806). BORIS expression appears to be restricted to testicular germ cells and to a vast majority of neoplastic cells including both cancer cell lines and primary tumors (Klenova EM, et al. Semin Cancer Biol 2002;12:399)

  9. Local immunotherapy in experimental murine lung inflammation

    OpenAIRE

    sprotocols

    2015-01-01

    Authors: Caroline Uebel, Sonja Koch, Anja Maier, Nina Sopel, Anna Graser, Stephanie Mousset & Susetta Finotto ### Abstract Innovative local immunotherapy for severe lung diseases such as asthma, chronic obstructive pulmonary disease or lung cancer requires a successful delivery to access the desired cellular target in the lung. An important route is the direct instillation into the airways in contrast to delivery through the digestive tract. This protocol details a method to deliv...

  10. 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.

  11. The integrin αvβ6: a novel target for CAR T-cell immunotherapy?

    Science.gov (United States)

    Whilding, Lynsey M; Vallath, Sabari; Maher, John

    2016-04-15

    Immunotherapy of cancer using chimeric antigen receptor (CAR) T-cells is a rapidly expanding field. CARs are fusion molecules that couple the binding of a tumour-associated cell surface target to the delivery of a tailored T-cell activating signal. Re-infusion of such genetically engineered T-cells to patients with haematological disease has demonstrated unprecedented response rates in Phase I clinical trials. However, such successes have not yet been observed using CAR T-cells against solid malignancies and this is, in part, due to a lack of safe tumour-specific targets. The αvβ6 integrin is strongly up-regulated in multiple solid tumours including those derived from colon, lung, breast, cervix, ovaries/fallopian tube, pancreas and head and neck. It is associated with poorer prognosis in several cancers and exerts pro-tumorigenic activities including promotion of tumour growth, migration and invasion. By contrast, physiologic expression of αvβ6 is largely restricted to wound healing. These attributes render this epithelial-specific integrin a highly attractive candidate for targeting using immunotherapeutic strategies such as CAR T-cell adoptive immunotherapy. This mini-review will discuss the role and expression of αvβ6 in cancer, as well as its potential as a therapeutic target. PMID:27068939

  12. Measuring Health Belief Model components in adopting preventive behaviors of cervical cancer

    OpenAIRE

    Azam Namdar; Shiva Bigizadeh; Mohammad Mehdi Naghizadeh

    2012-01-01

    Background & Objective: Cervical cancer is the second prevalent women cancer in the world. This cancer is found preventable because of having the prolong time before the appearance, its complications and the available proper screening program and possibility of the primary lesion treatment. Since the Health Belief Model is one of the applicable praxeology model in health education to prevent and control of diseases. Therefore, this study was aimed to determine the Health Belief Model componen...

  13. Review of the 25th annual scientific meeting of the International Society for Biological Therapy of Cancer

    Directory of Open Access Journals (Sweden)

    Jaffee Elizabeth M

    2011-05-01

    Full Text Available Abstract Led by key opinion leaders in the field, the 25th Annual Meeting of the International Society for Biological Therapy of Cancer (iSBTc, recently renamed the Society for Immunotherapy of Cancer, SITC provided a scientific platform for ~500 attendees to exchange cutting-edge information on basic, clinical, and translational research in cancer immunology and immunotherapy. The meeting included keynote addresses on checkpoint blockade in cancer therapy and recent advances in therapeutic vaccination against cancer induced by Human Papilloma Virus 16. Participants from 29 countries interacted through oral presentations, panel discussions, and posters on topics that included dendritic cells and cancer, targeted therapeutics and immunotherapy, innate/adaptive immune interplay in cancer, clinical trial endpoints, vaccine combinations, countering negative regulation, immune cell trafficking to tumor microenvironment, and adoptive T cell transfer. In addition to the 50 oral presentations and >180 posters on these topics, a new SITC/iSBTc initiative to create evidence-based Cancer Immunotherapy Guidelines was announced. The SITC/iSBTc Biomarkers Taskforce announced the release of recommendations on immunotherapy biomarkers and a highly successful symposium on Immuno-Oncology Biomarkers that took place on the campus of the National Institutes of Health (NIH immediately prior to the Annual Meeting. At the Annual Meeting, the NIH took the opportunity to publicly announce the award of the U01 grant that will fund the Cancer Immunotherapy Trials Network (CITN. In summary, the Annual Meeting gathered clinicians and scientists from academia, industry, and regulatory agencies from around the globe to interact and exchange important scientific advances related to tumor immunobiology and cancer immunotherapy.

  14. CD19 chimeric antigen receptor (CD19 CAR)-redirected adoptive T-cell immunotherapy for the treatment of relapsed or refractory B-cell Non-Hodgkin’s Lymphomas

    Science.gov (United States)

    Onea, Alexandra S; Jazirehi, Ali R

    2016-01-01

    Recovery rates for B-cell Non-Hodgkin’s Lymphoma (NHL) are up to 70% with current standard-of-care treatments including rituximab (chimeric anti-CD20 monoclonal antibody) in combination with chemotherapy (R-CHOP). However, patients who do not respond to first-line treatment or develop resistance have a very poor prognosis. This signifies the need for the development of an optimal treatment approach for relapsed/refractory B-NHL. Novel CD19- chimeric antigen receptor (CAR) T-cell redirected immunotherapy is an attractive option for this subset of patients. Anti-CD19 CAR T-cell therapy has already had remarkable efficacy in various leukemias as well as encouraging outcomes in phase I clinical trials of relapsed/refractory NHL. In going forward with additional clinical trials, complementary treatments that may circumvent potential resistance mechanisms should be used alongside anti-CD19 T-cells in order to prevent relapse with resistant strains of disease. Some such supplementary tactics include conditioning with lymphodepletion agents, sensitizing with kinase inhibitors and Bcl-2 inhibitors, enhancing function with multispecific CAR T-cells and CD40 ligand-expressing CAR T-cells, and safeguarding with lymphoma stem cell-targeted treatments. A therapy regimen involving anti-CD19 CAR T-cells and one or more auxiliary treatments could dramatically improve prognoses for patients with relapsed/refractory B-cell NHL. This approach has the potential to revolutionize B-NHL salvage therapy in much the same way rituximab did for first-line treatments. PMID:27186412

  15. Immunotherapy of melanoma: present options and future promises.

    Science.gov (United States)

    Rotte, Anand; Bhandaru, Madhuri; Zhou, Youwen; McElwee, Kevin J

    2015-03-01

    Metastatic melanoma is notorious for its immune evasion and resistance to conventional chemotherapy. The recent success of ipilimumab, a human monoclonal antibody against cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), in increasing the median survival time and stabilizing the disease progression renewed, hopes in treatment for melanoma. Currently, ipilimumab and high-dose interleukin-2 (IL-2; Aldesleukin) are approved as monotherapies for the treatment of patients with unresectable advanced melanoma, and pegylated interferon-α2b (p-IFN-α2b) is approved as an adjuvant for the treatment of patients with surgically resected high-risk melanoma. The present review describes the currently approved immune-modulators and the promising immune-based interventions that are currently in clinical trials. We present the four commonly used strategies to boost immune responses against the tumors; monoclonal antibodies, cytokines, cancer vaccines, and adoptive T cell transfer. The corresponding lists of ongoing clinical trials include details of the trial phase, target patients, intervention details, status of the study, and expected date of completion. Further, our review discusses the challenges faced by immunotherapy and the various strategies adopted to overcome them. PMID:25589384

  16. Near-Infrared Imaging of Adoptive Immune Cell Therapy in Breast Cancer Model Using Cell Membrane Labeling

    OpenAIRE

    Youniss, Fatma M.; Gobalakrishnan Sundaresan; Graham, Laura J.; Li Wang; Berry, Collin R.; Dewkar, Gajanan K.; Purnima Jose; Bear, Harry D; Jamal Zweit

    2014-01-01

    The overall objective of this study is to non-invasively image and assess tumor targeting and retention of directly labeled T-lymphocytes following their adoptive transfer in mice. T-lymphocytes obtained from draining lymph nodes of 4T1 (murine breast cancer cell) sensitized BALB/C mice were activated in-vitro with Bryostatin/Ionomycin for 18 hours, and were grown in the presence of Interleukin-2 for 6 days. T-lymphocytes were then directly labeled with 1,1-dioctadecyltetramethyl indotricarbo...

  17. 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......-presenting cells (mostly Langerhans and myeloid dendritic cells) exhibit a tolerogenic phenotype, despite constant exposure to danger signals from food and microbes. This reduces the induction of pro-inflammatory immune responses leading to systemic allergic reactions. Oral tissues contain relatively few mast...... 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...

  18. Immunotherapy of Melanoma.

    Science.gov (United States)

    Snyder, Alexandra; Zamarin, Dmitriy; Wolchok, Jedd D

    2015-01-01

    The history of immunotherapy is rooted in the treatment of melanoma and therapy with immune checkpoint-blocking agents is now a cornerstone for the treatment of metastatic melanoma. The first effective immunotherapies approved by the US Food and Drug Administration in melanoma included interleukin-2 for metastatic disease and interferon alpha in the adjuvant setting. These were followed by a group of new therapies, including checkpoint-blocking antibodies targeting cytotoxic T lymphocyte-associated protein 4 and programmed cell death protein 1. Therapies intended to 'reeducate' T cells, such as tumor-infiltrating lymphocyte therapy, oncolytic viruses and tumor vaccines, have yielded promising results and are under development. Finally, the integration of the above therapies as well as development of new coinhibitory and costimulatory agents, though in early stages, appear very promising and likely represent the next phase in drug development for the treatment of metastatic melanoma. PMID:26376963

  19. Restriction of GAGE protein expression to subpopulations of cancer cells is independent of genotype and may limit the use of GAGE proteins as targets for cancer immunotherapy

    DEFF Research Database (Denmark)

    Gjerstorff, M F; Johansen, L E; Nielsen, O;

    2006-01-01

    , and most GAGE-positive tumours also contained cancer cells lacking GAGE expression. Studies of genetically homogenous cell lines with similar intercellular heterogeneous GAGE expression showed that GAGE expression was not associated with a specific genotype, but defined a phenotypically distinct...

  20. Immune-Checkpoint Blockade and Active Immunotherapy for Glioma

    Energy Technology Data Exchange (ETDEWEB)

    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.

  1. 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.

  2. Immune-Checkpoint Blockade and Active Immunotherapy for Glioma

    International Nuclear Information System (INIS)

    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

  3. Allergen-specific immunotherapy

    Directory of Open Access Journals (Sweden)

    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. Adoptability and limitation of cancer treatment guidelines: a Chinese oncologist's perspective

    Institute of Scientific and Technical Information of China (English)

    DU Chang-zheng; GU Jin

    2012-01-01

    In recent years,great progress has been made in the treatment of cancer;one of the significant reasons is the wide adaptation and implementation of standardized treatment based on high-level clinical evidence.Undoubtedly,the advent of guidelines that represent the achievement of the latest and highest quality clinical studies made a significant contribution to the improvement of cancer treatment and management.Aside from cancer patient care,guidelines have also been widely used as standards or primary references in the diagnosis and treatment of other diseases.Numerous guidelines are being enacted each year by a variety of guideline-makers, including national, regional and intemational academic organizations, medical associations,as well as research institutions and hospitals.

  5. P53-specific T cell responses in patients with malignant and benign ovarian tumors : Implications for p53 based immunotherapy

    NARCIS (Netherlands)

    Lambeck, Annechien; Leffers, Ninke; Hoogeboom, Baukje-Nynke; Sluiter, Wim; Hamming, Ineke; Klip, Harry; ten Hoor, Klaske; Esajas, Martha; van Oven, Magda; Drijfhout, Jan-Wouter; Platteel, Inge; Offringa, Rienk; Hollema, Harry; Melief, Kees; van der Burg, Sjoerd; van der Zee, Ate; Daemen, Toos; Nijman, Hans

    2007-01-01

    Despite intensive treatment, 70% of the ovarian cancer patients will develop recurrent disease, emphasizing the need for new approaches such as immunotherapy. A promising antigenic target for immunotherapy in ovarian cancer is the frequently overexpressed p53 protein. The aim of the study was to eva

  6. Defining the level of evidence for technology adoption in the localized prostate cancer pathway.

    Science.gov (United States)

    Valerio, Massimo; El-Shater Bosaily, Ahmed; Emberton, Mark; Ahmed, Hashim U

    2014-08-01

    New technologies in prostate cancer are attempting to change the current prostate cancer pathway by aiming to reduce harms while maintaining the benefits associated with screening, diagnosis, and treatment. In this article, we discuss the optimal evaluation that new technologies should undergo to provide level 1 evidence typically required to change the practice. With this in mind, we focus on feasible and pragmatic trials that could be delivered in a timely fashion by many centers while retaining primary outcomes that focus on clinically meaningful outcomes. PMID:24332638

  7. Immunotherapy with GD2 specific monoclonal antibodies

    International Nuclear Information System (INIS)

    Targeted immunotherapy focuses anti-tumor activity of antibodies and effector cells, which are actively developed by the host or adoptively transferred, onto tumor cells and into tumor sites. Such tumor selective therapy can be more specific and efficient. The value of such an approach is evident in the classical interaction of antibodies. This paper reports that the ganglioside GD2 is an ideal antigen for specific tumor targeting because of its relative lack of heterogeneity among human neuroblastoma, its high density on tumor cells, its lack of antigen modulation upon binding to antibody, and its restricted distribution in normal tissues

  8. New targeted therapies in pancreatic cancer.

    Science.gov (United States)

    Seicean, Andrada; Petrusel, Livia; Seicean, Radu

    2015-05-28

    Patients with pancreatic cancer have a poor prognosis with a median survival of 4-6 mo and a 5-year survival of less than 5%. Despite therapy with gemcitabine, patient survival does not exceed 6 mo, likely due to natural resistance to gemcitabine. Therefore, it is hoped that more favorable results can be obtained by using guided immunotherapy against molecular targets. This review summarizes the new leading targeted therapies in pancreatic cancers, focusing on passive and specific immunotherapies. Passive immunotherapy may have a role for treatment in combination with radiochemotherapy, which otherwise destroys the immune system along with tumor cells. It includes mainly therapies targeting against kinases, including epidermal growth factor receptor, Ras/Raf/mitogen-activated protein kinase cascade, human epidermal growth factor receptor 2, insulin growth factor-1 receptor, phosphoinositide 3-kinase/Akt/mTOR and hepatocyte growth factor receptor. Therapies against DNA repair genes, histone deacetylases, microRNA, and pancreatic tumor tissue stromal elements (stromal extracellular matric and stromal pathways) are also discussed. Specific immunotherapies, such as vaccines (whole cell recombinant, peptide, and dendritic cell vaccines), adoptive cell therapy and immunotherapy targeting tumor stem cells, have the role of activating antitumor immune responses. In the future, treatments will likely include personalized medicine, tailored for numerous molecular therapeutic targets of multiple pathogenetic pathways. PMID:26034349

  9. Immunotherapy for Urothelial Carcinoma: Current Status and Perspectives

    International Nuclear Information System (INIS)

    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

  10. 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.

