Brinkman, Joeli A; Hughes, Sarah H; Stone, Pamela; Caffrey, Angela S; Muderspach, Laila I; Roman, Lynda D; Weber, Jeffrey S; Kast, W Martin
Cervical Cancer is the second leading cause of cancer-related deaths in women worldwide and is associated with Human Papillomavirus (HPV) infection, creating a unique opportunity to treat cervical cancer through anti-viral vaccination. Although a prophylactic vaccine may be available within a year, millions of women, already infected, will continue to suffer from HPV-related disease, emphasizing the need to develop therapeutic vaccination strategies. A majority of clinical trials examining therapeutic vaccination have shown limited efficacy due to examining patients with more advanced-stage cancer who tend to have decreased immune function. Current trends in clinical trials with therapeutic agents examine patients with pre-invasive lesions in order to prevent invasive cervical cancer. However, longer follow-up is necessary to correlate immune responses to lesion regression. Meanwhile, preclinical studies in this field include further exploration of peptide or protein vaccination, and the delivery of HPV antigens in DNA-based vaccines or in viral vectors. As long as pre-clinical studies continue to advance, the prospect of therapeutic vaccination to treat existing lesions seem good in the near future. Positive consequences of therapeutic vaccination would include less disfiguring treatment options and fewer instances of recurrent or progressive lesions leading to a reduction in cervical cancer incidence.
Joeli A. Brinkman
Full Text Available Cervical Cancer is the second leading cause of cancer–related deaths in women worldwide and is associated with Human Papillomavirus (HPV infection, creating a unique opportunity to treat cervical cancer through anti-viral vaccination. Although a prophylactic vaccine may be available within a year, millions of women, already infected, will continue to suffer from HPV-related disease, emphasizing the need to develop therapeutic vaccination strategies. A majority of clinical trials examining therapeutic vaccination have shown limited efficacy due to examining patients with more advanced-stage cancer who tend to have decreased immune function. Current trends in clinical trials with therapeutic agents examine patients with pre-invasive lesions in order to prevent invasive cervical cancer. However, longer follow-up is necessary to correlate immune responses to lesion regression. Meanwhile, preclinical studies in this field include further exploration of peptide or protein vaccination, and the delivery of HPV antigens in DNA-based vaccines or in viral vectors. As long as pre-clinical studies continue to advance, the prospect of therapeutic vaccination to treat existing lesions seem good in the near future. Positive consequences of therapeutic vaccination would include less disfiguring treatment options and fewer instances of recurrent or progressive lesions leading to a reduction in cervical cancer incidence.
Brinkman, Joeli A.; Hughes, Sarah H.; Stone, Pamela; Caffrey, Angela S.; Muderspach, Laila I.; Roman, Lynda D.; Weber, Jeffrey S.; Kast, W. Martin
Cervical Cancer is the second leading cause of cancer–related deaths in women worldwide and is associated with Human Papillomavirus (HPV) infection, creating a unique opportunity to treat cervical cancer through anti-viral vaccination. Although a prophylactic vaccine may be available within a year, millions of women, already infected, will continue to suffer from HPV-related disease, emphasizing the need to develop therapeutic vaccination strategies. A majority of clinical trials examining th...
a cystatin -like molecule, inhibits ERK-dependent lymphocyte proliferation. Mech Ageing Dev 126:1284-91 7. Gomez, C.R., Acuña-Castillo, C ., Nishimura...the development of better prostate cancer cell vaccines 2. Gomez, C.R., Kosari, F., Munz, J.M., Schreiber, C ., Knutson, G., Charlesworth, C ., Karnes...TITLE: Enhancing Therapeutic Cellular Prostate Cancer Vaccines PRINCIPAL INVESTIGATOR: Christian R. Gomez, Ph.D
Sipuleucel-T (Provenge) is a relatively nontoxic treatment option for men with hormone-resistant or castration-resistant prostate cancer. The FDA's approval of the vaccine represented the first proof of principle that immunotherapy can work in cancer.
...] Guidance for Industry: Clinical Considerations for Therapeutic Cancer Vaccines; Availability AGENCY: Food... Therapeutic Cancer Vaccines'' dated October 2011. The guidance document provides sponsors who wish to submit an Investigational New Drug application (IND) for a therapeutic cancer vaccine with recommendations...
Andersen, Mads Hald; Junker, Niels; Ellebaek, Eva
The clinical efficacy of most therapeutic vaccines against cancer has not yet met its promise. Data are emerging that strongly support the notion that combining immunotherapy with conventional therapies, for example, radiation and chemotherapy may improve efficacy. In particular combination...
Mackiewicz, Jacek; Mackiewicz, Andrzej
Advances in molecular and cellular biology as well as biotechnology led to definition of a group of drugs referred to as medicinal products of advanced technologies. It includes gene therapy products, somatic cell therapeutics and tissue engineering. Therapeutic cancer vaccines including whole cell tumor cells vaccines or gene modified whole cells belong to somatic therapeutics and/or gene therapy products category. The drug development is a multistep complex process. It comprises of two phases: preclinical and clinical. Guidelines on preclinical testing of cell based immunotherapy medicinal products have been defined by regulatory agencies and are available. However, clinical testing of therapeutic cancer vaccines is still under debate. It presents a serious problem since recently clinical efficacy of the number of cancer vaccines has been demonstrated that focused a lot of public attention. In general clinical testing in the current form is very expensive, time consuming and poorly designed what may lead to overlooking of products clinically beneficial for patients. Accordingly regulatory authorities and researches including Cancer Vaccine Clinical Trial Working Group proposed three regulatory solutions to facilitate clinical development of cancer vaccines: cost-recovery program, conditional marketing authorization, and a new development paradigm. Paradigm includes a model in which cancer vaccines are investigated in two types of clinical trials: proof-of-principle and efficacy. The proof-of-principle trial objectives are: safety; dose selection and schedule of vaccination; and demonstration of proof-of-principle. Efficacy trials are randomized clinical trials with objectives of demonstrating clinical benefit either directly or through a surrogate. The clinical end points are still under debate.
Andersen, Mads Hald; Junker, N.; Ellebaek, E.
The clinical efficacy of most therapeutic vaccines against cancer has not yet met its promise. Data are emerging that strongly support the notion that combining immunotherapy with conventional therapies, for example, radiation and chemotherapy may improve efficacy. In particular combination...... of proteins coupled to intrinsic properties of cancer cells. For example, proteins associated with drug resistance can be targeted, and form ideal target structures for use in combination with chemotherapy for killing of surviving drug resistant cancer cells. Proteins associated with the malignant phenotype...
Andersen, Mads Hald; Junker, Niels; Ellebaek, Eva
The clinical efficacy of most therapeutic vaccines against cancer has not yet met its promise. Data are emerging that strongly support the notion that combining immunotherapy with conventional therapies, for example, radiation and chemotherapy may improve efficacy. In particular combination...... of proteins coupled to intrinsic properties of cancer cells. For example, proteins associated with drug resistance can be targeted, and form ideal target structures for use in combination with chemotherapy for killing of surviving drug resistant cancer cells. Proteins associated with the malignant phenotype...
Cordeiro, Marcelo Nazário; De Lima, Rita de Cássia Pereira; Paolini, Francesca; Melo, Alanne Rayssa da Silva; Campos, Ana Paula Ferreira; Venuti, Aldo; De Freitas, Antonio Carlos
Cervical cancer and cervical intraepithelial neoplasia (CIN) are well-known outcomes of a human papillomavirus (HPV) infection. Viral oncogenes expressions like E6, E7, and, recently recognized E5, lead to HPV-related malignant progression. Although HPV prevention by powerful vaccines against most frequent and oncogenic genotypes is feasible, current treatment against cervical neoplasia is distant from an ideal one. In addition, late diagnosis is commonly associated with a poor prognosis. On top of that, radiotherapy, chemotherapy, or surgery are less effective in high-grade lesions. Areas covered: Due to their peculiarities, HPV oncogenes represent an excellent target for cancer immunotherapy. Safety, efficacy, and potential immunogenicity are features achieved by DNA vaccines targeting HPV. The literature search has indicated that genetic immunotherapy is becoming a pharmacological tool and therapeutic option against cervical disease, as more and more DNA vaccines are reaching clinical trial phases. Expert commentary: Among some of the promising results, a phase II randomized trial showed a clinical activity of a nucleic acid-based vaccine in HPV16 or HPV18 positive CIN patients. The concept of a synergic combination of anti-HPV DNA vaccines with radiotherapy, chemotherapy, sophisticated delivery methods, immunomodulators or immune adjuvants opens a new and interesting perspective in cervical malignancy treatment.
Overgaard, Nana Haahr; Frøsig, Thomas Mørch; Welner, Simon
Development of therapeutic cancer vaccines has largely been based on rodent models and the majority failed to establish therapeutic responses in clinical trials. We therefore used pigs as a large animal model for human cancer vaccine development due to the large similarity between the porcine...