  11. Epithermal neutron beam adoption for lung and pancreatic cancer treatment by boron neutron capture therapy

    International Nuclear Information System (INIS)

    The depth-dose distributions were evaluated for possible treatment of both lung and pancreatic cancers using an epithermal neutron beam. The Monte Carlo Neutron Photon (MCNP) calculations showed that physical dose in tumors were 6 and 7 Gy/h, respectively, for lung and pancreas, attaining an epithermal neutron flux of 5 x 108 ncm-2s-1. The boron concentrations were assumed at 100 ppm and 30 ppm, respectively, for lung and pancreas tumors and normal tissues contains 1/10 tumor concentrations. The dose ratios of tumor to normal tissue were 2.5 and 2.4, respectively, for lung and pancreas. The dose evaluation suggests that BNCT using an epithermal neutron beam could be applied for both lung and pancreatic cancer treatment. (author)

  12. RhoC a new target for therapeutic vaccination against metastatic cancer

    DEFF Research Database (Denmark)

    Wenandy, L.; Sorensen, R.B.; Straten, P.T.;

    2008-01-01

    Most cancer deaths are due to the development of metastases. Increased expression of RhoC is linked to enhanced metastatic potential in multiple cancers. Consequently, the RhoC protein is an attractive target for drug design. The clinical application of immunotherapy against cancer is rapidly...... moving forward in multiple areas, including the adoptive transfer of anti-tumor-reactive T cells and the use of "therapeutic" vaccines. The over-expression of RhoC in cancer and the fact that immune escape by down regulation or loss of expression of this protein would reduce the morbidity and mortality...... of cancer makes RhoC a very attractive target for anti-cancer immunotherapy. Herein, we describe an HLA-A3 restricted epitope from RhoC, which is recognized by cytotoxic T cells. Moreover, RhoC-specific T cells show cytotoxic potential against HLA-matched cancer cells of different origin. Thus, Rho...

  13. [Immunotherapy for Alzheimer's disease].

    Science.gov (United States)

    Falkentoft, Alexander Christian; Hasselbalch, Steen Gregers

    2016-01-18

    Passive anti-beta-amyloid (Aß) immunotherapy has been shown to clear brain Aß deposits. Results from phase III clinical trials in mild-to-moderate Alzheimer's disease (AD) patients with two monoclonal antibodies bapineuzumab and solanezumab and intravenous immunoglobulin have been disappointing. Subsequent analysis of pooled data from both phase III trials with solanezumab showed a reduction in cognitive decline in patients with mild AD. Solanezumab and new monoclonal antibodies are being tested in patients with prodromal and preclinical AD in search for a disease-modifying treatment. PMID:26815584

  14. 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.

  15. LNTgate: How scientific misconduct by the U.S. NAS led to governments adopting LNT for cancer risk assessment.

    Science.gov (United States)

    Calabrese, Edward J

    2016-07-01

    This paper provides a detailed rebuttal to the letter of Beyea (2016) which offered a series of alternative interpretations to those offered in my article in Environmental Research (Calabrese, 2015a) concerning the role of the U.S. National Academy of Sciences (NAS) Biological Effects of Atomic Radiation (BEAR) I Committee Genetics Panel in the adoption of the linear dose response model for cancer risk assessment. Significant newly uncovered evidence is presented which supports and extends the findings of Calabrese (2015a), reaffirming the conclusion that the Genetics Panel should be evaluated for scientific misconduct for deliberate misrepresentation of the research record in order to enhance an ideological agenda. This critique documents numerous factual errors along with extensive and deliberate filtering of information in the Beyea letter (2016) that leads to consistently incorrect conclusions and an invalid general perspective. PMID:27131569

  16. Epithermal neutron beam adoption for liver cancer treatment by boron and gadolinium neutron capture therapy

    International Nuclear Information System (INIS)

    Comparative evaluation was made on depth-dose distribution in boron neutron capture therapy (B-NCT) and gadolinium one (Gd-NCT) for the treatments of liver cancers. At present, epithermal neutron beam is expected to be applicable to the treatment of deep and widespread tumors. ICRU computational model of ADAM and EVA was used as a liver phantom loading a tumor at depth of 6 cm in its central region. Epithermal neutron beam of Musashi reactor was used as the primary neutron beam for the depth-dose calculation. Calculation was conducted using the three-dimensional continuous-energy Monte Carlo code MCNP4A. The doses observed in both NCTs were bumped over the tumor region but the dose for Gd-NCT was not so tumor-specific compared with that for BNCT because radiation in Gd-NCT was due to γ-ray. The mean physical dose was 4 Gy/h for boron 30 ppm and 5 Gy/h for Gd 1000 ppm when exposed to an epithermal neutron flux of 5x108 n/cm-2/sec and the dose ratio of tumor-to normal tissue was 2.7 for boron and 2.5 for Gd. The lethal dose of 50 Gy for the liver can be accomplished under conditions where the dose has not reached 25 Gy, the tolerance dose of the normal tissue. This seems very encouraging and indicating that both B-NCT and Gd-NCT are applicable for the treatment for liver cancer. However, if normal tissue contain 1/4 of the tumor concentration of boron or Gd, the BNCT would still possible when considering a large RBE value for 10B(n, α) reaction but the Gd-NCT would impossible for deep liver treatment. (M.N.)

  17. Immunotherapy of Cryptococcus infections.

    Science.gov (United States)

    Antachopoulos, C; Walsh, T J

    2012-02-01

    Despite appropriate antifungal treatment, the management of cryptococcal disease remains challenging, especially in immunocompromised patients, such as human immunodeficiency virus-infected individuals and solid organ transplant recipients. During the past two decades, our knowledge of host immune responses against Cryptococcus spp. has been greatly advanced, and the role of immunomodulation in augmenting the response to infection has been investigated. In particular, the role of 'protective' Th1 (tumour necrosis factor-α, interferon (IFN)-γ, interleukin (IL)-12, and IL-18) and Th17 (IL-23 and IL-17) and 'non-protective' Th2 (IL-4, IL-10, and IL-13) cytokines has been extensively studied in vitro and in animal models of cryptococcal infection. Immunomodulation with monoclonal antibodies against the capsular polysaccharide glucuronoxylomannan, glucosylceramides, melanin and β-glucan and, lately, with radioimmunotherapy has also yielded promising results in animal models. As a balance between sufficiently protective Th1 responses and excessive inflammation is important for optimal outcome, the effect of immunotherapy may range from beneficial to deleterious, depending on factors related to the host, the infecting organism, and the immunomodulatory regimen. Clinical evidence supporting immunomodulation in patients with cryptococcal infection remains too limited to allow firm recommendations. Limited human data suggest a role for IFN-γ. Identification of surrogate markers characterizing patients' immunological status could possibly suggest candidate patients for immunotherapy and the type of immunomodulation to be administered. PMID:22264261

  18. Adherence to Sublingual Immunotherapy.

    Science.gov (United States)

    Incorvaia, Cristoforo; Mauro, Marina; Leo, Gualtiero; Ridolo, Erminia

    2016-02-01

    Adherence is a major issue in any medical treatment. Allergen immunotherapy (AIT) is particularly affected by a poor adherence because a flawed application prevents the immunological effects that underlie the clinical outcome of the treatment. Sublingual immunotherapy (SLIT) was introduced in the 1990s, and the early studies suggested that adherence and compliance to such a route of administration was better than the traditional subcutaneous route. However, the recent data from manufacturers revealed that only 13% of patients treated with SLIT reach the recommended 3-year duration. Therefore, improved adherence to SLIT is an unmet need that may be achieved by various approaches. The utility of patient education and accurate monitoring during the treatment was demonstrated by specific studies, while the success of technology-based tools, including online platforms, social media, e-mail, and a short message service by phone, is currently considered to improve the adherence. This goal is of pivotal importance to fulfill the object of SLIT that is to modify the natural history of allergy, ensuring a long-lasting clinical benefit, and a consequent pharmaco-economic advantage, when patients complete at least a 3-year course of treatment. PMID:26758865

  19. Immunotherapy With IL-10 and IFN-γ Producing CD4 Effector Cells Modulate “Natural” And “Inducible” CD4 TReg Cell Subpopulation Levels: Observations In Four Cases Of Patients With Ovarian Cancer

    OpenAIRE

    Dobrzanski, Mark J.; Rewers-Felkins, Kathleen A.; Samad, Khaliquzzaman A.; Quinlin, Imelda S.; Phillips, Catherine A.; Robinson, William; Dobrzanski, David J.; Wright, Stephen E.

    2011-01-01

    Adoptive T cell therapy for cancer patients optimally requires participation of CD4 T cells. In this phase I/II study, we assessed the therapeutic effects of adoptively transferred IL-10 and IFN-γ-producing CD4 effector cells in patients with recurrent ovarian cancer. Using MUC1 peptide and IL-2 for ex vivo CD4 effector cell generation, we show that 3 monthly treatment cycles of autologous T cell restimulation and local intraperitoneal re-infusion modulated T cell mediated immune responses th...

  20. Inmunoterapia local Local immunotherapy

    Directory of Open Access Journals (Sweden)

    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

  1. Progress and controversies in developing cancer vaccines

    Directory of Open Access Journals (Sweden)

    Speiser Daniel E

    2005-04-01

    Full Text Available Abstract Immunotherapy has become a standard approach for cancer management, through the use of cytokines (eg: interleukin-2 and monoclonal antibodies. Cancer vaccines hold promise as another form of immunotherapy, and there has been substantial progress in identifying shared antigens recognized by T cells, in developing vaccine approaches that induce antigen-specific T cell responses in cancer patients, and in developing new technology for monitoring immune responses in various human tissue compartments. Dramatic clinical regressions of human solid tumors have occurred with some cancer vaccines, but the rate of those responses remains low. This article is part of a 2-part point:counterpoint series on peptide vaccines and adoptive therapy approaches for cancer. The current status of cancer vaccination, and associated challenges, are discussed. Emphasis is placed on the need to increase our knowledge of cancer immunobiology, as well as to improve monitoring of cellular immune function after vaccination. Progress in both areas will facilitate development of effective cancer vaccines, as well as of adoptive therapy. Effective cancer vaccines promise to be useful for treatment and prevention of cancer at low cost and with low morbidity.

  2. Novel anti-melanoma treatment:focus on immunotherapy

    Institute of Scientific and Technical Information of China (English)

    Meng-Ze Hao; Wen-Ya Zhou; Xiao-Ling Du; Ke-Xin Chen; Guo-Wen Wang; Yun Yang; Ji-Long Yang

    2014-01-01

    Melanoma is an intractable cancer that is aggressive, lethal, and metastatic. The prognosis of advanced melanoma is very poor because it is insensitive to chemotherapy and radiotherapy. The incidence of melanoma has been ascending stably for years worldwide, accompanied by increasing mortality. New approaches to managing this deadly disease are much anticipated to enhance the cure rate and to extend clinical benefits to patients with metastatic melanoma. Due to its high degree of immunogenicity, melanoma could be a good target for immunotherapy, which has been developed for decades and has achieved certain progress. This article provides an overview of immunotherapy for melanoma.

  3. Novel anti-melanoma treatment: focus on immunotherapy

    Directory of Open Access Journals (Sweden)

    Meng-Ze Hao

    2014-09-01

    Full Text Available Melanoma is an intractable cancer that is aggressive, lethal, and metastatic. The prognosis of advanced melanoma is very poor because it is insensitive to chemotherapy and radiotherapy. The incidence of melanoma has been ascending stably for years worldwide, accompanied by increasing mortality. New approaches to managing this deadly disease are much anticipated to enhance the cure rate and to extend clinical benefits to patients with metastatic melanoma. Due to its high degree of immunogenicity, melanoma could be a good target for immunotherapy, which has been developed for decades and has achieved certain progress. This article provides an overview of immunotherapy for melanoma.

  4. 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. PMID:26932732

  5. Conference Scene: novelties in immunotherapy.

    Science.gov (United States)

    Mitsias, Dimitris I; Kalogiros, Lampros A; Papadopoulos, Nikolaos G

    2013-10-01

    The only method aiming to permanently cure allergic disorders is allergen immunotherapy. Over the last 20 years there has been great progress in understanding the mechanisms that govern allergen immunotherapy in order to meet three basic prerequisites: safety, effectiveness and compliance. In the present summary report from the European Academy of Allergology and Clinical Immunology-World Allergy Organization Congress held last June in Milan, we review key points concerning the main axes as diagnosis, novel modalities, routes and protocols, as well as two important immunotherapy fields: food and insect venom allergy. PMID:24088073

  6. Gene therapy for carcinoma of the breast: Genetic immunotherapy

    International Nuclear Information System (INIS)

    Advances in gene transfer technology have greatly expanded the opportunities for developing immunotherapy strategies for breast carcinoma. Genetic immunotherapy approaches include the transfer of genes encoding cytokines and costimulatory molecules to modulate immune function, as well as genetic immunization strategies which rely on the delivery of cloned tumor antigens. Improved gene transfer vectors, coupled with a better understanding of the processes that are necessary to elicit an immune response and an expanding number of target breast tumor antigens, have led to renewed enthusiasm that effective immunotherapy may be achieved. It is likely that immunotherapeutic interventions will find their greatest clinical application as adjuvants to traditional first-line therapies, targeting micrometastatic disease and thereby reducing the risk of cancer recurrence

  7. Current therapeutic vaccination and immunotherapy strategies for HPV-related diseases.

    Science.gov (United States)

    Skeate, Joseph G; Woodham, Andrew W; Einstein, Mark H; Da Silva, Diane M; Kast, W Martin

    2016-06-01

    Carcinomas of the anogenital tract, in particular cervical cancer, remains one of the most common cancers in women, and represent the most frequent gynecological malignancies and the fourth leading cause of cancer death in women worldwide. Human papillomavirus (HPV)-induced lesions are immunologically distinct in that they express viral antigens, which are necessary to maintain the cancerous phenotype. The causal relationship between HPV infection and anogenital cancer has prompted substantial interest in the development of therapeutic vaccines against high-risk HPV types targeting the viral oncoproteins E6 and E7. This review will focus on the most recent clinical trials for immunotherapies for mucosal HPV-induced lesions as well as emerging therapeutic strategies that have been tested in pre-clinical models for HPV-induced diseases. Progress in peptide- and protein-based vaccines, DNA-based vaccines, viral/bacterial vector-based vaccines, immune checkpoint inhibition, immune response modifiers, and adoptive cell therapy for HPV will be discussed. PMID:26835746

  8. 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....

  9. Dendritic cell-based immunotherapy induces transient clinical response in advanced rat fibrosarcoma - comparison with preventive anti-tumour vaccination

    Czech Academy of Sciences Publication Activity Database

    Kučera, A.; Pýcha, K.; Pajer, Petr; Špíšek, R.; Škába, R.