Hailemichael, Yared; Overwijk, Willem W
Cancer vaccines can induce robust activation of tumor-specific CD8(+) T cells that can destroy tumors. Understanding the mechanism by which cancer vaccines work is essential in designing next-generation vaccines with more potent therapeutic activity. We recently reported that short peptides emulsified in poorly biodegradable, Incomplete Freund's Adjuvant (IFA) primed CD8(+) T cells that did not localize to the tumor site but accumulated at the persisting, antigen-rich vaccination site. The vaccination site eventually became a T cell graveyard where T cells responded to chronically released gp100 peptide by releasing cytokines, including interferon-γ (IFN-γ), which in turn upregulated Fas ligand (FasL) on host cells, causing apoptosis of Fas(+) T cells. T cells that escaped apoptosis rapidly became exhausted, memory formation was poor, and therapeutic impact was minimal. Replacing the non-biodegradable IFA-based formulation with water-based, short-lived formulation in the presence of immunostimulatory molecules allowed T cells to traffic to tumors, causing their regression. In this review, we discuss recent advances in immunotherapeutic approaches that could enhance vaccine-primed immune cells fitness and render the tumor microenvironment more accessible for immune cell infiltration. Copyright © 2014 Elsevier Ltd. All rights reserved.
Hu, Zhuting; Ott, Patrick A; Wu, Catherine J
Cancer vaccines, which are designed to amplify tumour-specific T cell responses through active immunization, have long been envisioned as a key tool of effective cancer immunotherapy. Despite a clear rationale for such vaccines, extensive past efforts were unsuccessful in mediating clinically relevant antitumour activity in humans. Recently, however, next-generation sequencing and novel bioinformatics tools have enabled the systematic discovery of tumour neoantigens, which are highly desirable immunogens because they arise from somatic mutations of the tumour and are therefore tumour specific. As a result of the diversity of tumour neoepitopes between individuals, the development of personalized cancer vaccines is warranted. Here, we review the emerging field of personalized cancer vaccination and discuss recent developments and future directions for this promising treatment strategy.
Finn, Olivera J; Khleif, Samir N; Herberman, Ronald B
Cancer vaccines based on antigens derived from self molecules rather than pathogens have been under basic and clinical investigations for many years. Up until very recently, they had been tested primarily in the setting of metastatic disease with the goal to engage the immune system in slowing down disease progression. Many therapeutic vaccine trials, either investigator initiated or led by pharmaceutical companies, have been completed and many are currently ongoing, following the FDA Guidance on therapeutic cancer vaccines published in 2011. In recent years, the target of cancer vaccines is being shifted to early cancer and even premalignant disease with the goal of preventing cancer. Although some issues addressed in the FDA Guidance on therapeutic vaccines apply to preventive vaccines, many do not. Here, we discuss a set of recommendations for revising the current Guidance to also cover preventive vaccines, or to include in a new Guidance dedicated specifically to vaccines for cancer prevention. ©2015 American Association for Cancer Research.
Wenandy, L.; Sorensen, R.B.; Straten, P.T.
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...
cell activation assays, respectively (Table 1). In addition, we found that most of these immunogenic epitopes were not related to breast cancer and... HLA - A*02-negative cells, and we plotted the peptides that were derived from these cells in relation to percentile ranks (Fig. 3). Fig. 2. The...1 Award Number: W81XWH-11-1-0549 TITLE: Enhancing the Breadth and Efficacy of Therapeutic Vaccines for Breast Cancer PRINCIPAL INVESTIGATOR
Soledad eMac Keon
Full Text Available Dendritic cells (DCs play a pivotal role in the orchestration of immune responses, and are thus key targets in cancer vaccine design. Since the 2010 FDA approval of the first cancer DC-based vaccine (Sipuleucel T there has been a surge of interest in exploiting these cells as a therapeutic option for the treatment of tumors of diverse origin. In spite of the encouraging results obtained in the clinic, many elements of DC-based vaccination strategies need to be optimized. In this context, the use of experimental cancer models can help direct efforts towards an effective vaccine design. This paper reviews recent findings in murine models regarding the antitumoral mechanisms of DC-based vaccination, covering issues related to antigen sources, the use of adjuvants and maturing agents, and the role of DC subsets and their interaction in the initiation of antitumoral immune responses. The summary of such diverse aspects will highlight advantages and drawbacks in the use of murine models, and contribute to the design of successful DC-based translational approaches for cancer treatment.
Wenandy, L.; Sorensen, R.B.; Straten, P.T.
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......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...... 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, RhoC may...
Diana Rosa Fernández Ruiz
Full Text Available Biotechnology is one of the scientific activities deployed by the Cuban State, which shows greater results and impact on the of the Cuban population health. It has increased the therapeutic repertoire in dealing with oncological diseases with products such as CIMAvax-EGF®, the first therapeutic vaccine of its kind, from the Molecular Immunology Center, against non-small cell lung cancer in advanced stages IIIB IV. The application of this product already extends to Primary Health Care with encouraging results, by prolonging the survival of patients with higher quality of life.
Rahimian, Sima; Fransen, Marieke F.; Kleinovink, Jan Willem; Christensen, Jonatan Riis; Amidi, Maryam|info:eu-repo/dai/nl/304834912; Hennink, Wim E.|info:eu-repo/dai/nl/070880409; Ossendorp, Ferry
The aim of the current study was to develop a cancer vaccine formulation for treatment of human papillomavirus (HPV)-induced malignancies. Synthetic long peptides (SLPs) derived from HPV16 E6 and E7 oncoproteins have been used for therapeutic vaccination in clinical trials with promising results. In
Full Text Available Effective priming and activation of tumor-specific CD8+ cytotoxic T lymphocytes (CTLs is crucial for realizing the potential of therapeutic cancer vaccination. This requires cytosolic antigens that feed into the MHC class I presentation pathway, which is not efficiently achieved with most current vaccination technologies. Photochemical internalization (PCI provides an emerging technology to route endocytosed material to the cytosol of cells, based on light-induced disruption of endosomal membranes using a photosensitizing compound. Here, we investigated the potential of PCI as a novel, minimally invasive, and well-tolerated vaccination technology to induce priming of cancer-specific CTL responses to peptide antigens. We show that PCI effectively promotes delivery of peptide antigens to the cytosol of antigen-presenting cells (APCs in vitro. This resulted in a 30-fold increase in MHC class I/peptide complex formation and surface presentation, and a subsequent 30- to 100-fold more efficient activation of antigen-specific CTLs compared to using the peptide alone. The effect was found to be highly dependent on the dose of the PCI treatment, where optimal doses promoted maturation of immature dendritic cells, thus also providing an adjuvant effect. The effect of PCI was confirmed in vivo by the successful induction of antigen-specific CTL responses to cancer antigens in C57BL/6 mice following intradermal peptide vaccination using PCI technology. We thus show new and strong evidence that PCI technology holds great potential as a novel strategy for improving the outcome of peptide vaccines aimed at triggering cancer-specific CD8+ CTL responses.
Witek, Matthew [Department of Radiation Oncology, Kimmel Cancer Center, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Blomain, Erik S.; Magee, Michael S.; Xiang, Bo; Waldman, Scott A. [Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania (United States); Snook, Adam E., E-mail: email@example.com [Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, Pennsylvania (United States)
Purpose: Radiation therapy (RT) is thought to produce clinical responses in cancer patients, not only through direct toxicity to cancer cells and supporting tumor stroma cells, but also through activation of immunologic effectors. More recently, RT has potentiated the local and systemic effects of cancer immunotherapy (IT). However, combination regimens that maximize immunologic and clinical efficacy remain undefined. Methods and Materials: We evaluated the impact of local RT on adenoviral-mediated vaccination against the colorectal cancer antigen GUCY2C (Ad5-GUCY2C) in a murine subcutaneous tumor model using mouse CT26 colon cancer cells (CT26-GUCY2C). Immune responses were assessed by ELISpot, and clinical responses were assessed by tumor size and incidence. Results: The specific sequence of tumor-directed RT preceding Ad5-GUCY2C IT transformed inactive therapeutic Ad5-GUCY2C vaccination into a curative vaccine. GUCY2C-specific T cell responses were amplified (P<.05), tumor eradication was maximized (P<.01), and tumor volumes were minimized (P<.001) in mice whose tumors were irradiated before, compared with after, Ad5-GUCY2C vaccination. The immunologic and antitumor efficacy of Ad5-GUCY2C was amplified comparably by unfractionated (8 Gy × 1), or biologically equivalent doses of fractionated (3.5 Gy × 3), RT. The antitumor effects of sequential RT and IT (RT-IT) depended on expression of GUCY2C by tumor cells and the adenoviral vaccine vector, and tumor volumes were inversely related to the magnitude of GUCY2C-specific T cell responses. Moreover, mice cured of CT26-GUCY2C tumors by RT-IT showed long-lasting antigen-dependent protection, resisting tumors formed by GUCY2C-expressing 4T1 breast cancer cells inoculated 50 days after CT26 cells. Conclusions: Optimal sequencing of RT and IT amplifies antigen-specific local and systemic immune responses, revealing novel acute and long-term therapeutic antitumor protection. These observations underscore the importance
Therapeutic vaccines aim to control chronic HIV infection and eliminate the need for lifelong antiretroviral therapy (ART). Therapeutic HIV vaccine is being pursued as part of a functional cure for HIV/AIDS. We have outlined a basic protocol for inducing new T cell immunity during chronic HIV-1...... infection directed to subdominant conserved HIV-1 epitopes restricted to frequent HLA supertypes. The rationale for selecting HIV peptides and adjuvants are provided. Peptide subunit vaccines are regarded as safe due to the simplicity, quality, purity, and low toxicity. The caveat is reduced immunogenicity...
Numerous therapeutic strategies are used to treat leishmaniasis. The treatment of cutaneous leishmaniasis (CL) is solely depends on antimonate derivatives with safety issues and questionable efficacy and there is no fully effective modality to treat CL caused by Leishmania tropica and Leishmania braziliensis. There is no prophylactic vaccine available against any form of leishmaniasis. Immunotherapy for CL has a long history; immunotherapy trials of first and second generation vaccines showed promising results. The current article briefly covers the prophylactic vaccines and explains different immunotherapy strategies that have been used to treat leishmaniasis. This paper does not include experimental vaccines and only lays emphasis on human trials and those vaccines which reached human trials. Immunotherapy is currently used to successfully treat several disorders; Low cost, limited side effects and no possibility to develop resistance make immunotherapy a valuable choice especially for infectious disease with chemotherapy problems. Efforts are needed to explore the immunological surrogate marker(s) of cure and protection in leishmaniasis and overcome the difficulties in standardization of crude Leishmania vaccines. One of the reasons for anti-leishmaniasis vaccine failure is lack of an appropriate adjuvant. So far, not enough attention has been paid to develop vaccines for immunotherapy of leishmaniasis.
Rong, Yefei; Jin, Dayong; Wu, Wenchuan; Lou, Wenhui; Wang, Danshong; Kuang, Tiantao; Ni, Xiaoling; Qin, Xinyu
Pancreatic cancer is a common, highly lethal disease with a rising incidence. MUC1 is a tumor-associated antigen that is over-expressed in pancreatic adenocarcinoma. Active immunotherapy that targets MUC1 could have great treatment value. Here we investigated the preventive and therapeutic effect of a MUC1 DNA vaccine on the pancreatic cancer. MUC1-various tandem repeat units(VNTR) DNA vaccine was produced by cloning one repeat of VNTR and inserting the cloned gene into the pcDNA3.1. In the preventive group, female C57BL/6 mice were immunized with the vaccine, pcDNA3.1 or PBS; and challenged with panc02-MUC1 or panc02 cell. In the therapeutic group the mice were challenged with panc02-MUC1 or panc02 cell, and then immunized with the vaccine, pcDNA3.1 or PBS. The tumor size and the survival time of the animals were compared between these groups. The DNA vaccine pcDNA3.1-VNTR could raise cytotoxic T lymphocyte (CTL) activity specific for MUC1. In the preventive experiment, the mice survival time was significantly longer in the vaccine group than in the control groups (P < 0.05). In the therapeutic experiment, the DNA vaccine prolonged the survival time of the panc02-MUC1-bearing mice (P < 0.05). In both the preventive and therapeutic experiments, the tumor size was significantly less in the vaccine group than in the control groups (P < 0.05). This pcDNA3.1-VNTR vaccine, however, could not prevent the mice attacked by panc02 cells and had no therapeutic effect on the mice attacked by panc02 cells. The MUC1 DNA vaccine pcDNA3.1-VNTR could induce a significant MUC1-specific CTL response; and had both prophylactic and therapeutic effect on panc02-MUC1 tumors. This vaccine might be used as a new adjuvant strategy against pancreatic cancer
Taylor, Graham S; Steven, Neil M
Epstein-Barr virus (EBV) infects most people worldwide. EBV has oncogenic potential and is strongly associated with several lymphomas and carcinomas, including nasopharyngeal carcinoma (NPC), that together total 200,000 cases of cancer each year. All EBV-associated cancers express viral proteins that allow highly selective immunotherapeutic targeting of the malignant cells. A number of therapeutic EBV vaccines have been tested in clinical trials with evidence of immune boosting and clinical responses in NPC patients. Therapeutic vaccination could be used after adoptive T-cell transfer to increase and sustain the number of infused T-cells or combined with immunotherapies acting at different stages of the cancer immunity cycle to increase efficacy. The therapeutic EBV vaccines tested to date have been well tolerated with minimal off-target toxicity. A safe therapeutic vaccine that was also able to be mass produced could, in principle, be used to vaccinate large numbers of patients after first line therapy to reduce recurrence.
Overgaard, Nana Haahr; Frøsig, Thomas Mørch; Welner, Simon
Immunotherapy against cancer has shown increased overall survival of metastatic cancer patients and is a promising new vaccine target. For this to succeed, appropriate tailoring of vaccine formulations to mount in vivo cytotoxic T cell (CTL) responses towards co-delivered cancer antigens...... is important. Previous development of therapeutic cancer vaccines has largely been based on studies in mice and the majority of these candidate vaccines failed to establish therapeutic responses in subsequent human clinical trials. Since the porcine immunome is more closely related to the human counterpart, we...... here introduce pigs as a superior large animal model for human cancer vaccine development via the use of our unique technology for swine leukocyte antigen (SLA) production. IDO and RhoC, both known to be important in human cancer development and progression, were used as vaccine targets. Pigs were...
Cancer Vaccines: The New Fight Against Cancer. N S Vasanthi. General Article Volume 11 Issue 11 November 2006 pp 48-55. Fulltext. Click here to view fulltext PDF. Permanent link: http://www.ias.ac.in/article/fulltext/reso/011/11/0048-0055. Keywords. Cancer; immunotherapy; therapeutic vaccine; prophylactic vaccine.
Pfaller, Christian K; Cattaneo, Roberto; Schnell, Matthias J
The order Mononegavirales includes five families: Bornaviridae, Filoviridae, Nyamaviridae, Paramyxoviridae, and Rhabdoviridae. The genome of these viruses is one molecule of negative-sense single strand RNA coding for five to ten genes in a conserved order. The RNA is not infectious until packaged by the nucleocapsid protein and transcribed by the polymerase and co-factors. Reverse genetics approaches have answered fundamental questions about the biology of Mononegavirales. The lack of icosahedral symmetry and modular organization in the genome of these viruses has facilitated engineering of viruses expressing fluorescent proteins, and these fluorescent proteins have provided important insights about the molecular and cellular basis of tissue tropism and pathogenesis. Studies have assessed the relevance for virulence of different receptors and the interactions with cellular proteins governing the innate immune responses. Research has also analyzed the mechanisms of attenuation. Based on these findings, ongoing clinical trials are exploring new live attenuated vaccines and the use of viruses re-engineered as cancer therapeutics. Copyright © 2015 Elsevier Inc. All rights reserved.
Gross, Stefanie; Geldmacher, Astrid; Sharav, Tumenjargal; Losch, Florian; Walden, Peter
Recent investigations revealed strong immunosuppressive mechanisms in tumors that may block anti-tumor T cells and be responsible for failures of immunotherapies. Current attempts to overcome this immunosuppression include blockade of co-inhibitory factors on T cells. Reports from the respective trials indicate that the strategy can improve efficacy of therapeutic vaccination, but at the cost of severe inflammatory and autoimmune reactions. We tried to circumvent tumor-associated immunosuppression by mimotope vaccination to broaden reactive anti-tumor T cell repertoires to include T cells that have not been rendered anergic by the tumor. Initial clinical observations suggest that this strategy bears considerable promise.
Roč. 52, č. 6 (2006), s. 202-204 ISSN 0015-5500 Grant - others:EU-FP6-Clinigene(XE) 018933 Institutional research plan: CEZ:AV0Z50520514 Keywords : Treg cells * cancer vaccines Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 0.387, year: 2006
White, Michael; Freistaedter, Andrew; Jones, Gwendolyn J B; Zervos, Emmanuel; Roper, Rachel L
Pancreatic cancer is the 5th leading cause of cancer deaths, and there are no effective treatments. We developed a poxvirus platform vaccine with improved immunogenicity and inserted the mesothelin gene to create an anti-mesothelin cancer vaccine. Mesothelin expression is mostly restricted to tumors in adult mammals and thus may be a good target for cancer treatment. We show here that the modified vaccinia virus Ankara (MVA) virus expressing mesothelin and the enhanced MVA virus missing the immunosuppressive A35 gene and expressing mesothelin were both safe in mice and were able to induce IFN-gamma secreting T cells in response to mesothelin expressing tumor cells. In addition, the MVA virus has oncolytic properties in vitro as it can replicate in and kill Panc02 pancreatic adenocarcinoma cell line tumor cells, even though it is unable to replicate in most mammalian cells. Deletion of the A35 gene in MVA improved T cell responses as expected. However, we were unable to demonstrate inhibition of Panc02 tumor growth in immunocompetent mice with pre-vaccination of mice, boosts, or even intratumoral injections of the recombinant viruses. Vaccine efficacy may be limited by shedding of mesothelin from tumor cells thus creating a protective screen from the immune system.