    2009-01-01

    Roč. 55, č. 4 (2009), s. 119-125. ISSN 0015-5500 Institutional research plan: CEZ:AV0Z50520514 Keywords : dendritic cells * immunotherapy * cancer immunotherapy * chemotherapy Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 0.924, year: 2009

  10. The Adoption of New Adjuvant Radiation Therapy Modalities Among Medicare Beneficiaries With Breast Cancer: Clinical Correlates and Cost Implications

    International Nuclear Information System (INIS)

    Purpose: New radiation therapy modalities have broadened treatment options for older women with breast cancer, but it is unclear how clinical factors, geographic region, and physician preference affect the choice of radiation therapy modality. Methods and Materials: We used the Surveillance, Epidemiology, and End Results-Medicare database to identify women diagnosed with stage I-III breast cancer from 1998 to 2007 who underwent breast-conserving surgery. We assessed the temporal trends in, and costs of, the adoption of intensity modulated radiation therapy (IMRT) and brachytherapy. Using hierarchical logistic regression, we evaluated the relationship between the use of these new modalities and patient and regional characteristics. Results: Of 35,060 patients, 69.9% received conventional external beam radiation therapy (EBRT). Although overall radiation therapy use remained constant, the use of IMRT increased from 0.0% to 12.6% from 1998 to 2007, and brachytherapy increased from 0.7% to 9.0%. The statistical variation in brachytherapy use attributable to the radiation oncologist and geographic region was 41.4% and 9.5%, respectively (for IMRT: 23.8% and 22.1%, respectively). Women undergoing treatment at a free-standing radiation facility were significantly more likely to receive IMRT than were women treated at a hospital-based facility (odds ratio for IMRT vs EBRT: 3.89 [95% confidence interval, 2.78-5.45]). No such association was seen for brachytherapy. The median radiation therapy cost per treated patient increased from $5389 in 2001 to $8539 in 2007. Conclusions: IMRT and brachytherapy use increased substantially from 1998 to 2007; overall, radiation therapy costs increased by more than 50%. Radiation oncologists played an important role in treatment choice for both types of radiation therapy, whereas geographic region played a bigger role in the use of IMRT than brachytherapy

  11. Immunotherapy of hematological malignancies using dendritic cells.

    Science.gov (United States)

    Van de Velde, Ann L R; Berneman, Zwi N; Van Tendeloo, Viggo F I

    2008-03-01

    The arsenal of therapeutic weapons against hematological malignancies is constantly growing. Unravelling the secrets of tumor immunobiology has allowed researchers to manipulate the immune system in order to stimulate tumor immunity or to bypass tumor-induced immunosuppression. An area of great interest is active specific immunotherapy where dendritic cell (DC)-based therapeutic vaccines for cancer have definitely grabbed the spotlight. DC are intensively investigated as cellular adjuvants to harness the immune system to fight off cancer by augmenting the number and effector functions of tumor-specific CD8+ cytotoxic T lymphocytes. In the present review we present a comprehensive synopsis and an update of the use of DC in hematological malignancies. In the future, more basic research as well as more clinical trials are warranted to fully establish the value of DC vaccination as an adjuvant therapy for modern hematological oncology. PMID:18390412

  12. Adoptive cellular immunotherapy. NK cells and bone marrow transplantation

    OpenAIRE

    Koh, C.Y.; Welniak, L A; Murphy, W.J.

    2000-01-01

    Allogeneic bone marrow transplantation (BMT) has been increasingly used for the treatment of both neoplastic and non-neoplastic disorders. However, serious obstacles currently limit the efficacy and thus more extensive use of BMT. These obstacles include: graft-versus-host disease (GVHD), relapse from the original tumor, and susceptibility of patients to opportunistic infections due to the immunosuppressive effects of the conditioning regimen.Overcoming these ...

  13. Cytokine-induced killer cell transplantation: an innovative adoptive therapy

    Directory of Open Access Journals (Sweden)

    Binh Thanh Vu

    2016-03-01

    Full Text Available Cytokine-induced killer (CIK cells areeffector immune cells with anti-tumor potency of T lymphocytes as well as non-major histocompatibility complex restricted elimination of natural killer cells. Preclinical models have shown that CIK cells have strong anti-tumor killing capacity against a variety of blood cancers and solid tumors. Clinical studies confirm the advantages of CIK cells, including the safety of CIK cell therapy in patients with advanced cancer. A preeminent property of CIK cells, which may help them to overcome some of the limitations of other adoptive immunotherapy strategies, is their ability to be expanded ex vivo to high numbers. Their robust in vitro proliferation provides adequate quantity for multiple adoptive infusions. The tumor-killing capacity of CIK cells is mainly based on the interaction between NKG2D molecules on CIK cells and MIC A/B or ULBP molecules on tumor cells. Moreover, CIK cells have a reduced allo-reactivity across HLA-barriers. This review summarizes the clinical applications of CIK cells and updates of combining CIK cells with other therapies. This review highlights the benefits of CIK cell use in clinical treatment of cancer. [Biomed Res Ther 2016; 3(3.000: 533-541

  14. Intranasal application of immuno-regulatory molecules: a method to investigate strategies for local cancer immuno-therapies in the lung

    OpenAIRE

    sprotocols

    2015-01-01

    Authors: Sarah Reppert, Katerina Andreev, Sandra Wittmann & Susetta Finotto ### Abstract Lung cancer is one of the most frequently occurring cancer types. Successful lung cancer therapies in patients require preliminary investigations of promising therapeutic reagents in animal models. This protocol describes a method to induce lung tumours in mice and to deliver an immunoregulatory molecule directly to the lung by intranasal application. Here we describe the usage of murine ce...

  15. 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.

  16. Adoptive Cell Therapy for Lymphoma with CD4 T Cells Depleted of CD137 Expressing Regulatory T Cells

    OpenAIRE

    Goldstein, Matthew J; Kohrt, Holbrook E.; Houot, Roch; Varghese, Bindu; Lin, Jack T.; Swanson, Erica; Levy, Ronald

    2012-01-01

    Adoptive immunotherapy with anti-tumor T cells is a promising novel approach to the treatment of cancer. However, T cell therapy may be limited by the co-transfer of regulatory T cells (Tregs). Here we explored this hypothesis by using two cell surface markers, CD44 and CD137, to isolate anti-tumor CD4 T cells while excluding Tregs. In a murine model of B cell lymphoma, only CD137negCD44hi CD4 T cells infiltrated tumor sites and provided protection. Conversely, the population of CD137posCD44h...

  17. Antibody-Mediated Autoimmune Encephalopathies and Immunotherapies.

    Science.gov (United States)

    Gastaldi, Matteo; Thouin, Anaïs; Vincent, Angela

    2016-01-01

    Over the last 15 years it has become clear that rare but highly recognizable diseases of the central nervous system (CNS), including newly identified forms of limbic encephalitis and other encephalopathies, are likely to be mediated by antibodies (Abs) to CNS proteins. The Abs are directed against membrane receptors and ion channel-associated proteins that are expressed on the surface of neurons in the CNS, such as N-methyl D-aspartate receptors and leucine-rich, glioma inactivated 1 protein and contactin-associated protein like 2, that are associated with voltage-gated potassium channels. The diseases are not invariably cancer-related and are therefore different from the classical paraneoplastic neurological diseases that are associated with, but not caused by, Abs to intracellular proteins. Most importantly, the new antibody-associated diseases almost invariably respond to immunotherapies with considerable and sometimes complete recovery, and there is convincing evidence of their pathogenicity in the relatively limited studies performed so far. Treatments include first-line steroids, intravenous immunoglobulins, and plasma exchange, and second-line rituximab and cyclophosphamide, followed in many cases by steroid-sparing agents in the long-term. This review focuses mainly on N-methyl D-aspartate receptor- and voltage-gated potassium channel complex-related Abs in adults, the clinical phenotypes, and treatment responses. Pediatric cases are referred to but not reviewed in detail. As there have been very few prospective studies, the conclusions regarding immunotherapies are based on retrospective studies. PMID:26692392

  18. Autologous Immune Enhancement Therapy for Cancer - Our experience since 2004

    OpenAIRE

    Hiroshi Terunuma

    2012-01-01

    Cancer, the major killer disease of the century requires a multi-pronged approach and among the latest modalities of treatments, Immunotherapy occupies a promising role. Immunotherapy for cancer was first started to be practised in the NIH and cell based immunotherapy for cancer is in practice for the past three decades. [1, 2] There are several literatures from various countries on the successful application of cell based Immunotherapies for various solid tumours and haematological malignanc...

  19. 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. PMID:26558320

  20. In the field: exploiting the untapped potential of immunogenic modulation by radiation in combination with immunotherapy for the treatment of cancer

    Directory of Open Access Journals (Sweden)

    Anna eKwilas

    2012-09-01

    Full Text Available Radiation has long been the standard of care for many types of cancer. It is employed to locally eradicate tumor cells as well as alter tumor stroma with either curative or palliative intent. Radiation-induced cell damage is an immunologically active process in which danger signals are released that stimulate immune cells to phagocytose and present locally released tumor-associated antigens (TAAs. Recent studies have indicated that radiotherapy can also induce immunogenic modulation; an alteration in the phenotype of cancer cells that remain after treatment and renders these cells more sensitive to immune mediated attack.. These cells upregulate TAAs as well as markers, including MHC and costimulatory molecules, that make them much more immunostimulatory. As our understanding of the immunomodulatory effects of radiation has improved, interest in combining this type of therapy with immune-based therapies for the treatment of cancer has grown. Therapeutic cancer vaccines have been shown to initiate the dynamic process of host immune system activation, culminating in the recognition of host cancer cells as foreign. The environment created after radiotherapy can be exploited by active therapeutic cancer vaccines in order to achieve further, more robust immune system activation. This review highlights preclinical studies that have examined the alteration of the tumor microenvironment with regard to immunostimulatory molecules following different types of radiotherapy, including external beam radiation, radiolabeled monoclonal antibodies, bone-seeking radionuclides, and brachytherapy. We also emphasize how combination therapy with a cancer vaccine can exploit these changes to achieve improved therapeutic benefit. Lastly, we describe how these laboratory findings are translating into clinical benefit for patients undergoing combined radiotherapy and cancer vaccination.

  1. Big Data Offers Novel Insights for Oncolytic Virus Immunotherapy

    Directory of Open Access Journals (Sweden)

    Stephanie L. Swift

    2016-02-01

    Full Text Available 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.

  2. Big Data Offers Novel Insights for Oncolytic Virus Immunotherapy.

    Science.gov (United States)

    Swift, Stephanie L; Stojdl, David F

    2016-02-01

    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

  3. 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

  4. Big Data Offers Novel Insights for Oncolytic Virus Immunotherapy

    OpenAIRE

    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 funct...

  5. Myeloma cell line–derived, pooled heat shock proteins as a universal vaccine for immunotherapy of multiple myeloma

    OpenAIRE

    Qian, Jianfei; Hong, Sungyoul; Wang, Siqing; Zhang, Liang; Sun, Luhong; Wang, Michael; Yang, Jing; Kwak, Larry W.; Hou, Jian; Yi, Qing

    2009-01-01

    Tumor cell–derived heat shock proteins are used as vaccines for immunotherapy of cancer patients. However, current approaches require the generation of custom-made products and are clinically ineffective. To improve the applicability of heat shock protein–based immunotherapy in cancers and to enhance clinical efficacy, we explored combinational treatments in a myeloma setting using pooled heterogeneous or allogeneic myeloma cell line–derived glycoprotein 96 (gp96) as universal vaccines, and c...

  6. LYMPHOCYTE PHENOTYPE IN PATIENTS WITH SKIN MELANOMA AFTER IMMUNOTHERAPY OF ACTIVATED LYMPHOCYTES

    Directory of Open Access Journals (Sweden)

    E. V. Abakushina

    2015-01-01

    Full Text Available The major medical problem in the treatment of skin melanoma is improvement methods of treatment, increasing their effectiveness and safety. In this study, adoptive immunotherapy, using lymphocytes activated in vitro, was performed in 15 patients with metastatic melanoma. Evaluated the phenotype of peripheral blood lymphocytes and activation markers (HLA-DR, CD25, CD314, CD38, CD69 before and 3-4 weeks after immunotherapy. It is shown that for these patients is characterized by increasing the number of CD25+ and Treg lymphocytes in the bloodstream, which has not changed after immunotherapy. Adoptive immunotherapy in combination with chemotherapy resulted in a decrease of absolute number of lymphocyte, B- and T-lymphocytes, T helper cells, NKT-cells, CD314+ lymphocytes, CD38+ lymphocytes and immature T-lymphocytes (CD3+CD38+ (р < 0,05. However, there was a positive dynamic to increase the percentage of NK-cells to 32% and CD69+NK-cells to 21% and significant increase in expression of HLA-DR on all lymphocytes (p < 0.05. Adoptive immunotherapy characterized by the absence of side effects and can be recommended as accompanying to basic radiation and chemotherapy.

  7. Adoption procedures

    OpenAIRE

    Marie Arendt

    1980-01-01

    In early Eastern Greek and Roman civilisations, a childless couple adopted a child to provide a direct heir or to perpetuate domestic ancestral worship, and in later centuries adoption was used to solve the problem of illegitimacy. Although the child often benefitted from adoption, it was used primarily as a means of giving a child to a family in the interests of the adults involved. Today, adoption is still used to smooth problems of rights and inheritance of the child, but it has also becom...

  8. 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

  9. 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 AI...

  10. The immunotherapy of Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Weksler Marc E

    2004-11-01

    Full Text Available Abstract Only a small percentage of patients with Alzheimer's disease benefit from current drug therapy and for only a relatively short time. This is not surprising as the goal of these drugs is to enhance existing cerebral function in Alzheimer patients and not to block the progression of cognitive decline. In contrast, immunotherapy is directed at clearing the neurotoxic amyloid beta peptide from the brain that directly or indirectly leads to cognitive decline in patients with Alzheimer's disease. The single trial of active immunization with the amyloid beta peptide provided suggestive evidence of a reduction in cerebral amyloid plaques and of stabilization in cognitive function of half the patients who developed good antibody responses to the amyloid beta peptide. However, 6% of actively immunized Alzheimer patients developed sterile meningoencephalitis that forced the cessation of the clinical trial. Passive immunotherapy in animal models of Alzheimer's disease has provided similar benefits comparable to those seen with active immunotherapy and has the potential of being effective in the half of Alzheimer's disease patients who do not make a significant anti-amyloid beta peptide antibody response and without inducing T-cell-mediated encephalitis. Published studies of 5 patients with sporadic Alzheimer disease treated with intravenous immunoglobulin containing anti-amyloid beta peptide antibodies showed that amyloid beta peptide was mobilized from the brain and cognitive decline was interrupted. Further studies of passive immunotherapy are urgently required to confirm these observations.

  11. Myeloid-derived suppressor cells have a central role in attenuated Listeria monocytogenes-based immunotherapy against metastatic breast cancer in young and old mice

    OpenAIRE

    Chandra, D; Jahangir, A.; Quispe-Tintaya, W; Einstein, M H; Gravekamp, C

    2013-01-01

    Background: Myeloid-derived suppressor cells (MDSCs) are present in large numbers in blood of mice and humans with cancer, and they strongly inhibit T-cell and natural killer (NK) cell responses, at young and old age. We found that a highly attenuated bacterium Listeria monocytogenes (Listeriaat)-infected MDSC and altered the immune-suppressing function of MDSC. Methods: Young (3 months) and old (18 months) BALB/cByJ mice with metastatic breast cancer (4T1 model) were immunised with Listeriaa...