Strioga, Marius M; Darinskas, Adas; Pasukoniene, Vita; Mlynska, Agata; Ostapenko, Valerijus; Schijns, Virgil
Accumulation of firm evidence that clinically apparent cancer develops only when malignant cells manage to escape immunosurveillance led to the introduction of tumor immunotherapy strategies aiming to reprogramm the cancer-dysbalanced antitumor immunity and restore its capacity to control tumor growth. There are several immunotherapeutical strategies, among which specific active immunotherapy or therapeutic cancer vaccination is one of the most promising. It targets dendritic cells (DCs) which have a unique ability of inducing naive and central memory T cell-mediated immune response in the most efficient manner. DCs can be therapeutically targeted either in vivo/in situ or by ex vivo manipulations followed by their re-injection back into the same patient. The majority of current DC targeting strategies are based on autologous or allogeneic tumor-associated antigens (TAAs) which possess various degrees of inherent tolerogenic potential. Therefore still limited efficacy of various tumor immunotherapy approaches may be attributed, among various other mechanisms, to the insufficient immunogenicity of self-protein-derived TAAs. Based on such an idea, the use of homologous xenogeneic antigens, derived from different species was suggested to overcome the natural immune tolerance to self TAAs. Xenoantigens are supposed to differ sufficiently from self antigens to a degree that renders them immunogenic, but at the same time preserves an optimal homology range with self proteins still allowing xenoantigens to induce cross-reactive T cells. Here we discuss the concept of xenogeneic vaccination, describe the cons and pros of autologous/allogeneic versus xenogeneic therapeutic cancer vaccines, present the results of various pre-clinical and several clinical studies and highlight the future perspectives of integrating xenovaccination into rapidly developing tumor immunotherapy regimens. Copyright © 2014. Published by Elsevier Ltd.
P. Rocca -Serra, P. T. Spellman, H. C. Causton, A. Farne, E. Holloway, R. A. Irizarry, J . Liu, D. S. Maier, M. Miller, K. Petersen, J . Quackenbush, G...REFERENCES:  A. J . Zajac, K. Murali-Krishna, J . N. Blattman, and R. Ahmed, “Therapeutic vaccination against chronic viral infection: the...importance of cooperation between CD4+ and CD8+ T cells,” Curr. Opin. Immunol., vol. 10, no. 4, pp. 444–449, Aug. 1998.  R. J . Simpson
Autran, Brigitte; Carcelain, Guislaine; Combadiere, Béhazine; Debre, Patrice
Therapeutic vaccines aim to prevent severe complications of a chronic infection by reinforcing host defenses when some immune control, albeit insufficient, can already be demonstrated and when a conventional antimicrobial therapy either is not available or has limited efficacy. We focus on the rationale and challenges behind this still controversial strategy and provide examples from three major chronic infectious diseases-human immunodeficiency virus, hepatitis B virus, and human papillomavirus-for which the efficacy of therapeutic vaccines is currently being evaluated.
Differential Adverse Event Profiles Associated with BCG as a Preventive Tuberculosis Vaccine or Therapeutic Bladder Cancer Vaccine Identified by Comparative Ontology-Based VAERS and Literature Meta-Analysis.
Full Text Available M. bovis strain Bacillus Calmette-Guérin (BCG has been the only licensed live attenuated vaccine against tuberculosis (TB for nearly one century and has also been approved as a therapeutic vaccine for bladder cancer treatment since 1990. During its long time usage, different adverse events (AEs have been reported. However, the AEs associated with the BCG preventive TB vaccine and therapeutic cancer vaccine have not been systematically compared. In this study, we systematically collected various BCG AE data mined from the US VAERS database and PubMed literature reports, identified statistically significant BCG-associated AEs, and ontologically classified and compared these AEs related to these two types of BCG vaccine. From 397 VAERS BCG AE case reports, we identified 64 AEs statistically significantly associated with the BCG TB vaccine and 14 AEs with the BCG cancer vaccine. Our meta-analysis of 41 peer-reviewed journal reports identified 48 AEs associated with the BCG TB vaccine and 43 AEs associated with the BCG cancer vaccine. Among all identified AEs from VAERS and literature reports, 25 AEs belong to serious AEs. The Ontology of Adverse Events (OAE-based ontological hierarchical analysis indicated that the AEs associated with the BCG TB vaccine were enriched in immune system (e.g., lymphadenopathy and lymphadenitis, skin (e.g., skin ulceration and cyanosis, and respiratory system (e.g., cough and pneumonia; in contrast, the AEs associated with the BCG cancer vaccine mainly occurred in the urinary system (e.g., dysuria, pollakiuria, and hematuria. With these distinct AE profiles detected, this study also discovered three AEs (i.e., chills, pneumonia, and C-reactive protein increased shared by the BCG TB vaccine and bladder cancer vaccine. Furthermore, our deep investigation of 24 BCG-associated death cases from VAERS identified the important effects of age, vaccine co-administration, and immunosuppressive status on the final BCG
Differential Adverse Event Profiles Associated with BCG as a Preventive Tuberculosis Vaccine or Therapeutic Bladder Cancer Vaccine Identified by Comparative Ontology-Based VAERS and Literature Meta-Analysis
Xie, Jiangan; Codd, Christopher; Mo, Kevin; He, Yongqun
M. bovis strain Bacillus Calmette–Guérin (BCG) has been the only licensed live attenuated vaccine against tuberculosis (TB) for nearly one century and has also been approved as a therapeutic vaccine for bladder cancer treatment since 1990. During its long time usage, different adverse events (AEs) have been reported. However, the AEs associated with the BCG preventive TB vaccine and therapeutic cancer vaccine have not been systematically compared. In this study, we systematically collected various BCG AE data mined from the US VAERS database and PubMed literature reports, identified statistically significant BCG-associated AEs, and ontologically classified and compared these AEs related to these two types of BCG vaccine. From 397 VAERS BCG AE case reports, we identified 64 AEs statistically significantly associated with the BCG TB vaccine and 14 AEs with the BCG cancer vaccine. Our meta-analysis of 41 peer-reviewed journal reports identified 48 AEs associated with the BCG TB vaccine and 43 AEs associated with the BCG cancer vaccine. Among all identified AEs from VAERS and literature reports, 25 AEs belong to serious AEs. The Ontology of Adverse Events (OAE)-based ontological hierarchical analysis indicated that the AEs associated with the BCG TB vaccine were enriched in immune system (e.g., lymphadenopathy and lymphadenitis), skin (e.g., skin ulceration and cyanosis), and respiratory system (e.g., cough and pneumonia); in contrast, the AEs associated with the BCG cancer vaccine mainly occurred in the urinary system (e.g., dysuria, pollakiuria, and hematuria). With these distinct AE profiles detected, this study also discovered three AEs (i.e., chills, pneumonia, and C-reactive protein increased) shared by the BCG TB vaccine and bladder cancer vaccine. Furthermore, our deep investigation of 24 BCG-associated death cases from VAERS identified the important effects of age, vaccine co-administration, and immunosuppressive status on the final BCG-associated death
Kim, Joseph W.; Bilusic, Marijo; Heery, Christopher J.; Madan, Ravi A., E-mail: firstname.lastname@example.org [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)
Despite recent advances in cancer immunotherapy, no prospectively validated intermediate biomarkers exist to predict response. These biomarkers are highly desirable given modern immunotherapy’s paradoxical pattern of clinical benefit; that is, improvement in overall survival without short-term change in progression. Immunotherapy clinical trials have evaluated biomarkers that may correlate with clinical outcomes. Many of them are performed on peripheral blood to evaluate the systemic response, such as tumor-targeted humoral and cellular immunity, and cytokine responses. Accumulating evidence suggests that immune infiltrates in tumors may suggest evidence for the therapy’s mechanism of action, and have greater potential for providing prognostic and predictive information. In addition, a non-immunologic biomarker, such as tumor growth kinetics, may explain this paradoxical pattern of clinical benefit, and predict survival in patients treated with an immunotherapy. Prospective assessment and validation of these and other intermediate markers would be required to better understand their potential clinical role.