  12. Near-infrared imaging of adoptive immune cell therapy in breast cancer model using cell membrane labeling.

    Directory of Open Access Journals (Sweden)

    Fatma M Youniss

    Full Text Available The overall objective of this study is to non-invasively image and assess tumor targeting and retention of directly labeled T-lymphocytes following their adoptive transfer in mice. T-lymphocytes obtained from draining lymph nodes of 4T1 (murine breast cancer cell sensitized BALB/C mice were activated in-vitro with Bryostatin/Ionomycin for 18 hours, and were grown in the presence of Interleukin-2 for 6 days. T-lymphocytes were then directly labeled with 1,1-dioctadecyltetramethyl indotricarbocyanine Iodide (DiR, a lipophilic near infrared fluorescent dye that labels the cell membrane. Assays for viability, proliferation, and function of labeled T-lymphocytes showed that they were unaffected by DiR labeling. The DiR labeled cells were injected via tail vein in mice bearing 4T1 tumors in the flank. In some cases labeled 4T1 specific T-lymphocytes were injected a week before 4T1 tumor cell implantation. Multi-spectral in vivo fluorescence imaging was done to subtract the autofluorescence and isolate the near infrared signal carried by the T-lymphocytes. In recipient mice with established 4T1 tumors, labeled 4T1 specific T-lymphocytes showed marked tumor retention, which peaked 6 days post infusion and persisted at the tumor site for up to 3 weeks. When 4T1 tumor cells were implanted 1-week post-infusion of labeled T-lymphocytes, T-lymphocytes responded to the immunologic challenge and accumulated at the site of 4T1 cell implantation within two hours and the signal persisted for 2 more weeks. Tumor accumulation of labeled 4T1 specific T-lymphocytes was absent in mice bearing Meth A sarcoma tumors. When lysate of 4T1 specific labeled T-lymphocytes was injected into 4T1 tumor bearing mice the near infrared signal was not detected at the tumor site. In conclusion, our validated results confirm that the near infrared signal detected at the tumor site represents the DiR labeled 4T1 specific viable T-lymphocytes and their response to immunologic challenge

  13. Adoptive chemoimmunotherapy using ex vivo activated memory T-cells and cyclophosphamide: tumor lysis syndrome of a metastatic soft tissue sarcoma.

    Science.gov (United States)

    Gold, J E; Malamud, S C; LaRosa, F; Osband, M E

    1993-09-01

    Adoptively transferred immune cells in combination with chemotherapeutic agents form the basis for adoptive chemoimmunotherapy (ACIT) of neoplastic disease. Autolymphocytes (ALT-cells) are ex vivo activated peripheral blood lymphocytes (PBL) from tumor-bearing hosts (TBH) that consist primarily of tumor-specific CD45RO+ (memory) T-cells. These ALT-cells combined with cimetidine (CIM) as autolymphocyte therapy (ALT), have previously been demonstrated to be a safe and active form of outpatient adoptive immunotherapy (AIT) in human TBH with metastatic renal cell cancer (RCC). We have previously described an effective ACIT protocol using ALT and cyclophosphamide (CY) for patients with relapsed and refractory non-RCC solid tumors. We now report a case of a patient with a metastatic gastric leiomyosarcoma to the liver, who developed a clinical picture consistent with a tumor-lysis syndrome (TLS), following salvage therapy for his tumor with ACIT using ALT and CY. TLS is a well-known complication resulting from the treatment of rapidly proliferating hematopoietic tumors such as Burkitt's lymphoma and acute lymphocytic leukemia. TLS has also been rarely described in chronic lymphocytic leukemia, as well as certain solid tumors such as breast cancer, small cell lung cancer, and medulloblastoma. However, there have been no previous reports of TLS occurring either secondary to immunotherapy or in sarcomas. The nature of these unusual findings is discussed. PMID:8342564

  14. In vivo colocalization of antigen and CpG [corrected] within dendritic cells is associated with the efficacy of cancer immunotherapy.

    NARCIS (Netherlands)

    Nierkens, S.; Brok, M.H.M.G.M. den; Sutmuller, R.P.M.; Grauer, O.M.; Bennink, E.; Morgan, M.E.; Figdor, C.G.; Ruers, T.J.M.; Adema, G.J.

    2008-01-01

    Immunostimulatory cytidyl guanosyl (CpG) motifs are of great interest as cancer vaccine adjuvants. They act as potent inducers of Th1 responses, including the activation of cytotoxic CD8(+) T lymphocytes (CTL). Whereas animal models have provided clear evidence that CpG enhances antitumor immunity,

  15. Recent progress in allergen immunotherapy.

    Science.gov (United States)

    Nouri-Aria, Kayhan T

    2008-03-01

    The efficacy of allergen immunotherapy for the treatment of allergic rhinoconjunctivitis with or without seasonal bronchial asthma and anaphylaxis caused by the sting of the hymenoptera class of insects has been clearly demonstrated in numerous well-designed, placebo-controlled trials. Immunotherapy whether by subcutaneous injection of allergen extract or by oral/sublingual routes modifies peripheral and mucosal TH2 responses in favour of TH1 responses and augments IL-10 synthesis by TRegs both locally and by peripheral T cells. Recent researches into the cellular and molecular basis of allergic reactions have advanced our understanding of the mechanisms involved in allergic diseases. They have also helped the development of innovative approaches that are likely to further improve the control of allergic responses in the future. Novel approaches to immunotherapy that are currently being explored include the use of peptide-based allergen preparations, which do not bind IgE and therefore do not activate mast cells, but reduce both Th1 and Th2-cytokine synthesis, while increasing levels of IL-10. Alternative strategies include the use of adjuvants, such as nucleotide immunostimulatory sequences derived from bacteria CpG or monophosphoryl lipid A that potentiate Th1 responses. Blocking the effects of IgE using anti-IgE such as omalizumab, a recombinant humanized monoclonal antibody that selectively binds to IgE, has been shown to be a useful strategy in the treatment of allergic asthma and rhinitis. The combination of anti-IgE-monoclonal antibody omalizumab with allergen immunotherapy has proved beneficial for the treatment of allergic diseases, offering improved efficacy, limited adverse effects, and potential immune-modifying effects. This combination may also accelerate the rapidity by which immunotherapy induces TReg cells. If allergic diseases are due to a lack of allergen-specific TReg cells, then effective therapies should target the induction and the

  16. FOXP3+ Tregs and B7-H1+/PD-1+ T lymphocytes co-infiltrate the tumor tissues of high-risk breast cancer patients: Implication for immunotherapy

    International Nuclear Information System (INIS)

    Recent studies have demonstrated a direct involvement of B7-H1, PD-1 and FOXP3 molecules in the immune escape of cancer. B7-H1 is an inhibitory molecule that binds to PD-1 on T lymphocytes, while FOXP3 is a marker for regulatory T cells (Tregs). We have previously demonstrated the association of B7-H1-expressing T infiltrating lymphocytes (TIL) with high-risk breast cancer patients while other studies reported the involvement of FOXP3+ Tregs as a bad prognostic factor in breast tumors. Although the co-existence between the two types of cells has been demonstrated in vitro and animal models, their relative infiltration and correlation with the clinicopathological parameters of cancer patients have not been well studied. Therefore, we investigated TIL-expressing the B7-H1, PD-1, and FOXP3 molecules, in the microenvironment of human breast tumors and their possible association with the progression of the disease. Using immunohistochemistry, tumor sections from 62 breast cancer patients were co-stained for B7-H1, PD-1 and FOXP3 molecules and their expression was statistically correlated with factors known to be involved in the progression of the disease. A co-existence of B7-H1+ T lymphocytes and FOXP3+ Tregs was evidenced by the highly significant correlation of these molecules (P < .0001) and their expression by different T lymphocyte subsets was clearly demonstrated. Interestingly, concomitant presence of FOXP3+ Tregs, B7-H1+ and PD-1+ TIL synergistically correlated with high histological grade (III) (P < .001), estrogen receptor negative status (P = .017), and the presence of severe lymphocytic infiltration (P = .022). Accumulation of TIL-expressing such inhibitory molecules may deteriorate the immunity of high-risk breast cancer patients and this should encourage vigorous combinatorial immunotherapeutic approaches targeting Tregs and B7-H1/PD-1 molecules

  17. Systems biology applied to vaccine and immunotherapy development

    Directory of Open Access Journals (Sweden)

    Marincola Francesco M

    2011-09-01

    Full Text Available Abstract Immunotherapies, including vaccines, represent a potent tool to prevent or contain disease with high morbidity or mortality such as infections and cancer. However, despite their widespread use, we still have a limited understanding of the mechanisms underlying the induction of protective immune responses. Immunity is made of a multifaceted set of integrated responses involving a dynamic interaction of thousands of molecules; among those is a growing appreciation for the role the innate immunity (i.e. pathogen recognition receptors - PRRs plays in determining the nature and duration (immune memory of adaptive T and B cell immunity. The complex network of interactions between immune manipulation of the host (immunotherapy on one side and innate and adaptive responses on the other might be fully understood only employing the global level of investigation provided by systems biology. In this framework, the advancement of high-throughput technologies, together with the extensive identification of new genes, proteins and other biomolecules in the "omics" era, facilitate large-scale biological measurements. Moreover, recent development of new computational tools enables the comprehensive and quantitative analysis of the interactions between all of the components of immunity over time. Here, we review recent progress in using systems biology to study and evaluate immunotherapy and vaccine strategies for infectious and neoplastic diseases. Multi-parametric data provide novel and often unsuspected mechanistic insights while enabling the identification of common immune signatures relevant to human investigation such as the prediction of immune responsiveness that could lead to the improvement of the design of future immunotherapy trials. Thus, the paradigm switch from "empirical" to "knowledge-based" conduct of medicine and immunotherapy in particular, leading to patient-tailored treatment.

  18. 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.

  19. [The reaction of the T-immunity system in patients with malignant skin melanoma and stomach cancer to active nonspecific immunotherapy].

    Science.gov (United States)

    Glinkina, L S; Bruvere, R Zh

    1992-01-01

    Changes in E-receptor-bearing T-lymphocyte level (total and that of active T-lymphocytes) were studied in peripheral blood and resected material obtained from skin malignant melanoma and gastric cancer patients treated with rigvir, an original immunomodulator of the viral origin. Injection of rigvir into peripheral blood was followed by an increase in active T-lymphocyte level and stimulated their migration into tumor. The latter was determined by stage and rate of tumor advancement. PMID:1300766

  20. Activated human γδ T cells as stimulators of specific CD8+ T cell responses to subdominant Epstein Barr virus (EBV) epitopes: Potential for immunotherapy of cancer

    OpenAIRE

    Landmeier, Silke; Altvater, Bianca; Pscherer, Sibylle; Juergens, Heribert; Varnholt, Lena; Hansmeier, Anna; Bollard, Catherine M.; Moosmann, Andreas; Bisping, Guido; Rossig, Claudia

    2009-01-01

    The efficacy of current cancer vaccines is limited by the functional heterogeneity and poor availability and expansion of professional antigen-presenting cells (APCs). Besides their potent innate effector properties, γδ T cells have been suggested to be involved in the initiation and maintenance of adaptive immune responses. Here, we investigated the capacity of human γδ T cells to induce expansion of virus-specific T cells to Epstein Barr virus (EBV) antigens. Aminobisphosphonate-stimulated ...

  1. Tumor cells engineered to codisplay on their surface 4-1BBL and LIGHT costimulatory proteins as a novel vaccine approach for cancer immunotherapy

    OpenAIRE

    Sharma, Rajesh Kumar; Yolcu, Esma S.; Elpek, Kutlu G.; Shirwan, Haval

    2010-01-01

    Primary tumor cells genetically modified to express on their surface a collection of immunological ligands may have utility as therapeutic autologous cancer vaccines. However, genetic modification of primary tumor cells is not only cost, labor, and time intensive, but also has safety repercussions. As an alternative, we developed the ProtEx™ technology that involves generation of immunological ligands with core streptavidin (SA) and their display on biotinylated cells in a rapid and efficient...

  2. Elevation of plasma prolactin in patients undergoing autologous blood stem-cell transplantation for breast cancer: is its modulation a step toward posttransplant immunotherapy?

    Science.gov (United States)

    Hinterberger-Fischer, M; Ogris, E; Kier, P; Bauer, K; Kittl, E; Habertheuer, K H; Ruckser, R; Schmid, A; Selleny, S; Fangl, M; Sebesta, C; Hinterberger, W

    2000-08-01

    Prolactin is a suspected promotor of breast cancer cell growth, and it shares pleiotropic immunoregulatory properties. We studied plasma prolactin and its drug-induced modulation in 20 women with breast cancer undergoing high-dose chemotherapy and autologous blood stem-cell transplantation. Plasma prolactin levels were serially assayed before and during conditioning and within and beyond 30 days after transplant. Before transplant, prolactin plasma levels were in the age-adjusted range of normal women. During conditioning and within 30 days after transplant, prolactin levels increased in all patients (p < 0.0001), but remained in the normal range. Antiemetic drugs such as metoclopramide and phenothiazines, known to enhance pituitary prolactin secretion, further elevated prolactin plasma levels (p < 0.00001). Patients remaining in continuous complete remission after transplant (median follow-up, 3 years) disclosed higher prolactin levels compared with those obtaining only partial remission or ensuing early relapse. Prolactin levels are regularly elevated during conditioning and within 30 days after autologous transplantation for breast cancer. Further elevations of prolactin plasma levels are induced by metoclopramide and other antiemetic drugs. Elevated plasma prolactin had no adverse effect on disease-free survival after transplant. We propose to investigate further the upregulation of prolactin after transplant aiming to induce a posttransplant consolidative immune reaction. PMID:10955855

  3. Effects of laser immunotherapy on tumor microenvironment

    Science.gov (United States)

    Acquaviva, Joseph T.; Wood, Ethan W.; Hasanjee, Aamr; Chen, Wei R.; Vaughan, Melville B.

    2014-02-01

    The microenvironments of tumors are involved in a complex and reciprocal dialog with surrounding cancer cells. Any novel treatment must consider the impact of the therapy on the microenvironment. Recently, clinical trials with laser immunotherapy (LIT) have proven to effectively treat patients with late-stage, metastatic breast cancer and melanoma. LIT is the synergistic combination of phototherapy (laser irradiation) and immunological stimulation. One prominent cell type found in the tumor stroma is the fibroblast. Fibroblast cells can secrete different growth factors and extracellular matrix modifying molecules. Furthermore, fibroblast cells found in the tumor stroma often express alpha smooth muscle actin. These particular fibroblasts are coined cancer-associated fibroblast cells (CAFs). CAFs are known to facilitate the malignant progression of tumors. A collagen lattice assay with human fibroblast cells is used to elucidate the effects LIT has on the microenvironment of tumors. Changes in the contraction of the lattice, the differentiation of the fibroblast cells, as well as the proliferation of the fibroblast cells will be determined.

  4. Adoption procedures

    Directory of Open Access Journals (Sweden)

    Marie Arendt

    1980-09-01

    Full Text Available In early Eastern Greek and Roman civilisations, a childless couple adopted a child to provide a direct heir or to perpetuate domestic ancestral worship, and in later centuries adoption was used to solve the problem of illegitimacy. Although the child often benefitted from adoption, it was used primarily as a means of giving a child to a family in the interests of the adults involved. Today, adoption is still used to smooth problems of rights and inheritance of the child, but it has also become, much more, a way of giving a family to a child who needs substitute parents from whom he can receive the love and nurture which are so necessary for his full development.

  5. Galectin-1 drives lymphoma CD20 immunotherapy resistance: validation of a preclinical system to identify resistance mechanisms.

    Science.gov (United States)

    Lykken, Jacquelyn M; Horikawa, Mayuka; Minard-Colin, Veronique; Kamata, Masahiro; Miyagaki, Tomomitsu; Poe, Jonathan C; Tedder, Thomas F

    2016-04-14

    Non-Hodgkin lymphoma (NHL) is the most commonly diagnosed hematologic cancer of adults in the United States, with the vast majority of NHLs deriving from malignant B lymphocytes that express cell surface CD20. CD20 immunotherapy (rituximab) is widely used to treat NHL, even though the initial effectiveness of rituximab varies widely among patients and typically wanes over time. The mechanisms through which lymphomas initially resist or gain resistance to immunotherapy are not well established. To address this, a preclinical mouse model system was developed to comprehensively identify lymphoma transcriptomic changes that confer resistance to CD20 immunotherapy. The generation of spontaneous primary and familial lymphomas revealed that sensitivity to CD20 immunotherapy was not regulated by differences in CD20 expression, prior exposure to CD20 immunotherapy, or serial in vivo passage. An unbiased forward exome screen of these primary lymphomas was used to validate the utility of this expansive lymphoma cohort, which revealed that increased lymphoma galectin-1 (Gal-1) expression strongly correlated with resistance to immunotherapy. Genetically induced lymphoma Gal-1 expression ablated antibody-dependent lymphoma phagocytosis in vitro and lymphoma sensitivity to CD20 immunotherapy in vivo. Human NHLs also express elevated Gal-1 compared with nonmalignant lymphocytes, demonstrating the ability of this preclinical model system to identify molecular targets that could be relevant to human therapy. This study therefore established a powerful preclinical model system that permits the comprehensive identification of the dynamic lymphoma molecular network that drives resistance to immunotherapy. PMID:26888257

  6. Intercountry adoption

    OpenAIRE

    International Child Development Centre

    2007-01-01

    This Digest looks at intercountry adoption as one of a series of possible solutions for children unable to live with their families. Broadly accepted international instruments specify the conditions under which intercountry adoption should be undertaken if the rights and best interests of the children concerned are to be protected and fully respected. Although substantial efforts are being made to implement the standards and procedures set, current practices are often in violation of these no...

  7. Tissue factor expression in ovarian cancer: implications for immunotherapy with hI-con1, a factor VII-IgGF(c) chimeric protein targeting tissue factor.

    Science.gov (United States)

    Cocco, Emiliano; Varughese, Joyce; Buza, Natalia; Bellone, Stefania; Lin, Ken-Yu; Bellone, Marta; Todeschini, Paola; Silasi, Dan-Arin; Azodi, Masoud; Schwartz, Peter E; Rutherford, Thomas J; Carrara, Luisa; Tassi, Renata; Pecorelli, Sergio; Lockwood, Charles J; Santin, Alessandro D

    2011-10-01

    We evaluated the expression of tissue factor (TF) in ovarian cancer (EOC) and the potential of hI-con1, an antibody-like molecule targeting TF, as a novel form of therapy against chemotherapy-resistant ovarian disease. We studied the expression of TF in 88 EOC by immunohistochemistry (IHC) and real-time-PCR (qRT-PCR) and the levels of membrane-bound-complement-regulatory-proteins CD46, CD55 and CD59 in primary EOC cell lines by flow-cytometry. Sensitivity to hI-con1-dependent-cell-mediated-cytotoxicity (IDCC), complement-dependent-cell-cytotoxicity and inhibition of IDCC by γ-immunoglobulin were evaluated in 5-h (51)chromium-release-assays. Cytoplasmic and/or membrane TF expression was observed in 24 out of 25 (96%) of the EOC samples tested by IHC, but not in normal ovarian-tissue. EOC with clear cell histology significantly overexpress TF when compared to serous, endometrioid, or undifferentiated tumors by qRT-PCR. With a single exception, all primary EOC that overexpressed TF demonstrated high levels of CD46, CD55 and CD59 and regardless of their histology or resistance to chemotherapy, were highly sensitive to IDCC. The effect of complement and physiologic doses of γ-immunoglobulin on IDCC in ovarian cancer cell lines overexpressing TF was tumor specific and related to the overexpression of CD59 on tumor cells. Small-interfering-RNA-mediated knockdown of CD59 expression in ovarian tumors significantly increased hI-con1-mediated cytotoxic activity in vitro. Finally, low doses of interleukin-2 further increased the cytotoxic effect induced by hI-con1 (P < 0.01). hI-con1 molecule induces strong cytotoxicity against primary chemotherapy-resistant ovarian cancer cell lines overexpressing TF and may represent a novel therapeutic agent for the treatment of ovarian tumors refractory to standard treatment modalities. PMID:21725665

  8. Tissue factor expression in ovarian cancer: implications for immunotherapy with hI-con1, a factor VII-IgGFc chimeric protein targeting tissue factor

    Science.gov (United States)

    Cocco, Emiliano; Varughese, Joyce; Buza, Natalia; Bellone, Stefania; Lin, Ken-Yu; Bellone, Marta; Todeschini, Paola; Silasi, Dan-Arin; Azodi, Masoud; Schwartz, Peter E.; Rutherford, Thomas J.; Carrara, Luisa; Tassi, Renata; Pecorelli, Sergio; Lockwood, Charles J.

    2013-01-01

    We evaluated the expression of tissue factor (TF) in ovarian cancer (EOC) and the potential of hI-con1, an antibody-like molecule targeting TF, as a novel form of therapy against chemotherapy-resistant ovarian disease. We studied the expression of TF in 88 EOC by immunohistochemistry (IHC) and real-time-PCR (qRT-PCR) and the levels of membrane-bound-complement-regulatory-proteins CD46, CD55 and CD59 in primary EOC cell lines by flow-cytometry. Sensitivity to hI-con1-dependent-cell-mediated-cytotoxicity (IDCC), complement-dependent-cell-cytotoxicity and inhibition of IDCC by γ-immunoglobulin were evaluated in 5-h 51chromium-release-assays. Cytoplasmic and/or membrane TF expression was observed in 24 out of 25 (96%) of the EOC samples tested by IHC, but not in normal ovarian-tissue. EOC with clear cell histology significantly overexpress TF when compared to serous, endometrioid, or undifferentiated tumors by qRT-PCR. With a single exception, all primary EOC that overexpressed TF demonstrated high levels of CD46, CD55 and CD59 and regardless of their histology or resistance to chemotherapy, were highly sensitive to IDCC. The effect of complement and physiologic doses of γ-immunoglobulin on IDCC in ovarian cancer cell lines overexpressing TF was tumor specific and related to the overexpression of CD59 on tumor cells. Small-interfering-RNA-mediated knockdown of CD59 expression in ovarian tumors significantly increased hI-con1-mediated cytotoxic activity in vitro. Finally, low doses of interleukin-2 further increased the cytotoxic effect induced by hI-con1 (P < 0.01). hI-con1 molecule induces strong cytotoxicity against primary chemotherapy-resistant ovarian cancer cell lines overexpressing TF and may represent a novel therapeutic agent for the treatment of ovarian tumors refractory to standard treatment modalities. PMID:21725665

  9. Cancer incidence and novel therapies developed in Japan

    Directory of Open Access Journals (Sweden)

    Masaru Iwasaki

    2012-01-01

    Oncology. JMAJ 54(1: 44–46, 20114.Hildebrandt B, Wust P, Ahlers O, et al. The cellular and molecular basis of hyperthermia. Critical Reviews in Oncology/Hematology 2002; 43(1:33–56.5.Levin WP, Kooy H, Loeffler JS, DeLaney TF. Proton beam therapy. Br J Cancer.2005; 93(8:849-54. 6.Widakowich C, de Castro G Jr, de Azambuja E, Dinh P, Awada A. Review: side effects of approved molecular targeted therapies in solid cancers. Oncologist. 2007; 12(12:1443-55.7.Egawa K. Immuno-cell therapy of cancer in Japan. Anticancer Res. 2004;24(5C:3321-6. 8.Takayama T, Sekine T, Makuuchi M, Yamasaki S, Kosuge T, Yamamoto J, Shimada K, Sakamoto M, Hirohashi S, Ohashi Y, Kakizoe T. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet. 2000; 356(9232:802-7. 9.Kimura H, Yamaguchi Y. A phase III randomized study of interleukin-2 lymphokine-activated killer cell immunotherapy combined with chemotherapy or radiotherapy after curative or noncurative resection of primary lung carcinoma. Cancer. 1997;80(1:42-9. 10.Kono K, Takahashi A, Ichihara F, Amemiya H, Iizuka H, Fujii H, Sekikawa T, Matsumoto Y: Prognostic significance of adoptive immunotherapy with tumor-associated lymphocytes in patients with advanced gastric cancer: a randomized trial. Clin Cancer Res. 2002; 8: 1767-71. 11.Fujita K, Ikarashi H, Takakuwa K, Kodama S, Tokunaga A, Takahashi T, Tanaka K. Prolonged disease-free period in patients with advanced epithelial ovarian cancer after adoptive transfer of tumor-infiltrating lymphocytes. Clin Cancer Res. 1995; 1(5:501-7.12.Goto S, Shirotani N, Hatakeyama M, Tagami C, Arakawa H, Kuwata E, Noguchi K, Egawa K. Clinical benefit of non-toxic therapy in patients with advanced cancer (opinion. Anticancer Res. 2002; 22(4:2461-4.

  10. Allergen immunotherapy in polysensitized patient.

    Science.gov (United States)

    Hrubiško, M; Špičák, V

    2016-05-01

    Specific allergen immunotherapy (AIT) is the only therapeutic method with positive impact on natural course of allergic disease - affecting clinical development (including the progression of rhinitis to asthma) and new sensitisations. The actual problem is the increasing number of patients manifesting poly-sensitivity in allergy skin tests and / or in specific IgE tests. Usually, AIT is not recommended in such individuals. The objective we are facing is that in many patients tested as poly-reactive, we have to distinguish in which cases it is a true polysensitization, and when it is due to cross-reactivity of specific IgE antibodies induced by panallergens. This may really determine when AIT may be an appropriate course of action. The article focuses on this problem in more detail, applying the long time Czech and Slovak experience with allergy testing and allergen immunotherapy. PMID:27152601

  11. New strategies for allergen immunotherapy.

    Science.gov (United States)

    Carnés, Jerónimo; Robinson, Douglas S

    2008-06-01

    Specific allergen immunotherapy, consisting in the administration of increasing amounts of offending allergens into sensitive patients was first used nearly one hundred years ago and remains in use worldwide for treatment of allergic rhinitis and asthma. It has been recognised as the only effective treatment for type I allergic diseases when the appropriate quantities of allergens are used. The immunological mechanisms by which specific immunotherapy is effective include the modulation of T cells and the response of B-cells and is accompanied by significant decreases of specific IgE and increases in allergen specific IgG antibodies, mainly IgG4. While specific allergen injection immunotherapy is highly effective and the most common way of administration other routes such as oral or intranasal ways have been considered as and alternative to subcutaneous injections. During the last century, allergenic vaccines have been prepared using individual allergens adsorbed to different adjuvant substances. These vaccines have demonstrated efficacy and good results in different clinical trials. However, many novel approaches to allergen immunotherapy have been developed in the last years in order to increase the safety and efficacy of allergenic vaccines. In that way, different and modern vaccines have been prepared including more purified products such as depigmented allergen extracts; allergoids, consisting on big molecules of thousands of kDa, which contain all the individual allergens and show a significant decrease in severe adverse reactions; peptides or small aminoacid sequences; recombinant allergens; hypoallergenic vaccines where the IgE binding sites have been modified; or allergen-CpG fusion molecules. New presentations are under study and new treatments will be developed in the near future with the objective that the prevention of allergic disease may become a reality. The review article also discuss recent patent related to the field. PMID:19075996

  12. New routes for allergen immunotherapy

    OpenAIRE

    Johansen, Pål; von Moos, Seraina; Mohanan, Deepa; Kündig, Thomas M.; Senti, Gabriela

    2012-01-01

    IgE-mediated allergy is a highly prevalent disease in the industrialized world. Allergen-specific immunotherapy (SIT) should be the preferred treatment, as it has long lasting protective effects and can stop the progression of the disease. However, few allergic patients choose to undergo SIT, due to the long treatment time and potential allergic adverse events. Since the beneficial effects of SIT are mediated by antigen presenting cells inducing Th1, Treg and antibody responses, whereas the a...

  13. Antibody Peptide Based Antifungal Immunotherapy

    OpenAIRE

    Magliani, Walter; Conti, Stefania; Giovati, Laura; Zanello, Pier Paolo; Sperindè, Martina; Ciociola, Tecla; Polonelli, Luciano

    2012-01-01

    Fungal infections still represent relevant human illnesses worldwide and some are accompanied by unacceptably high mortality rates. The limited current availability of effective and safe antifungal agents makes the development of new drugs and approaches of antifungal vaccination/immunotherapy every day more needed. Among them, small antibody(Ab)-derived peptides are arousing great expectations as new potential antifungal agents. In this topic, the search path from the study of the yeast kill...

  14. The immunotherapy of Alzheimer's disease

    OpenAIRE

    Weksler Marc E

    2004-01-01

    Abstract Only a small percentage of patients with Alzheimer's disease benefit from current drug therapy and for only a relatively short time. This is not surprising as the goal of these drugs is to enhance existing cerebral function in Alzheimer patients and not to block the progression of cognitive decline. In contrast, immunotherapy is directed at clearing the neurotoxic amyloid beta peptide from the brain that directly or indirectly leads to cognitive decline in patients with Alzheimer's d...

  15. Adoptive transfer of Tc1 or Tc17 cells elicits anti-tumor immunity against established melanoma through distinct mechanisms1

    OpenAIRE

    Yu, Yu; Cho, Hyun-II; Wang, Dapeng; Kaosaard, Kane; Anasetti, Claudio; Celis, Esteban; Yu, Xue-Zhong

    2013-01-01

    Adoptive cell transfer (ACT) of ex vivo activated autologous tumor-reactive T cells is currently one of the most promising approaches for cancer immunotherapy. Recent studies provided some evidence that Th17/Tc17 cells may exhibit potent anti-tumor activity, but the specific mechanisms have not been completely defined. In the present study, we used a murine melanoma lung-metastasis model and tested the therapeutic effects of gp100-specific polarized Tc1 or Tc17 cells combined with autologous ...