Motta, Santo; Castiglione, Filippo; Lollini, Pierluigi; Pappalardo, Francesco
We present a systematic approach to search for an effective vaccination schedule using mathematical computerized models. Our study is based on our previous model that simulates the cancer vs immune system competition activated by tumor vaccine. This model accurately reproduces in-vivo experiments results on HER-2/neu mice treated with the immuno-prevention cancer vaccine (Triplex) for mammary carcinoma. In vivo experiments have shown the effectiveness of Triplex vaccine in protection of mice from mammary carcinoma. The full protection was conferred using chronic (prophylactic) vaccination protocol while therapeutic vaccination was less effcient. In the present paper we use the computer simulations to systematically search for a vaccination schedule which prevents solid tumor formation. The strategy we used for defining a successful vaccination schedule is to control the number of cancer cells with vaccination cycles. We found that, applying the vaccination scheme used in in-vivo experiments, the number of vaccine injections can be reduced roughly by 30%. PMID:16305756
Aurisicchio, Luigi; Peruzzi, Daniela; Koo, Gloria; Wei, Wei-Zen; La Monica, Nicola; Ciliberto, Gennaro
Several cancer vaccine efforts have been directed to simultaneously cotarget multiple tumor antigens, with the intent to achieve broader immune responses and more effective control of cancer growth. Genetic cancer vaccines based on in vivo muscle electro-gene-transfer of plasmid DNA (DNA-EGT) and adenoviral vectors represent promising modalities to elicit powerful immune responses against tumor-associated antigens (TAAs) such as carcinoembryonic antigen (CEA) and human epidermal growth factor receptor-2 (HER2)/neu. Combinations of these modalities of immunization (heterologous prime-boost) can induce superior immune reactions as compared with single-modality vaccines. We have generated a dual component-dual target genetic cancer vaccine consisting of a DNA moiety containing equal amounts of two plasmids, one encoding the extracellular and transmembrane domains of HER2 (ECD.TM) and the other encoding CEA fused to the B subunit of Escherichia coli heat-labile toxin (LTB), and of an adenoviral subtype 6 dicistronic vector carrying the same two tumor antigens gene constructs. The CEA/HER2 vaccine was tested in two different CEA/HER2 double-transgenic mouse models and in NOD/scid-DR1 mice engrafted with the human immune system. The immune response was measured by enzyme-linked immunospot assay, flow cytometry, and ELISA. The CEA/HER2 vaccine was able to break immune tolerance against both antigens. Induction of a T cell and antibody immune response was detected in immune-tolerant mice. Most importantly, the vaccine was able to slow the growth of HER2/neu⁺ and CEA⁺ tumors. A significant T cell response was measured in NOD/scid-DR1 mice engrafted with human cord blood cells. In conclusion, the CEA/HER2 genetic vaccine was immunogenic and able to confer significant therapeutic effects. These data warrant the evaluation of this vaccination strategy in human clinical trials.
PBL) from HLA -A2+ breast cancer patients, and PBL from control donors. Using this method on hybridomas with known TCRs, we showed that 85% of the...technology to identify shared T cell clonotypes in tumors of breast cancer patients. Patients were consented, HLA -typed, and their tissue samples were...alpha-beta pairs shared among 7-15 of 20 patients, but not control blood from female HLA -A2+ or HLA -A2- donors without breast cancer (Figure 4
Domchek, Susan M
This grant supports studies to understand the potential of universal tumor antigens for cancer immunotherapy, with a particular focus on the characterization of the human telomerase reverse transcriptase (hTERT) as tumor antigen...
Roscilli, Giuseppe; Marra, Emanuele; Luberto, Laura; Mancini, Rita; La Monica, Nicola; Ciliberto, Gennaro
Abstract We have generated a xenogeneic vaccine against human carcinoembryonic antigen (hCEACAM-5 or commonly hCEA) using as immunogen rhesus CEA (rhCEA). RhCEA cDNA was codon-usage optimized (rhCEAopt) and delivered by sequential DNA electro-gene-transfer (DNA-EGT) and adenoviral (Ad) vector. RhCEAopt was capable to break tolerance to CEA in hCEA transgenic mice and immune responses were detected against epitopes distributed over the entire length of the protein. Xenovaccination with rhCEA resulted in the activation of CD4+ T-cell responses in addition to self-reactive CD8+ T-cells, the development of high-titer antibodies against hCEA, and significant antitumor effects upon challenge with hCEA+ tumor cells. The superior activity of rhCEAopt compared with hCEAopt was confirmed in hCEA/HHD double-transgenic mice, where potent CD8+ T-cell responses against specific human HLA A*0201 hCEA epitopes were detected. Our data show that xenogeneic gene-based vaccination with rhCEA is a viable approach to break tolerance against CEA, thus suggesting further development in the clinical setting. PMID:25869226
Therapeutic anti-cancer vaccines containing tumor-specific antigens recognized by T lymphocytes are thought to stimulate high numbers of anti-vaccine cytolytic T lymphocytes (CTL) which then can lyse the tumor cells. To understand why these vaccines are followed by tumor regressions in only 10% of the patients, we analysed the tumor-specific immune responses of these patients. Contrary to our expectations, the anti-vaccine CTL responses were of very low level. However, regressing tumors were massively infiltrated by anti-tumor T cells of other specificities, including new anti-tumor CTL clonotypes that emerged following vaccination. We now believe that the role of the anti-vaccine CTL is to activate or restimulate large numbers of other anti-tumor CTL. Their ability to initiate this response is probably more important than their number. These results have important consequences for the improvement of the clinical efficacy of anti-cancer vaccines.
Full Text Available Treating cancer with vaccines has been a challenging field of investigation since the 1950s. Over the years, the lack of effective active immunotherapies has led to the development of numerous novel strategies. However, the use of therapeutic cancer vaccines may be on the verge of becoming an effective modality. Recent phase II/III clinical trials have achieved hopeful results in terms of overall survival. Yet despite these encouraging successes, in general, very little is known about the basic immunological mechanisms involved in vaccine immunotherapy. Gaining a better understanding of the mechanisms that govern the specific immune responses (i.e., cytotoxic T lymphocytes, CD4 T helper cells, T regulatory cells, cells of innate immunity, tumor escape mechanisms elicited by each of the various vaccine platforms should be a concern of cancer vaccine clinical trials, along with clinical benefits. This review focuses on current strategies employed by recent clinical trials of therapeutic cancer vaccines and analyzes them both clinically and immunologically.
Vaccines are primarily used worldwide as a preventive medicine for infectious diseases and have recently been applied to cancer. We and others have developed therapeutic vaccines designed for cardiovascular diseases that are notably different from previous vaccines. In the case of cancer vaccines, a specific protein in cancer cells is a target antigen, and the activation of cytotoxic T cells (CTL) is required to kill and remove the antigen-presenting cancer cells. Our therapeutic vaccines work against hypertension by targeting angiotensin II (Ang II) as the antigen, which is an endogenous hormone. Therapeutic vaccines must avoid CTL activation and induce the blocking antibodies for Ang II. The goal of our therapeutic vaccine for cardiovascular diseases is to induce the specific antibody response toward the target protein without inducing T-cell or antibody-mediated inflammation through the careful selection of the target antigen, carrier protein and adjuvants. The goal of our therapeutic vaccine is similar to that of antibody therapy. Recently, multiple antibody-based drugs have been developed for cancer, immune-related diseases, and dyslipidemia, which are efficient but expensive. If the effect of a therapeutic vaccine is nearly equivalent to antibody therapy as an alternative approach, the lower medical cost and improvement in drug adherence can be advantages of therapeutic vaccines. In this review, we will describe our concept of therapeutic vaccines for cardiovascular diseases and the future directions of therapeutic vaccines as novel antibody therapies. Copyright © 2017. Published by Elsevier Ltd.
Nachbagauer, R; Krammer, F
Current influenza virus vaccines are effective when well matched to the circulating strains. Unfortunately, antigenic drift and the high diversity of potential emerging zoonotic and pandemic viruses make it difficult to select the right strains for vaccine production. This problem causes vaccine mismatches, which lead to sharp drops in vaccine effectiveness and long response times to manufacture matched vaccines in case of novel pandemic viruses. To provide an overview of universal influenza virus vaccines and therapeutic antibodies in preclinical and clinical development. PubMed and clinicaltrials.gov were used as sources for this review. Universal influenza virus vaccines that target conserved regions of the influenza virus including the haemagglutinin stalk domain, the ectodomain of the M2 ion channel or the internal matrix and nucleoproteins are in late preclinical and clinical development. These vaccines could confer broad protection against all influenza A and B viruses including drift variants and thereby abolish the need for annual re-formulation and re-administration of influenza virus vaccines. In addition, these novel vaccines would enhance preparedness against emerging influenza virus pandemics. Finally, novel therapeutic antibodies against the same conserved targets are in clinical development and could become valuable tools in the fight against influenza virus infection. Both universal influenza virus vaccines and therapeutic antibodies are potential future options for the control of human influenza infections. Copyright © 2017 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.
Hansen, M; Met, Ö; Svane, I M
Cancer vaccines designed to re-calibrate the existing host-tumour interaction, tipping the balance from tumor acceptance towards tumor control holds huge potential to complement traditional cancer therapies. In general, limited success has been achieved with vaccines composed of tumor...... to transiently affect in vitro migration via autocrine receptor-mediated endocytosis of CCR7. In the current review, we discuss optimal design of DC maturation focused on pre-clinical as well as clinical results from standard and polarized dendritic cell based cancer vaccines....