  16. The future of sublingual immunotherapy.

    Science.gov (United States)

    Marcucci, F; Duse, M; Frati, F; Incorvaia, C; Marseglia, G L; La Rosa, M

    2009-01-01

    Sublingual immunotherapy (SLIT) is currently the most prescribed form of allergen immunotherapy in many European countries. Its use has been accepted in the international consensus publications, and recently also the scepticism of USA scientists is attenuated. Still, this treatment may be improved, and the possible developments consist of modification of the materials, use of adjuvants and use of recombinant allergens. Moreover, new applications of SLIT, such as food allergy, seem promising. Concerning materials, the future form of SLIT is likely to be represented by tablets, which were already tested for efficacy and safety with grass pollen extracts, and are likely to increase the convenience for the patient by the use of no-updosing schedule. Adjuvants fitting with the characteristics of SLIT seem to be CpG oligodeoxynucleotides (CpG), able to interact with the Toll-like receptor 9 (TLR9) whose activation induces a Th1-like pattern of cytokine release, combination of 1,25-dihydroxyvitamin D3 plus dexamethasone (VitD3-Dex), and Lactobacillus plantarum. The approach with recombinant allergens, named component-resolved diagnosis, offers the possibility to tailor immunotherapy, which was found to be effective in two randomized trials of subcutaneous SIT (16-17), while studies with SLIT are not yet available. Regarding food allergy, an important controlled study demonstrated that SLIT with hazelnut is able to increase patients tolerance over possible reactions from inadvertent assumption of the culprit food, and warrants for further trials with other foods. PMID:19944008

  17. A novel strategy to improve antigen presentation for active immunotherapy in cancer. Fusion of the human papillomavirus type 16 E7 antigen to a cell penetrating peptide

    International Nuclear Information System (INIS)

    Facilitating the delivery of exogenous antigens to antigen-presenting cells, ensuing processing and presentation via the major histocompatibility complex class I and induction of an effective immune response are fundamental for an effective therapeutic cancer vaccine. In this regard, we propose the use of cell-penetrating peptides fused to a tumor antigen. To demonstrate this concept we designed a fusion protein comprising a novel cell-penetrating and immunostimulatory peptide corresponding to residues 32 to 51 of the Limulus anti-lipopolysaccharide factor protein (LALF32-51) linked to human papillomavirus 16 E7 antigen (LALF32-51-E7). In this work, we demonstrated that the immunization with LALF32-51-E7 using the TC-1 mouse model induces a potent and long-lasting anti-tumor response supported on an effective E7-specific CD8+T-cell response. The finding that therapeutic immunization with LALF32-51 or E7 alone, or an admixture of LALF32-51 and E7, does not induce significant tumor reduction indicates that covalent linkage between LALF32-51 and E7 is required for the anti-tumor effect. These results support the use of this novel cell-penetrating peptide as an efficient means for delivering therapeutic targets into cellular compartments with the induction of a cytotoxic CD8+T lymphocyte immune response. This approach is promissory for the treatment of tumors associated with the human papillomavirus 16, which is responsible for the 50% of cervical cancer cases worldwide and other malignancies. Furthermore, protein-based vaccines can circumvent the major histocompatibility complex specificity limitation associated with peptide vaccines providing a greater extent in their application

  18. Adopting a family approach to theory and practice: measuring distress in cancer patient-partner dyads with the distress thermometer

    OpenAIRE

    Zwahlen, D; Hagenbuch, N; Jenewein, J.; Carley, M I; Buchi, S

    2011-01-01

    Objective: Significant others are central to patients' experience and management of their cancer illness. Building on our validation of the Distress Thermometer (DT) for family members, this investigation examines individual and collective distress in a sample of cancer patients and their matched partners, accounting for the aspects of gender and role.Method: Questionnaires including the DT were completed by a heterogeneous sample of 224 couples taking part in a multisite study.Results: Our i...

  19. Development of a 'mouse and human cross-reactive' affinity-matured exosite inhibitory human antibody specific to TACE (ADAM17) for cancer immunotherapy.

    Science.gov (United States)

    Kwok, Hang Fai; Botkjaer, Kenneth A; Tape, Christopher J; Huang, Yanchao; McCafferty, John; Murphy, Gillian

    2014-06-01

    We previously showed that a human anti-TACE antibody, D1(A12), is a potent inhibitor of TNF-α converting enzyme (TACE) ectodomain proteolysis and has pharmacokinetic properties suitable for studies of the inhibition of TACE-dependent growth factor shedding in relation to possible therapeutic applications. However, the lack of murine TACE immunoreactivity limits pre-clinical in vivo studies to human xenograft models which are poor analogies to in situ pathology and are not considered clinically predictive. Here, to overcome these limitations, we set out to develop a 'mouse and human cross-reactive' specific anti-TACE antibody. We first re-investigated the originally selected anti-TACE ectodomain phage-display clones, and isolated a lead 'mouse-human cross-reactive' anti-TACE scFv, clone A9. We reformatted scFv-A9 into an IgG2 framework for comprehensive biochemical and cellular characterization and further demonstrated that A9 is an exosite TACE inhibitor. However, surface plasmon resonance analysis and quenched-fluorescent (QF) peptide assay indicated that IgG reformatting of A9 caused low binding affinity and an 80-fold reduction in TACE ectodomain inhibition, severely limiting its efficacy. To address this, we constructed second generation phage-display randomization libraries focused on the complementarity-determining region 3, and carried out affinity selections shuffling between human and mouse TACE ectodomain as antigen in addition to an off-rate selection to increase the chance of affinity improvement. The bespoke 'three-step' selections enabled a 100-fold affinity enhancement of A9 IgG, and also improved its IC50 in a QF peptide assay to 0.2 nM. In human and mouse cancer cell assays, matured A9 IgG showed significant cell-surface TACE inhibition as a monotherapy or combination therapy with chemotherapeutic agent. Collectively, these data suggest that we successfully developed an exosite inhibitor of TACE with sub-nanomolar affinity, which possesses both

  20. Immunological data from cancer patients treated with Ad5/3-E2F-Δ24-GMCSF suggests utility for tumor immunotherapy.

    Science.gov (United States)

    Hemminki, Otto; Parviainen, Suvi; Juhila, Juuso; Turkki, Riku; Linder, Nina; Lundin, Johan; Kankainen, Matti; Ristimäki, Ari; Koski, Anniina; Liikanen, Ilkka; Oksanen, Minna; Nettelbeck, Dirk M; Kairemo, Kalevi; Partanen, Kaarina; Joensuu, Timo; Kanerva, Anna; Hemminki, Akseli

    2015-02-28

    Oncolytic viruses that selectively replicate in tumor cells can be used for treatment of cancer. Accumulating data suggests that virus induced oncolysis can enhance anti-tumor immunity and break immune tolerance. To capitalize on the immunogenic nature of oncolysis, we generated a quadruple modified oncolytic adenovirus expressing granulocyte-macrophage colony-stimulating factor (GMCSF). Ad5/3-E2F-Δ24-GMCSF (CGTG-602) was engineered to contain a tumor specific E2F1 promoter driving an E1 gene deleted at the retinoblastoma protein binding site ("Δ24"). The fiber features a knob from serotype 3 for enhanced gene delivery to tumor cells. The virus was tested preclinically in vitro and in vivo and then 13 patients with solid tumors refractory to standard therapies were treated. Treatments were well tolerated and frequent tumor- and adenovirus-specific T-cell immune responses were seen. Overall, with regard to tumor marker or radiological responses, signs of antitumor efficacy were seen in 9/12 evaluable patients (75%). The radiological disease control rate with positron emission tomography was 83% while the response rate (including minor responses) was 50%. Tumor biopsies indicated accumulation of immunological cells, especially T-cells, to tumors after treatment. RNA expression analyses of tumors indicated immunological activation and metabolic changes secondary to virus replication. PMID:25714011

  1. Early carcinogenesis involves the establishment of immune privilege via intrinsic and extrinsic regulation of Indoleamine 2,3-dioxygenase-1: Translational implications in cancer immunotherapy

    Directory of Open Access Journals (Sweden)

    Alisha eHoltzhausen

    2014-10-01

    Full Text Available Although prolonged genetic pressure has been conjectured to be necessary for the eventual development of tumor immune evasion mechanisms, recent work is demonstrating that early genetic mutations are capable of moonlighting as both intrinsic and extrinsic modulators of the tumor immune microenvironment. The indoleamine 2,3-dioxygenase-1 (IDO immunoregulatory enzyme is emerging as a key player in tumor-mediated immune tolerance. While loss of the tumor suppressor, BIN-1, and the over-expression of cyclooxygenase-2 (COX-2 have been implicated in intrinsic regulation of IDO, recent findings have demonstrated the loss of TβRIII and the upregulation of Wnt5a by developing cancers to play a role in the extrinsic control of IDO activity by local dendritic cell populations residing within tumor and tumor-draining lymph node tissues. Together, these genetic changes are capable of modulating paracrine signaling pathways in the early stages of carcinogenesis to establish a site of immune privilege by promoting the differentiation and activation of local regulatory T cells. Additional investigation of these immune evasion pathways promises to provide opportunities for the development of novel strategies to synergistically enhance the efficacy of the evolving class of T cell-targeted ‘checkpoint’ inhibitors.

  2. Effect of Five-Element-Music Combined with Immunotherapy for the Quality of Life of Cancer Patients with Anxiety%五行音乐联合免疫疗法对癌症焦虑患者生存质量的影响

    Institute of Scientific and Technical Information of China (English)

    苏秋兰; 李艳; 李冬梅

    2014-01-01

    Objective To investigate the effect of five-element-music combined with immunotherapy for the quality of life of cancer patients with anxiety. Methods 40 cases of cancer patients treated with radiotherapy were randomly divided into two groups, with 20 cases in each group. The control group received routine nursing intervention, while the experimental received five-element-music combined with immunotherapy. The anxiety level was evaluated by Zung's self-rating anxiety scale (SAS) and Hamilton anxiety scale (HAMA), and compared between two groups. Results There were no statistical differences between two groups in the SAS score and HAMA score before therapy (P>0.05);After therapy, SAS score and HAMA score decreased in both groups, and there were statistical differences between two groups in the SAS score and HAMA score (P 0.05),治疗后两组SAS和HAMA评分均有下降,但治疗后试验组SAS和HAMA评分情况明显优于对照组,组间比较差异有统计学意义(P<0.05)。结论五行音乐联合免疫疗法有助于改善癌症焦虑患者的生存质量。

  3. Perspectivas para el desarrollo de vacunas e inmunoterapia contra cáncer cervicouterino Perspectives for vaccines and immunotherapy against cervical cancer

    Directory of Open Access Journals (Sweden)

    LILIANA GUZMÁN-ROJAS

    1998-01-01

    Full Text Available El cáncer cervicouterino representa un grave problema de salud pública, debido a la asociación de la neoplasia con el virus del papiloma humano; actualmente se realizan estudios usando estrategias dirigidas a combatir este patógeno, mediante vacunas, que podrían ser de gran utilidad para el control de la progresión de la enfermedad. El estudio tanto de la inmunología humoral como celular ha servido para el desarrollo de vacunas. Así, la utilización de partículas virales sintéticas para el estudio de anticuerpos neutralizantes y el uso de proteínas tempranas virales, entre otras, para la inducción de inmunidad mediada por células, han sido la pauta para realizar estudios que dirijan la respuesta inmune para prevenir la infección celular tanto hacia células infectadas no transformadas como hacia células transformadas viralmente con resultados favorables.Cervical cancer represents a severe public health problem and has been associated to the presence of human papillomavirus. Strategies are presently being tested which target the virus to attempt to control disease progress. Studies on the humoral and cell-mediated immunity of the papillomavirus infection have been useful in the development of a vaccine. Synthetic virus-like particles have been validated as vaccine against several animal papillomaviruses and used to map the seroepidemiology of the human papillomavirus infection, and define neutralizing antibodies. Induction of cell-mediated immunity to HPV early proteins is bound to become a therapeutic approach to HPV infections. Recent advances have centered on directing the immune response to prevent infection, to virus-infected cells and to virally transformed cells, with favourable results.

  4. Immunotherapy in Metastatic Renal Cell Carcinoma: A Comprehensive Review

    Directory of Open Access Journals (Sweden)

    Rachna Raman

    2015-01-01

    Full Text Available Localized renal cell carcinoma (RCC is often curable by surgery alone. However, metastatic RCC is generally incurable. In the 1990s, immunotherapy in the form of cytokines was the mainstay of treatment for metastatic RCC. However, responses were seen in only a minority of highly selected patients with substantial treatment-related toxicities. The advent of targeted agents such as vascular endothelial growth factor tyrosine kinase inhibitors VEGF-TKIs and mammalian target of rapamycin (mTOR inhibitors led to a change in this paradigm due to improved response rates and progression-free survival, a better safety profile, and the convenience of oral administration. However, most patients ultimately progress with about 12% being alive at 5 years. In contrast, durable responses lasting 10 years or more are noted in a minority of those treated with cytokines. More recently, an improved overall survival with newer forms of immunotherapy in other malignancies (such as melanoma and prostate cancer has led to a resurgence of interest in immune therapies in metastatic RCC. In this review we discuss the rationale for immunotherapy and recent developments in immunotherapeutic strategies for treating metastatic RCC.

  5. Imunotherapy opportunities in ovarian cancer

    Directory of Open Access Journals (Sweden)

    I. Zh. Shubina

    2013-01-01

    Full Text Available In the last decade, accumulated evidence in favor of that ovarian cancer is an immunogenic tumor. Immunotherapy is aimed at stimulating the innate and adaptive immunity, may cause an effective response in patients with ovarian cancer. Various approaches immunotherapy include cytokinetherapy, use of monoclonal antibodies and cell therapy.

  6. Mechanisms of immunotherapy to aeroallergens.

    Science.gov (United States)

    Shamji, M H; Durham, S R

    2011-09-01

    Allergen immunotherapy is allergen-specific, allergen dose- and time-dependent and is associated with long-term clinical and immunological tolerance that persists for years after discontinuation. Successful immunotherapy is accompanied by the suppression of numbers of T-helper 2 (Th2) effector cells, eosinophils, basophils, c-kit+mast cells and neutrophils infiltration in target organs, induction of IL-10 and/or TGF-β+Treg cells and increases in 'protective' non-inflammatory blocking antibodies, particularly IgG4 and IgA2 subclasses with inhibitory activity. These events are accompanied by a reduction and/or a redirection of underlying antigen-specific Th2-type T cell-driven hypersensitivity to the allergen(s) used for therapy. This suppression occurs within weeks or months as a consequence of the appearance of a population of regulatory T cells that exert their effects by mechanisms involving cell-cell contact, but also by the release of cytokines such as IL-10 (increases IgG4) and TGF-β (increases specific IgA). The more delayed-in-time appearance of antigen-specific T-helper 1 responses and alternative mechanisms such as Th2 cell anergy and/or apoptosis may also be involved. The mechanisms of sublingual immunotherapy are similar to those following a subcutaneous administration of allergen, whereas it is likely that additional events following antigen presentation in the sublingual mucosa and regional lymph nodes are involved. These insights have resulted in novel approaches and portend future biomarkers that may be surrogate or predictive of the clinical response to treatment. PMID:21762223

  7. Oral Immunotherapy for Food Allergy.

    Science.gov (United States)

    Burbank, Allison J; Sood, Puja; Vickery, Brian P; Wood, Robert A

    2016-02-01

    Food allergy is a potentially life-threatening condition with no approved therapies, apart from avoidance and injectable epinephrine for acute allergic reactions. Oral immunotherapy (OIT) is an experimental treatment in which food-allergic patients consume gradually increasing quantities of the food to increase their threshold for allergic reaction. This therapy carries significant risk of allergic reactions. The ability of OIT to desensitize patients to particular foods is well-documented, although the ability to induce tolerance has not been established. This review focuses on recent studies for the treatment of food allergies such as cow's milk, hen's egg, and peanut. PMID:26617227

  8. 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. PMID:25709743

  9. Interstitial laser immunotherapy for treatment of metastatic mammary tumors in rats

    Science.gov (United States)

    Figueroa, Daniel; Joshi, Chet; Wolf, Roman F.; Walla, Jonny; Goddard, Jessica; Martin, Mallory; Kosanke, Stanley D.; Broach, Fred S.; Pontius, Sean; Brown, Destiny; Li, Xiaosong; Howard, Eric; Nordquist, Robert E.; Hode, Tomas; Chen, Wei R.

    2011-03-01

    Thermal therapy has been used for cancer treatment for more than a century. While thermal effect can be direct, immediate, and controllable, it is not sufficient to completely eradicate tumors, particularly when tumors have metastasized locally or to the distant sites. Metastases are the major cause of treatment failure and cancer deaths. Current available therapies, such as surgery, radiation, and chemotherapy, only have limited curative effects in patients with late-stage, metastatic cancers. Immunotherapy has been considered as the ultimate approach for cancer treatment since a systemic, anti-tumor, immunological response can be induced. Using the combination of photothermal therapy and immunotherapy, laser immunotherapy (LIT),a novel immunotherapy modality for late-stage cancer treatment, has been developed. LIT has shown great promise in pre-clinical studies and clinical breast cancer and melanoma pilot trials. However, the skin color and the depth of the tumor have been challenges for effective treatment with LIT. To induce a thermal destruction zone of appropriate size without causing thermal damage on the skin, we have developed interstitial laser immunotherapy (ILIT) using a cylindrical diffuser. To determine the effectiveness of ILIT, we treated the DMBA-4 metastatic tumors in rats. The thermal damage in tumor tissue was studied using TTC immersion and hematoxolin and eosin (H & E) staining. Also observed was the overall survival of the treated animals. Our results demonstrated that the ILIT could impact a much larger tumor area, and it significantly reduced the surface damage compared with the early version of non-invasive LIT. The survival data also indicate that ILIT has the potential to become an effective tool for the treatment of deeper, larger, and metastatic tumors, with reduced side effects.

  10. A balanced review of the status T cell-based therapy against cancer

    Directory of Open Access Journals (Sweden)

    Marincola Francesco M

    2005-04-01

    Full Text Available Abstract A recent commentary stirred intense controversy over the status of anti-cancer immunotherapy. The commentary suggested moving beyond current anti-cancer vaccines since active-specific immunization failed to match expectations toward a more aggressive approach involving the adoptive transfer of in vitro expanded tumor antigen-specific T cells. Although the same authors clarified their position in response to others' rebuttal more discussion needs to be devoted to the current status of T cell-based anti-cancer therapy. The accompanying publications review the status of adoptive transfer of cancer vaccines on one hand and active-specific immunization on the other. Hopefully, reading these articles will offer a balanced view of the current status of antigen-specific ant-cancer therapies and suggest future strategies to foster unified efforts to complement either approach with the other according to specific biological principles.

  11. Allergen specific immunotherapy in nasobronchial allergy.

    Directory of Open Access Journals (Sweden)

    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.

  12. Synergistic innate and adaptive immune response to combination immunotherapy with anti-tumor antigen antibodies and extended serum half-life IL-2.

    Science.gov (United States)

    Zhu, Eric F; Gai, Shuning A; Opel, Cary F; Kwan, Byron H; Surana, Rishi; Mihm, Martin C; Kauke, Monique J; Moynihan, Kelly D; Angelini, Alessandro; Williams, Robert T; Stephan, Matthias T; Kim, Jacob S; Yaffe, Michael B; Irvine, Darrell J; Weiner, Louis M; Dranoff, Glenn; Wittrup, K Dane

    2015-04-13

    Cancer immunotherapies under development have generally focused on either stimulating T cell immunity or driving antibody-directed effector functions of the innate immune system such as antibody-dependent cell-mediated cytotoxicity (ADCC). We find that a combination of an anti-tumor antigen antibody and an untargeted IL-2 fusion protein with delayed systemic clearance induces significant tumor control in aggressive isogenic tumor models via a concerted innate and adaptive response involving neutrophils, NK cells, macrophages, and CD8(+) T cells. This combination therapy induces an intratumoral "cytokine storm" and extensive lymphocyte infiltration. Adoptive transfer of anti-tumor T cells together with this combination therapy leads to robust cures of established tumors and development of immunological memory. PMID:25873172

  13. Immunotherapy-induced CD8+ T Cells Instigate Immune Suppression in the Tumor

    Science.gov (United States)

    McGray, A J Robert; Hallett, Robin; Bernard, Dannie; Swift, Stephanie L; Zhu, Ziqiang; Teoderascu, Florentina; VanSeggelen, Heather; Hassell, John A; Hurwitz, Arthur A; Wan, Yonghong; Bramson, Jonathan L

    2014-01-01

    Despite clear evidence of immunogenicity, cancer vaccines only provide a modest clinical benefit. To evaluate the mechanisms that limit tumor regression following vaccination, we have investigated the weak efficacy of a highly immunogenic experimental vaccine using a murine melanoma model. We discovered that the tumor adapts rapidly to the immune attack instigated by tumor-specific CD8+ T cells in the first few days following vaccination, resulting in the upregulation of a complex set of biological networks, including multiple immunosuppressive processes. This rapid adaptation acts to prevent sustained local immune attack, despite continued infiltration by increasing numbers of tumor-specific T cells. Combining vaccination with adoptive transfer of tumor-specific T cells produced complete regression of the treated tumors but did not prevent the adaptive immunosuppression. In fact, the adaptive immunosuppressive pathways were more highly induced in regressing tumors, commensurate with the enhanced level of immune attack. Examination of tumor infiltrating T-cell functionality revealed that the adaptive immunosuppression leads to a progressive loss in T-cell function, even in tumors that are regressing. These novel observations that T cells produced by therapeutic intervention can instigate a rapid adaptive immunosuppressive response within the tumor have important implications for clinical implementation of immunotherapies. PMID:24196579

  14. The iSBTc/SITC primer on tumor immunology and biological therapy of cancer: a summary of the 2010 program

    Directory of Open Access Journals (Sweden)

    Urba Walter J

    2011-01-01

    Full Text Available Abstract The Society for Immunotherapy of Cancer, SITC (formerly the International Society for Biological Therapy of Cancer, iSBTc, aims to improve cancer patient outcomes by advancing the science, development and application of biological therapy and immunotherapy. The society and its educational programs have become premier destinations for interaction and innovation in the cancer biologics community. For over a decade, the society has offered the Primer on Tumor Immunology and Biological Therapy of Cancer™ in conjunction with its Annual Scientific Meeting. This report summarizes the 2010 Primer that took place October 1, 2010 in Washington, D.C. as part of the educational offerings associated with the society's 25th anniversary. The target audience was basic and clinical investigators from academia, industry and regulatory agencies, and included clinicians, post-doctoral fellows, students, and allied health professionals. Attendees were provided a review of basic immunology and educated on the current status and most recent advances in tumor immunology and clinical/translational caner immunology. Ten prominent investigators presented on the following topics: innate immunity and inflammation; an overview of adaptive immunity; dendritic cells; tumor microenvironment; regulatory immune cells; immune monitoring; cytokines in cancer immunotherapy; immune modulating antibodies; cancer vaccines; and adoptive T cell therapy. Presentation slides, a Primer webinar and additional program information are available online on the society's website.

  15. Commercialization of cellular immunotherapies for cancer.

    Science.gov (United States)

    Walker, Anthony; Johnson, Robert

    2016-04-15

    Successful commercialization of a cell therapy requires more than proving safety and efficacy to the regulators. The inherent complexity of cellular products delivers particular manufacturing, logistical and reimbursement hurdles that threaten commercial viability for any therapy with a less than spectacular clinical profile that truly changes the standard of care. This is particularly acute for autologous cell therapies where patients receive bespoke treatments manufactured from a sample of their own cells and where economies of scale, which play an important role in containing the production costs for small molecule and antibody therapeutics, are highly limited. Nevertheless, the promise of 'game-changing' efficacy, as exemplified by very high levels of complete responses in refractory haematological malignancies, has attracted capital investments on a vast scale, and the attendant pace of technology development provides promising indicators for future clinical and commercial success. PMID:27068936

  16. 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.

  17. [Aβ immunotherapy for Alzheimer's disease].

    Science.gov (United States)

    Sakai, Kenji; Yamada, Masahito

    2013-04-01

    Alzheimer's disease (AD) is one of the neurodegenerative diseases characterized by the deposition of amyloid-β-protein (Aβ) as senile plaques in the brain parenchyma and phosphorylated-tau accumulation as neurofibrillary tangles in the neurons. Although details of the disease pathomechanisms remain unclear, Aβ likely acts as a key protein for AD initiation and progression, followed by abnormal tau phosphorylation and neuronal death (amyloid-cascade hypothesis). According to this hypothesis, Aβ immunization therapies are created to eliminate Aβ from the brain, and to prevent the neurons from damage by these pathogenic proteins. There are two methods for Aβ immunotherapies: active and passive immunization. Previous studies have shown Aβ removal and improved cognitive function in animal models of AD. Clinical trials on various drugs, including AN1792, bapineuzumab, and solanezumab, have been carried out; however, all trials have failed to demonstrate apparent clinical benefits. On the contrary, side effects emerged, such as meningoencephalitis, vasogenic edema, which are currently called amyloid related imaging abnormalities (ARIA)-E and microhemorrhage (ARIA-H). In neuropathological studies of immunized cases, Aβ was removed from the brain parenchyma and phosphorylated-tau was reduced in the neuronal processes. Moreover, deterioration of the cerebral amyloid angiopathy (CAA) and an increase of microhemorrhages and microinfarcts were described. Aβ is cleared from the brain mainly via the lymphatic drainage pathway. ARIA could stem from severe CAA due to dysfunction of the drainage pathway after immunotherapy. Aβ immunization has a potential of cure for AD patients, although the above-described problems must be overcome before applying this therapy in clinical treatment. PMID:23568994

  18. Grass pollen immunotherapy: where are we now.

    Science.gov (United States)

    Würtzen, Peter A; Gupta, Shashank; Brand, Stephanie; Andersen, Peter S

    2016-04-01

    During allergen immunotherapy (AIT), the allergic patient is exposed to the disease-inducing antigens (allergens) in order to induce clinical and immunological tolerance and obtain disease modification. Large trials of grass AIT with highly standardized subcutaneous and sublingual tablet vaccines have been conducted to document the clinical effect. Induction of blocking antibodies as well as changes in the balance between T-cell phenotypes, including induction of regulatory T-cell subtypes, have been demonstrated for both treatment types. These observations increase the understanding of the immunological mechanism behind the clinical effect and may make it possible to use the immunological changes as biomarkers of clinical effect. The current review describes the recent mechanistic findings for subcutaneous immunotherapy and sublingual immunotherapy/tablet treatment and discusses how the observed immunological changes translate into a scientific foundation for the observed clinical effects of grass pollen immunotherapy and lead to new treatment strategies for grass AIT. PMID:26973122

  19. L1 Cell Adhesion Molecule-Specific Chimeric Antigen Receptor-Redirected Human T Cells Exhibit Specific and Efficient Antitumor Activity against Human Ovarian Cancer in Mice.

    Directory of Open Access Journals (Sweden)

    Hao Hong

    Full Text Available New therapeutic modalities are needed for ovarian cancer, the most lethal gynecologic malignancy. Recent clinical trials have demonstrated the impressive therapeutic potential of adoptive therapy using chimeric antigen receptor (CAR-redirected T cells to target hematological cancers, and emerging studies suggest a similar impact may be achieved for solid cancers. We sought determine whether genetically-modified T cells targeting the CE7-epitope of L1-CAM, a cell adhesion molecule aberrantly expressed in several cancers, have promise as an immunotherapy for ovarian cancer, first demonstrating that L1-CAM was highly over-expressed on a panel of ovarian cancer cell lines, primary ovarian tumor tissue specimens, and ascites-derived primary cancer cells. Human central memory derived T cells (TCM were then genetically modified to express an anti-L1-CAM CAR (CE7R, which directed effector function upon tumor antigen stimulation as assessed by in vitro cytokine secretion and cytotoxicity assays. We also found that CE7R+ T cells were able to target primary ovarian cancer cells. Intraperitoneal (i.p. administration of CE7R+ TCM induced a significant regression of i.p. established SK-OV-3 xenograft tumors in mice, inhibited ascites formation, and conferred a significant survival advantage compared with control-treated animals. Taken together, these studies indicate that adoptive transfer of L1-CAM-specific CE7R+ T cells may offer a novel and effective immunotherapy strategy for advanced ovarian cancer.

  20. Allergen specific immunotherapy in nasobronchial allergy.

    OpenAIRE

    Joshi S; Tripathi D; Dhar H

    2003-01-01

    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 modera...

  1. Use of new technology to improve utilization and adherence to immunotherapy

    OpenAIRE

    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 pai...

  2. Microsatellite instability as a predictive factor for immunotherapy in malignant melanoma.

    Science.gov (United States)

    Kubecek, Ondrej; Trojanova, Petronela; Molnarova, Veronika; Kopecky, Jindrich

    2016-08-01

    Immunotherapy has attracted attention as a novel treatment modality for malignant melanoma. Although the use of immunotherapy in metastatic melanoma has shown promising results, there remains a lack of predictive biomarkers indicating treatment benefit from immunotherapy. There is growing evidence suggesting that microsatellite instability (MSI) as a product of DNA mismatch repair deficiency, may be one of possible predictive markers in malignant melanoma. It has been proposed that the immunogenicity of some tumors might be determined by mutational heterogeneity and could be the key to the success of immune therapies. This is also supported by the fact that tumors with the highest amount of somatic mutations, such as malignant melanoma have showed positive results with immune checkpoint inhibitors. There are promising data regarding the association between MSI status and immunogenicity from studies with colorectal cancer, where MSI is linked to improved prognosis compared to microsatellite stable cancers. MSI in colon cancer is linked to a significant increase of immunocompetent cells responsible for the antitumor activity - CD3(+), CD8(+), CD45RO(+), and T-bet(+) lymphocytes and decrease of inhibition factors such as Foxp3, IL-6, IL-17, and TGF-β. On the other hand, taking into account the progression-dependent accumulation of somatic mutations in MSI tumors and consequent high levels of neo-antigens, the possible drug resistance of MSI tumors to traditional treatment, and the presence of inhibition checkpoints within the MSI tumors, there is a solid rationale for the use of novel therapeutic strategies such as immunotherapy in MSI melanomas. We presume that the MSI phenotype in malignant melanoma might be helpful to identify patients, who would be more likely to profit from immunotherapy than from conventional therapy. PMID:27372860

  3. Melanoma immunotherapy dominates the field.

    Science.gov (United States)

    Diamantopoulos, Panagiotis; Gogas, Helen

    2016-07-01

    The incidence of melanoma is increasing worldwide and despite early detection and intervention, the number of patients dying from metastatic disease continues to rise. The prognosis of advanced melanoma remains poor, with median survival between 6 and 9 months. Over the past 30 years and despite extensive clinical research, the treatment options for metastatic disease were limited and melanoma is still considered as one of the most therapy-resistant malignancies. Single-agent and combination chemotherapy, hormonal therapy, biochemotherapy, immunotherapy, targeted agent therapy and combination regimens failed to show a significant improvement in overall survival (OS). Recent advances and in-depth understanding of the biology of melanoma, have contributed to the development of new agents. Based on the molecular and immunological background of the disease, these new drugs have shown benefit in overall and progression-free survival (PFS). As the picture of the disease begins to change, oncologists need to alter their approach to melanoma treatment and consider disease biology together with targeted individualized treatment. In this review the authors attempt to offer an insight in the present and past melanoma treatment options, with a focus on the recently approved immunotherapeutic agents and the clinical perspectives of these new weapons against metastatic melanoma. PMID:27563656

  4. Mechanisms of subcutaneous allergen immunotherapy.

    Science.gov (United States)

    Soyer, Ozge U; Akdis, Mubeccel; Akdis, Cezmi A

    2011-05-01

    Allergen-specific immunotherapy (SIT) is the only curative approach in the treatment of allergic diseases defined up-to-date. Peripheral T-cell tolerance to allergens, the goal of successful allergen-SIT, is the primary mechanism in healthy immune responses to allergens. By repeated administration of increased doses of the causative allergen, allergen-SIT induces a state of immune tolerance to allergens through the constitution of T regulatory (Treg) cells, including allergen-specific interleukin (IL)-10-secreting Treg type 1 cells and CD4(+)CD25(+)Treg cells; induction of suppressive cytokines, such as IL-10 and transforming growth factor β; suppression of allergen-specific IgE and induction of IgG4 and IgA; and suppression of mast cells, basophils, eosinophils, and inflammatory dendritic cells. This review summarizes the current knowledge on the mechanisms of allergen-SIT with emphasis on the roles of Treg cells in allergen-SIT. PMID:21530813