Berinstein Neil L
Full Text Available Abstract Background DepoVaxTM is a novel non-emulsion depot-forming vaccine platform with the capacity to significantly enhance the immunogenicity of peptide cancer antigens. Naturally processed HLA-A2 restricted peptides presented by breast, ovarian and prostate cancer cells were used as antigens to create a therapeutic cancer vaccine, DPX-0907. Methods A phase I clinical study was designed to examine the safety and immune activating potential of DPX-0907 in advanced stage breast, ovarian and prostate cancer patients. A total of 23 late stage cancer patients were recruited and were divided into two dose/volume cohorts in a three immunization protocol. Results DPX-0907 was shown to be safe with injection site reactions being the most commonly reported adverse event. All breast cancer patients (3/3, most of ovarian (5/6 and one third of prostate (3/9 cancer patients exhibited detectable immune responses, resulting in a 61% immunological response rate. Immune responses were generally observed in patients with better disease control after their last prior treatment. Antigen-specific responses were detected in 73% of immune responders (44% of evaluable patients after the first vaccination. In 83% of immune responders (50% of evaluable patients, peptide-specific T cell responses were detected at ≥2 time points post vaccination with 64% of the responders (39% of evaluable patients showing evidence of immune persistence. Immune monitoring also demonstrated the generation of antigen-specific T cell memory with the ability to secrete multiple Type 1 cytokines. Conclusions The novel DepoVax formulation promotes multifunctional effector memory responses to peptide-based tumor associated antigens. The data supports the capacity of DPX-0907 to elicit Type-1 biased immune responses, warranting further clinical development of the vaccine. This study underscores the importance of applying vaccines in clinical settings in which patients are more likely to be
Biomira is developing a therapeutic cancer vaccine [THERATOPE] for treatment of breast and other cancers. This profile has been selected from R&D Insight, a pharmaceutical intelligence database produced by Adis International Ltd. THERATOPE consists of the mucin antigen, sialyl-Tn (STn), a carbohydrate located on the surface of breast, colorectal and ovarian cancer cells, conjugated to keyhole limpet haemocyanin (KLH). Merck KGaA has acquired a worldwide licence to THERATOPE for treatment of breast cancer. Under the terms of the licence, Biomira and Merck KGaA, via its US affiliate, EMD Pharmaceuticals, will jointly market the vaccine in the US. Merck KGaA holds exclusive marketing rights for the rest of the world, except in Canada (where Biomira retains rights), Israel and the Palestine Autonomy Area. Merck KGaA is now collaborating on phase III development for breast cancer. Biomira stands to receive $US150 million in licence, milestone payments and equity investments. The development costs will be shared between the two companies in North America but Merck KGaA will be solely responsible for these costs in countries outside the US. Previously, Chiron Corporation had purchased a licence to THERATOPE in 1997; however, Chiron terminated this agreement in June 2000. Under the terms of the termination, Biomira paid Chiron $US2.25 million to compensate the company for its investment in the development of THERATOPE. In addition, Biomira will make another payment of $US3.25 million to Chiron upon FDA approval of the vaccine. No further payments or royalties will be made. In the third quarter of 2002, an independent review of interim data from the trial was conducted. This was the fifth scheduled review of the data by the Independent Data Safety Monitoring Board (DSMB), all of which produced a positive response. Following the completion of the review, the DSMB stated that the trial should continue and that it had no safety concerns regarding this trial. Although the data
Aurisicchio, Luigi; Ciliberto, Gennaro
The recent approval of the first therapeutic cancer vaccine by the US Regulatory Agency represents a breakthrough event in the history of cancer treatment. The past scepticism towards this type of therapeutic intervention is now replaced by great expectations. The field is now moving towards the development of alternative vaccination technologies, which are capable of generating stronger, more durable and efficient immune responses against specific tumour-associated antigens (TAAs) in combination with cheaper and more standardised manufacturing. In this context, genetic vaccines are emerging among the most promising methodologies. Several evidences point to combinations of different genetic immunisation modalities (heterologous prime/boost) as a powerful approach to induce superior immune responses and achieve greater clinical efficacy. In this review, we provide an overview of the current status of development of genetic cancer vaccines with particular emphasis on adenoviral vector prime/DNA boost vaccination schedules. We believe that therapeutic genetic cancer vaccines have the strong potential to become an established therapeutic modality for cancer in next coming years, in a manner similar to what have now become monoclonal antibodies.
Simon, Ph; Monnier, S; Buxant, F; Noël, J C
The aim of this review is to present a new light about the HPV infections, their spontaneous evolutions, and their consequences on the transformation of the target tissues. It enlightens the need for vaccination both as a preventive tool and therapeutic agent and the progresses reached so far. HPV infection is often transient and spontaneously reversible. HR HPV persistence is the major cause of cancerous transformation of several tissues. Preventive vaccination has already demonstrated a remarkable efficiency against the development of risk HPV ano-genital infections. Therapeutic vaccination is now also developed to cure the pre existing lesions. Some new screening protocol can be derived from these experiments. Both preventive and therapeutic HPV vaccinations will probably change within the next few years our approach for the screening and therapy of HPV related diseases. Mass vaccination of adolescent female should lower the frequency of these very frequently lethal affections.
Plemper, Richard K; Hammond, Anthea L
The measles virus is a major human pathogen responsible for approximately 150,000 deaths annually. The disease is vaccine preventable and eradication of the virus is considered feasible, in principle. However, a herd immunity exceeding 95% is required to prevent sporadic viral outbreaks in a population. Declining disease prevalence, combined with public anxiety over the vaccination's safety, has led to increased vaccine refusal, especially in Europe. This has led to the resurgence of measles in some areas. This article discusses whether synergizing effective measles therapeutics with the measles vaccination could contribute to finally eradicating measles. The authors identify key elements in a desirable drug profile and review current disease management strategies and the state of experimental inhibitor candidates. The authors also evaluate the risk associated with viral escape from inhibition, and consider the potential of measles therapeutics in the management of persistent central nervous system (CNS) viral infection. Finally, the authors contemplate the possible impact of therapeutics in controlling the threat imposed by closely related zoonotic pathogens of the same genus as measles. Efficacious therapeutics used for post-exposure prophylaxis of high-risk social contacts of confirmed index cases may aid measles eradication by closing herd immunity gaps; this is due to vaccine refusal or failure in populations with overall good vaccination coverage. The envisioned primarily prophylactic application of measles therapeutics to a predominantly pediatric and/or adolescent population, dictates the drug profile. It also has to be safe and efficacious, orally available, shelf-stable at ambient temperature and amenable to cost-effective manufacturing.
Full Text Available Breast cancer (BC is a persistent global challenge for its high frequency in women (although it seldom occurs in men, due to the large diffusion of risk factors and gene mutations, and for its peculiar biology and microenvironment. To date, BC can benefit from different therapeutic strategies involving surgery, ablation, chemotherapy, radiotherapy, and more specific approaches such as hormone therapy and the administration of various substances impairing cancer growth, aggressivity, and recurrence with different modalities. Despite these relatively wide chances, also used in combinatory protocols, relevant mortality and relapse rates, often associated with resistant phenotypes, stress the need for a personalized-medicine based on prompting the patient’s immune system (IS against cancer cells. BC immunogenicity was latterly proven, so the whole immunotherapy field for BC is still at a very early stage. This immunotherapeutic approach exploits both the high specificity of adaptive immune response and the immunological memory. This review is focused on some of the majorly relevant BC vaccines available (NeuVax, AVX901, and INO-1400, providing a description of the more promising clinical trials. The efficacy of cancer vaccines highly depends on the patient’s IS, and a wide optimization is needed in terms of targets’ selection, drug design and combinations, dose finding, protocol structuring, and patients’ recruitment; moreover, new standards are being discussed for the outcome evaluation. However, early-phases excellent results suggest that the manipulation of the IS via specific vaccines is a highly attractive approach for BC.
Met, Ozcan; Wang, Mingjun; Pedersen, Anders E
Dendritic cells (DCs) were pulsed with the H-2K(b) binding OVA(257-264)-peptide (SIINFEKL), and used as one single-injection vaccine in combination with anti-CTLA-4 monoclonal antibody (mAb) to treat mice inoculated 3 days previously with 3x10(5) E.G7-OVA lymphoma cells. Neither DC vaccination nor...... CTLA-4 blockage alone prevented tumor growth in tumor challenged mice. In contrast, the combination of one vaccination and injection of anti-CTLA-4 mAb lead to rejection or retarded tumor growth in more than 60% of the mice. The OVA-transgene or the SIINFEKL-epitope was not lost in the progressing...... tumors of vaccinated mice, however, the highest degree of anti-SIINFEKL reactivity of host CTLs in an IFN-gamma ELISPOT assay was found only in mice showing complete tumor rejection. Vaccinated mice having rejected E.G7-OVA tumors were capable of rejecting subsequent challenges with 1x10(6) E.G7-OVA...
Hansen, M; Met, Ö; Svane, I M
Cancer vaccines designed to re-calibrate the existing host-tumour interaction, tipping the balance from tumor acceptance towards tumor control holds huge potential to complement traditional cancer therapies. In general, limited success has been achieved with vaccines composed of tumor...... to induce IL-12 secreting type 1 polarized DCs mimicing pathogen-derived molecular activation of DCs. Correct timing and potential synergisms of clinical-grade toll-like receptor ligands, interferons (IFN) and CD40L enhance IL-12 production in DCs. However, cytokine exhaustion, predominant expression...... especially following encounter with CD40L-expressing cells and furthermore, PGE(2) imprints DCs for preferential interaction with tolerogenic T cells. In addition, type 1 polarized DCs matured without PGE(2) also seem to be capable of migrating in vivo, although concomitant production of CCL19 seems...