  5. New routes for allergen immunotherapy.

    Science.gov (United States)

    Johansen, Pål; von Moos, Seraina; Mohanan, Deepa; Kündig, Thomas M; Senti, Gabriela

    2012-10-01

    IgE-mediated allergy is a highly prevalent disease in the industrialized world. Allergen-specific immunotherapy (SIT) should be the preferred treatment, as it has long lasting protective effects and can stop the progression of the disease. However, few allergic patients choose to undergo SIT, due to the long treatment time and potential allergic adverse events. Since the beneficial effects of SIT are mediated by antigen presenting cells inducing Th1, Treg and antibody responses, whereas the adverse events are caused by mast cells and basophils, the therapeutic window of SIT may be widened by targeting tissues rich in antigen presenting cells. Lymph nodes and the epidermis contain high density of dendritic cells and low numbers of mast cells and basophils. The epidermis has the added benefit of not being vascularised thereby reducing the chances of anaphylactic shock due to leakage of allergen. Hence, both these tissues represent highly promising routes for SIT and are the focus of discussion in this review. PMID:23095873

  6. Immunotherapy in renal cell carcinoma.

    Science.gov (United States)

    Bukowski, R M

    1999-06-01

    Patients with metastatic renal cell carcinoma continue to present a therapeutic challenge. Current therapeutic approaches involve surgery and various types of immunotherapy. The rationale for this latter form of therapy include the observations of spontaneous tumor regression, the presence of a T-cell-mediated immune response, and the tumor responses observed in patients receiving cytokine therapy. Analysis of prognostic factors in these patients demonstrates that clinical responses occur most frequently in individuals with good performance status. The cytokines interleukin-2 (IL-2, aldesleukin [Proleukin], interferon-alfa (Intron A, Roferon-A), or the combination produce responses in 15% to 20% of patients. Randomized trials suggest that administration of interferon-alfa may result in a modest improvement in median survival. Investigation of the molecular genetics of renal cell carcinoma and the presence of T-lymphocyte immune dysregulation have suggested new therapeutic strategies. Further preclinical and clinical studies investigating inhibitors of angiogenesis or pharmacologic methods to reverse immune dysregulation are ongoing. Therapeutic results in patients with renal cell carcinoma remain limited, and investigational approaches are warranted. PMID:10378218

  7. Regressing and progressing metastatic lesions: resistance to immunotherapy is predetermined by irreversible HLA class I antigen alterations.

    Science.gov (United States)

    Aptsiauri, Natalia; Carretero, Rafael; Garcia-Lora, Angel; Real, Luis M; Cabrera, Teresa; Garrido, Federico

    2008-11-01

    Despite the significant efforts to enhance immune reactivity against malignancies the clinical effect of anti-tumor vaccines and cancer immunotherapy is still below expectations. Understanding of the possible causes of such poor clinical outcome has become very important for improvement of the existing cancer treatment modalities. In particular, the critical role of HLA class I antigens in the success of T cell based immunotherapy has led to a growing interest in investigating the expression and function of these molecules in metastatic cancer progression and, especially in response to immunotherapy. In this report, we illustrate that two types of metastatic lesions are commonly generated in response to immunotherapy according to the pattern of HLA class I expression. We found that metastatic lesions, that progress after immunotherapy have low level of HLA class I antigens, while the regressing lesions demonstrate significant upregulation of these molecules. Presumably, immunotherapy changes tumor microenvironment and creates an additional immune selection pressure on tumor cells. As a result, two subtypes of metastatic lesions arise from pre-existing malignant cells: (a) regressors, with upregulated HLA class I expression after therapy, and (b) progressors with resistance to immunotherapy and with low level of HLA class I. Tumor cells with reversible defects (soft lesions) respond to therapy by upregulation of HLA class I expression and regress, while tumor cells with structural irreversible defects (hard lesions) demonstrate resistance to immunostimulation, fail to upregulate HLA class I antigens and eventually progress. These two types of metastases appear independently of type of the immunotherapy used, either non-specific immunomodulators (cytokines or BCG) or autologous tumor vaccination. Similarly, we also detected two types of metastatic colonies in a mouse fibrosarcoma model after in vitro treatment with IFN-gamma. One type of metastases characterized by

  8. Combinations of Radiation Therapy and Immunotherapy for Melanoma: A Review of Clinical Outcomes

    International Nuclear Information System (INIS)

    Radiation therapy has long played a role in the management of melanoma. Recent advances have also demonstrated the efficacy of immunotherapy in the treatment of melanoma. Preclinical data suggest a biologic interaction between radiation therapy and immunotherapy. Several clinical studies corroborate these findings. This review will summarize the outcomes of studies reporting on patients with melanoma treated with a combination of radiation therapy and immunotherapy. Vaccine therapies often use irradiated melanoma cells, and may be enhanced by radiation therapy. The cytokines interferon-α and interleukin-2 have been combined with radiation therapy in several small studies, with some evidence suggesting increased toxicity and/or efficacy. Ipilimumab, a monoclonal antibody which blocks cytotoxic T-lymphocyte antigen-4, has been combined with radiation therapy in several notable case studies and series. Finally, pilot studies of adoptive cell transfer have suggested that radiation therapy may improve the efficacy of treatment. The review will demonstrate that the combination of radiation therapy and immunotherapy has been reported in several notable case studies, series and clinical trials. These clinical results suggest interaction and the need for further study

  9. Combinations of Radiation Therapy and Immunotherapy for Melanoma: A Review of Clinical Outcomes

    Energy Technology Data Exchange (ETDEWEB)

    Barker, Christopher A., E-mail: barkerc@mskcc.org [Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Postow, Michael A. [Department of Medicine, Melanoma and Sarcoma Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, New York (United States)

    2014-04-01

    Radiation therapy has long played a role in the management of melanoma. Recent advances have also demonstrated the efficacy of immunotherapy in the treatment of melanoma. Preclinical data suggest a biologic interaction between radiation therapy and immunotherapy. Several clinical studies corroborate these findings. This review will summarize the outcomes of studies reporting on patients with melanoma treated with a combination of radiation therapy and immunotherapy. Vaccine therapies often use irradiated melanoma cells, and may be enhanced by radiation therapy. The cytokines interferon-α and interleukin-2 have been combined with radiation therapy in several small studies, with some evidence suggesting increased toxicity and/or efficacy. Ipilimumab, a monoclonal antibody which blocks cytotoxic T-lymphocyte antigen-4, has been combined with radiation therapy in several notable case studies and series. Finally, pilot studies of adoptive cell transfer have suggested that radiation therapy may improve the efficacy of treatment. The review will demonstrate that the combination of radiation therapy and immunotherapy has been reported in several notable case studies, series and clinical trials. These clinical results suggest interaction and the need for further study.

  10. Strengthening Adoption Practice, Listening to Adoptive Families

    Science.gov (United States)

    Atkinson, Anne; Gonet, Patricia

    2007-01-01

    In-depth interviews with 500 adoptive families who received postadoption services through Virginia's Adoptive Family Preservation (AFP) program paint a richly detailed picture of the challenges adoptive families face and what they need to sustain adoption for many years after finalization. Findings document the need for support in a variety of…

  11. Immunogenicity of murine solid tumor models as a defining feature of in vivo behavior and response to immunotherapy.

    Science.gov (United States)

    Lechner, Melissa G; Karimi, Saman S; Barry-Holson, Keegan; Angell, Trevor E; Murphy, Katherine A; Church, Connor H; Ohlfest, John R; Hu, Peisheng; Epstein, Alan L

    2013-01-01

    Immune profiling has been widely used to probe mechanisms of immune escape in cancer and identify novel targets for therapy. Two emerging uses of immune signatures are to identify likely responders to immunotherapy regimens among individuals with cancer and to understand the variable responses seen among subjects with cancer in immunotherapy trials. Here, the immune profiles of 6 murine solid tumor models (CT26, 4T1, MAD109, RENCA, LLC, and B16) were correlated to tumor regression and survival in response to 2 immunotherapy regimens. Comprehensive profiles for each model were generated using quantitative reverse transcriptase polymerase chain reaction, immunohistochemistry, and flow cytometry techniques, as well as functional studies of suppressor cell populations (regulatory T cells and myeloid-derived suppressor cells), to analyze intratumoral and draining lymphoid tissues. Tumors were stratified as highly or poorly immunogenic, with highly immunogenic tumors showing a significantly greater presence of T-cell costimulatory molecules and immune suppression in the tumor microenvironment. An absence of tumor-infiltrating cytotoxic T lymphocytes and mature dendritic cells was seen across all models. Delayed tumor growth and increased survival with suppressor cell inhibition and tumor-targeted chemokine+/-dendritic cells vaccine immunotherapy were associated with high tumor immunogenicity in these models. Tumor MHC class I expression correlated with the overall tumor immunogenicity level and was a singular marker to predict immunotherapy response with these regimens. By using experimental tumor models as surrogates for human cancers, these studies demonstrate how select features of an immune profile may be utilized to identify patients most likely to respond to immunotherapy regimens. PMID:24145359

  12. 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.

  13. Current Immunotherapeutic Approaches in Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Shigeo Koido

    2011-01-01

    Full Text Available Pancreatic cancer is a highly aggressive and notoriously difficult to treat. As the vast majority of patients are diagnosed at advanced stage of the disease, only a small population is curative by surgical resection. Although gemcitabine-based chemotherapy is typically offered as standard of care, most patients do not survive longer than 6 months. Thus, new therapeutic approaches are needed. Pancreatic cancer cells that develop gemcitabine resistance would still be suitable targets for immunotherapy. Therefore, one promising treatment approach may be immunotherapy that is designed to target pancreatic-cancer-associated antigens. In this paper, we detail recent work in immunotherapy and the advances in concept of combination therapy of immunotherapy and chemotherapy. We offer our perspective on how to increase the clinical efficacy of immunotherapies for pancreatic cancer.

  14. 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

  15. Cancer Regression in Patients After Transfer of Genetically Engineered Lymphocytes

    Science.gov (United States)

    Morgan, Richard A.; Dudley, Mark E.; Wunderlich, John R.; Hughes, Marybeth S.; Yang, James C.; Sherry, Richard M.; Royal, Richard E.; Topalian, Suzanne L.; Kammula, Udai S.; Restifo, Nicholas P.; Zheng, Zhili; Nahvi, Azam; de Vries, Christiaan R.; Rogers-Freezer, Linda J.; Mavroukakis, Sharon A.; Rosenberg, Steven A.

    2006-10-01

    Through the adoptive transfer of lymphocytes after host immunodepletion, it is possible to mediate objective cancer regression in human patients with metastatic melanoma. However, the generation of tumor-specific T cells in this mode of immunotherapy is often limiting. Here we report the ability to specifically confer tumor recognition by autologous lymphocytes from peripheral blood by using a retrovirus that encodes a T cell receptor. Adoptive transfer of these transduced cells in 15 patients resulted in durable engraftment at levels exceeding 10% of peripheral blood lymphocytes for at least 2 months after the infusion. We observed high sustained levels of circulating, engineered cells at 1 year after infusion in two patients who both demonstrated objective regression of metastatic melanoma lesions. This study suggests the therapeutic potential of genetically engineered cells for the biologic therapy of cancer.

  16. Generation of IgE-based immunotherapies against HER-2 overexpressing tumours

    International Nuclear Information System (INIS)

    In combination with chemotherapy or radiation, passive immunotherapy with monoclonal antibodies is state of the art in cancer therapy. For this purpose, two properties of antibodies are harnessed: i) via the Fab fragment they bind a specific tumour antigen and ii) via the Fc portion they recruit effector cells and activate the complement system. One of these antibodies is trastuzumab (Herceptin), a growth-inhibitory humanized monoclonal IgG1 antibody recognizing the tumour antigen HER-2, which is overexpressed in 30% of human breast cancers. Interestingly, all antibodies applied for passive immunotherapy are so far exclusively of the IgG subclass. In contrast, antibodies of the IgE subclass are best-known for their detrimental function in type I hypersensitivity. It is little-known that IgE has anti-tumour capacity which could be exploited for immunotherapy of cancer. Thus, the aim of this doctoral thesis was to examine alternative strategies for cancer treatment based on IgE antibodies, and to compare their efficacy with that of IgG. The oral immunization route is well suited for the induction of a Th2 immunity including high affine IgE responses to administered antigens. Therefore, the establishment of an IgE dependent food allergy model in mice is described, which we applied also for our cancer studies. When mice were fed with different concentrations of ovalbumin under concomitant anti-acid medication, an antigen-specific IgE induction in a Th2 environment could be achieved. This oral vaccination regimen was also used for feeding HER-2 mimotopes, i.e. epitope-mimics of the anti-HER-2 IgG antibody trastuzumab. Indeed, these mimotopes induced IgE antibodies recognizing the tumour antigen which were able to bind HER-2 overexpressing breast cancer cells and led to tumour cell lysis. Complementary to this active immunotherapeutic approach a trastuzumab-like IgE antibody for passive immunotherapy was constructed. We could show that this trastuzumab IgE exhibited the

  17. Enhancing immunotherapy using chemotherapy and radiation to modify the tumor microenvironment

    OpenAIRE

    Kershaw, Michael H; Devaud, Christel; John, Liza B; Jennifer A Westwood; Darcy, Phillip K

    2013-01-01

    The tumor microenvironment is a complex assortment of cells that includes a variety of leukocytes. The overall effect of the microenvironment is to support the growth of tumors and suppress immune responses. Immunotherapy is a highly promising form of cancer treatment, but its efficacy can be severely compromised by an immunosuppressive tumor microenvironment. Chemotherapy and radiation treatment can mediate tumor reduction through cytotoxic effects, but it is becoming increasingly clear that...

  18. Penile tuberculosis following intravesical Bacille Calmette-Guérin immunotherapy

    OpenAIRE

    Chowdhury, Anadi Roy; Dey, Ranjan Kumar

    2013-01-01

    Bacille Calmette-Guérin (BCG) is an effective treatment for patients with superficial bladder cancer and bladder carcinoma in situ (CIS). It may cause side effects usually due to local and systemic inflammatory effects. We report a case of a male patient with non-invasive urothelial carcinoma of urinary bladder (Stage T1) who developed caseating granulomas on his glans penis as a complication of intravesical BCG immunotherapy. Though there are other reported cases of BCG dissemination noted i...

  19. Adoption of Preoperative Radiation Therapy for Rectal Cancer From 2000 to 2006: A Surveillance, Epidemiology, and End Results Patterns-of-Care Study

    International Nuclear Information System (INIS)

    study, there was widespread, rapid adoption of preoperative RT for locally advanced rectal cancer. However, preoperative RT may be underused in certain sociodemographic groups.

  20. Therapeutic vaccines as a promising treatment modality against prostate cancer: rationale and recent advances

    OpenAIRE

    Singh, B Harpreet; Gulley, James L.

    2014-01-01

    Cancer immunotherapy was deemed the medical breakthrough of 2013, in part because it can induce a rapid, durable, self-propagating and adaptable immune response. Specifically in prostate cancer, immunotherapy has emerged as a viable and attractive treatment strategy. To date, therapeutic cancer vaccines and immune checkpoint inhibitors are the two classes of immunotherapy that have demonstrated improvements in overall survival in patients with advanced tumors. The 2010 Food and Drug Administr...