Gouttefangeas, Cécile; Rammensee, Hans-Georg
Therapeutic cancer vaccines have shown limited clinical efficacy so far. Nevertheless, in the meantime, our understanding of immune cell function and the interactions of immune cells with growing tumors has advanced considerably. We are now in a position to invest this knowledge into the design of more powerful vaccines and therapy combinations aimed at increasing immunogenicity and decreasing tumor-induced immunosuppression. This review focuses essentially on peptide-based human vaccines. We will discuss two aspects that are critical for increasing their intrinsic immunogenicity: the selection of the antigen(s) to be targeted, and the as yet unmet need for strong adjuvants.
Shapiro, Stuart Z
The HIV cure agenda has rekindled interest in the development of a therapeutic HIV vaccine. An iterative clinical trial strategy that proved successful for the development of effective cancer chemotherapies in the 1960s may be applicable to the development of a CD8 T lymphocyte-based therapeutic HIV vaccine. However, while cancer chemotherapy development could begin with iterative clinical trials to improve the use of active drugs, the first step in therapeutic HIV vaccine design should be discovery of immunogen constructs with potential for activity and their optimization to meet the challenges of HIV-1 sequence diversity and human polymorphism in T cell antigen presentation. A strategy for doing this is discussed in this article. The proposed strategy relies on a major commitment by funding organizations to fund organized and coordinated manufacture and clinical testing of a series of first- and second-generation constructs to test basic concepts in product design. This is presented as an alternative to funding a more traditional competition among private manufacturers and product champions of individual, already designed products.
Strioga, M.M.; Darinskas, A.; Pasukoniene, V.; Mlynska, A.; Ostapenko, V.; Schijns, V.E.J.C.
Accumulation of firm evidence that clinically apparent cancer develops only when malignant cells manage to escape immunosurveillance led to the introduction of tumor immunotherapy strategies aiming to reprogramm the cancer-dysbalanced antitumor immunity and restore its capacity to control tumor
Yang, Andrew; Farmer, Emily; Lin, John; Wu, T-C; Hung, Chien-Fu
Human papillomavirus (HPV) is known to be a necessary factor for many gynecologic malignancies and is also associated with a subset of head and neck malignancies. This knowledge has created the opportunity to control these HPV-associated cancers through vaccination. However, despite the availability of prophylactic HPV vaccines, HPV infections remain extremely common worldwide. In addition, while prophylactic HPV vaccines have been effective in preventing infection, they are ineffective at clearing pre-existing HPV infections. Thus, there is an urgent need for therapeutic and T cell-based vaccines to treat existing HPV infections and HPV-associated lesions and cancers. Unlike prophylactic vaccines, which generate neutralizing antibodies, therapeutic, and T cell-based vaccines enhance cell-mediated immunity against HPV antigens. Our review will cover various therapeutic and T cell-based vaccines in development for the treatment of HPV-associated diseases. Furthermore, we review the strategies to enhance the efficacy of therapeutic vaccines and the latest clinical trials on therapeutic and T cell-based HPV vaccines. Copyright © 2016 Elsevier B.V. All rights reserved.
Wisniewski, Thomas; Drummond, Eleanor
Alzheimer's disease (AD) is the most common form of dementia worldwide. It is characterized by an imbalance between the production and clearance of amyloid β (Aβ) and tau proteins. In AD these normal proteins accumulate, leading to aggregation and a conformational change forming oligomeric and fibrillary species with a high β-sheet content. Active and passive immunotherapeutic approaches result in dramatic reduction of Aβ pathology in AD animal models. However, there is much more limited evidence in human studies of significant clinical benefits from these strategies and it is becoming apparent that they may only be effective very early in AD. Vaccination targeting only tau pathology has shown benefits in some mouse studies but human studies are limited. Greater therapeutic efficacy for the next generation of vaccine approaches will likely benefit from specifically targeting the most toxic species of Aβ and tau, ideally simultaneously.
Full Text Available Background: In general, the preferable characteristic of the target molecules for development of cancer vaccines are high immunogenicity, very common expression in cancer cells, specific expression in cancer cells and essential molecules for cell survival (to avoid loss of expression. We previously reported that three novel HLA-A24-restricted immunodominant peptides, which were derived from three different oncoantigens, TTK, LY6K, and IMP-3,were promising targets for cancer vaccination for esophageal squamous cell carcinoma (ESCCpatients. Then, we had performed a phase I clinical trial using three HLA-A24-binding peptides and the results had been shown to be promising for ESCC. Therefore, we further performed a multicenter, non-randomized phase II clinical trial. Patients and Methods: Sixty ESCC patients were enrolled to evaluate OS, PFS, immunological response employing ELISPOT and pentamer assays. Each of the three peptides was administered with IFA weekly. All patients received the vaccination without knowing an HLA-A type, and the HLA types were key-opened at the analysis point. Hence, the endpoints were set to evaluate differences between HLA-A*2402-positive (24(+ and -negative (24(- groups. Results: The OS in the 24 (+ group (n=35 tended to be better than that in the 24(- group (n=25 (MST 4.6 vs. 2.6 month, respectively, p = 0.121, although the difference was not statistically significant. However, the PFS in the 24(+ group was significantly better than that in the 24(- group (p = 0.032. In the 24(+ group, ELISPOT assay indicated that the LY6K-, TTK-, and IMP3-specific CTL responses were observed after the vaccination in 63%, 45%, and 60% of the 24(+ group, respectively. The patients having LY6K-, TTK-, and IMP3-specific CTL responses revealed the better OS than those not having CTL induction, respectively. The patients showing the CTL induction for multiple peptides have better clinical responses. Conclusion: The immune response induced
Finn, Olivera J
An important role of the immune system is in the surveillance for abnormal or transformed cells, which is known as cancer immunosurveillance. Through this process, the first changes to normal tissue homeostasis caused by infectious or other inflammatory insults can be detected by the immune system through the recognition of antigenic molecules (including tumour antigens) expressed by abnormal cells. However, as they develop, tumour cells can acquire antigenic and other changes that allow them to escape elimination by the immune system. To bias this process towards elimination, immunosurveillance can be improved by the administration of vaccines based on tumour antigens. Therapeutic cancer vaccines have been extensively tested in patients with advanced cancer but have had little clinical success, which has been attributed to the immunosuppressive tumour microenvironment. Thus, the administration of preventive vaccines at pre-malignant stages of the disease holds promise, as they function before tumour-associated immune suppression is established. Accordingly, immunological and clinical studies are yielding impressive results.
Cervical cancer can be prevented with HPV vaccines. NCI-supported researchers helped establish HPV as a cause of cervical cancer. They also helped create the first HPV vaccines, were involved in the vaccine trials, and contribute to ongoing studies.
erate in an uncontrolled manner. Newer strategies are being researched to overcome this immunological toler- ance to cancer. Provoking the body's immune system .... periodically. In addition to the cellular side of the immune system described above, some cancer vaccines stimulate the. When a vaccine is injected into the.
Cameron A. Wade; Natasha Kyprianou
The major challenge in the treatment of patients with advanced lethal prostate cancer is therapeutic resistance to androgen-deprivation therapy (ADT) and chemotherapy. Overriding this resistance requires understanding of the driving mechanisms of the tumor microenvironment, not just the androgen receptor (AR)-signaling cascade, that facilitate therapeutic resistance in order to identify new drug targets. The tumor microenvironment enables key signaling pathways promoting cancer cell survival ...
cancer cells from normal cells allows cancer cells to prolif- erate in an uncontrolled manner. Newer strategies are being researched to overcome this immunological toler- ance to cancer. Provoking the body's immune system to generate vaccines against cancer is emerging as an impor- tant type of immunotherapy to treat ...
Petr G. Lokhov, Elena E. Balashova
Full Text Available A recent advance in anti-cancer therapies has been the use of cancer cells to develop vaccines. However, immunization with cancer cell-based vaccines has not resulted in significant long-term therapeutic benefits. A possible reason for this is that while cancer cells provide surface antigens that are targets for a desired immune response, they also contain a high abundance of housekeeping proteins, carbohydrates, nucleic acids, lipids, and other intracellular contents that are ubiquitous in all mammalian cells. These ubiquitous molecules are not the intended targets of this therapy approach, and thus, the immune response generated is not sufficient to eliminate the cancer cells present. In this review, a discussion of the cell surface of cancer cells is presented in relation to the goals of improving antigen composition of cancer cell-based vaccines. Strategies to enrich vaccines for cancer-specific antigens are also discussed.
Schendel Dolores J
Full Text Available Abstract Background Given the considerable toxicity and modest benefit of adjuvant chemotherapy for non-small cell lung cancer (NSCLC, there is clearly a need for new treatment modalities in the adjuvant setting. Active specific immunotherapy may represent such an option. However, clinical responses have been rare so far. Manipulating the host by inducing lymphopenia before vaccination resulted in a magnification of the immune response in the preclinical setting. To evaluate feasibility and safety of an irradiated, autologous tumor cell vaccine given following induction of lymphopenia by chemotherapy and reinfusion of autologous peripheral blood mononuclear cells (PBMC, we are currently conducting a pilot-phase I clinical trial in patients with NSCLC following surgical resection. This paper reports on the first clinical experience and evidence of an immune response in patients suffering from NSCLC. Methods NSCLC patients stages I-IIIA are recruited. Vaccines are generated from their resected lung specimens. Patients undergo leukapheresis to harvest their PBMC prior to or following the surgical procedure. Furthermore, patients receive preparative chemotherapy (cyclophosphamide 350 mg/m2 and fludarabine 20 mg/m2 on 3 consecutive days for induction of lymphopenia followed by reconstitution with their autologous PBMC. Vaccines are administered intradermally on day 1 following reconstitution and every two weeks for a total of up to five vaccinations. Granulocyte-macrophage-colony-stimulating-factor (GM-CSF is given continuously (at a rate of 50 μg/24 h at the site of vaccination via minipump for six consecutive days after each vaccination. Results To date, vaccines were successfully manufactured for 4 of 4 patients. The most common toxicities were local injection-site reactions and mild constitutional symptoms. Immune responses to chemotherapy, reconstitution and vaccination are measured by vaccine site and delayed type hypersensitivity (DTH skin
Bot, Adrian; Obrocea, Mihail; Marincola, Francesco M
..., for both solid and blood borne cancers. Cancer Vaccines: Challenges and Opportunities in Translation is the first text in the field to bring immunotherapy treatments from the laboratory trial to the bedside for the practicing oncologist. Cancer Vaccines...
Hansen, M; Met, Ö; Svane, I M
-associated antigens introduced to dendritic cells (DCs) generated in vitro. This may in part result from suboptimal maturation of DCs leading to insufficient production of IL-12, a key driver of cellular immunity. Therefore, tremendous efforts have been put into the design of maturation cocktails that are able...... of tolerogenic molecules and activation-induced dendritic cell death should be avoided. Thus, compounds such as IFN-γ may initially induce immunity but later on tolerance. Maturation with PGE(2) obviously promotes migration via expression of CCR7 but on the down side PGE(2) limits the production of IL-12...... to transiently affect in vitro migration via autocrine receptor-mediated endocytosis of CCR7. In the current review, we discuss optimal design of DC maturation focused on pre-clinical as well as clinical results from standard and polarized dendritic cell based cancer vaccines....
Horton; Parker; Wloch; Norman
Vaccination with a tumour antigen-expressing plasmid DNA (pDNA) is a novel approach to human cancer immunotherapy. Initial results in preclinical rodent tumour models are promising, revealing that pDNA cancer vaccines can elicit both humoral, as well as cell-mediated immunity and, in some cases, protect against tumour growth. Compared to peptide, viral or dendritic cell vaccines, the delivery of tumour antigens using pDNA has the advantages of ease of manufacture, lack of toxicity and broad applicability to large populations. With advances in modern genomics strategies and the identification of an increasing number of tumour antigen genes, pDNA-based cancer vaccines may be used in the future to treat a wide variety of human cancers.
Full Text Available José Juan Escobar-Chávez1, Clara Luisa Domínguez-Delgado2, Isabel Marlen Rodríguez-Cruz21Unidad de Investigación Multidisciplinaria, Facultad de Estudios Superiores Cuautitlán-Universidad Nacional Autónoma de México, Cuautitlán Izcalli, Estado de México, México; 2División de Estudios de Posgrado (Tecnología Farmacéutica, Facultad de Estudios Superiores Cuautitlán-Universidad Nacional Autónoma de México, Cuautitlán Izcalli, Estado de México, MéxicoAbstract: Cigarette smoking is the primary cause of lung cancer, cardiovascular diseases, reproductive disorders, and delayed wound healing all over the world. The goals of smoking cessation are both to reduce health risks and to improve quality of life. The development of novel and more effective medications for smoking cessation is crucial in the treatment of nicotine dependence. Currently, first-line smoking cessation therapies include nicotine replacement products and bupropion. The partial nicotinic receptor agonist, varenicline, has recently been approved by the US Food and Drug Administration (FDA for smoking cessation. Clonidine and nortriptyline have demonstrated some efficacy, but side effects may limit their use to second-line treatment products. Other therapeutic drugs that are under development include rimonabant, mecamylamine, monoamine oxidase inhibitors, and dopamine D3 receptor antagonists. Nicotine vaccines are among newer products seeking approval from the FDA. Antidrug vaccines are irreversible, provide protection over years and need booster injections far beyond the critical phase of acute withdrawal symptoms. Interacting with the drug in the blood rather than with a receptor in the brain, the vaccines are free of side effects due to central interaction. For drugs like nicotine, which interacts with different types of receptors in many organs, this is a further advantage. Three anti-nicotine vaccines are today in an advanced stage of clinical evaluation. Results
Nanotechnology offers invaluable tools to tailor cancer vaccines in order to generate robust antitumor immune response. Among the types of vehicles for cancer vaccines, nanoparticles (NPs) are easier to produce with better scalability. Several nanostructures have been discussed in literature as potential delivery systems for cancer antigens. Here, we focus on polymeric NPs fabricated from poly(D,L-lactic-co-glycolic) acid (PLGA). We describe how to prepare and characterize such NPs loaded with ovalbumin (OVA) antigen and immune adjuvant monophosphoryl lipid A (MPLA). We further describe methods to test the immune efficacy of such NPs in vitro and in vivo.
Synthetic long peptides (SLP) derived from cancer-associated antigens hold great promise as well-defined antigens for cancer immunotherapy. Clinical studies showed that SLP vaccines have functional potency when applied to pre-malignant stage patients, but need to be improved for use as a therapeutic
Cervical cancer, mainly caused by Human Papillomavirus infection, is the leading cancer in Indian women and the second most common cancer in women worldwide. Though there are several methods of prevention of cervical cancer, prevention by vaccination is emerging as the most effective option, with the availability of two vaccines. Several studies have been published examining the vaccine's efficacy, immunogenicity and safety. Questions and controversy remain regarding mandatory vaccination, need for booster doses and cost-effectiveness, particularly in the Indian context.
Overgaard, Nana Haahr; Frøsig, Thomas Mørch; Welner, Simon
Immunotherapy has increased overall survival of metastatic cancer patients, and cancer antigens are promising vaccine targets. To fulfill the promise, appropriate tailoring of the vaccine formulations to mount in vivo cytotoxic T cell (CTL) responses toward co-delivered cancer antigens is essential....... Previous development of therapeutic cancer vaccines has largely been based on studies in mice, and the majority of these candidate vaccines failed to induce therapeutic responses in the subsequent human clinical trials. Given that antigen dose and vaccine volume in pigs are translatable to humans...... and the porcine immunome is closer related to the human counterpart, we here introduce pigs as a supplementary large animal model for human cancer vaccine development. IDO and RhoC, both important in human cancer development and progression, were used as vaccine targets and 12 pigs were immunized with overlapping...
Aurisicchio, Luigi, E-mail: email@example.com [Takis, via di Castel Romano 100, 00128 Rome (Italy); BIOGEM scarl, via Camporeale, 83031 Ariano Irpino (AV) (Italy); Ciliberto, Gennaro [Takis, via di Castel Romano 100, 00128 Rome (Italy); Dipartimento di Medicina Sperimentale e Clinica, Università degli studi di Catanzaro “Magna Graecia”, 88100 Catanzaro (Italy)
Therapeutic vaccination against cancer is an important approach which, when combined with other therapies, can improve long-term control of cancer. In fact, the induction of adaptive immune responses against Tumor Associated Antigens (TAAs) as well as innate immunity are important factors for tumor stabilization/eradication. A variety of immunization technologies have been explored in last decades and are currently under active evaluation, such as cell-based, protein, peptide and heat-shock protein-based cancer vaccines. Genetic vaccines are emerging as promising methodologies to elicit immune responses against a wide variety of antigens, including TAAs. Amongst these, Adenovirus (Ad)-based vectors show excellent immunogenicity profile and have achieved immunological proof of concept in humans. In vivo electroporation of plasmid DNA (DNA-EP) is also a desirable vaccine technology for cancer vaccines, as it is repeatable several times, a parameter required for the long-term maintenance of anti-tumor immunity. Recent findings show that combinations of different modalities of immunization (heterologous prime/boost) are able to induce superior immune reactions as compared to single-modality vaccines. In this review, we will discuss the challenges and requirements of emerging cancer vaccines, particularly focusing on the genetic cancer vaccines currently under active development and the promise shown by Ad and DNA-EP heterologous prime-boost.
Full Text Available Traditionally, cancer therapy has relied on surgery, radiation therapy, and chemotherapy. In recent years, these interventions have become increasingly replaced or complemented by more targeted approaches that are informed by a deeper understanding of the underlying biology. Still, the implementation of fully rational patient-specific drug design appears to be years away. Here, we present a vision of rational drug design for cancer that is defined by two major components: modularity and image guidance. We suggest that modularity can be achieved by combining a nanocarrier and an oligonucleotide component into the therapeutic. Image guidance can be incorporated into the nanocarrier component by labeling with a specific imaging reporter, such as a radionuclide or contrast agent for magnetic resonance imaging. While limited by the need for additional technological advancement in the areas of cancer biology, nanotechnology, and imaging, this vision for the future of cancer therapy can be used as a guide to future research endeavors.
Joniau, Steven; Abrahamsson, Per-Anders; Bellmunt, Joaquim; Figdor, Carl; Hamdy, Freddie; Verhagen, Paul; Vogelzang, Nicholas J; Wirth, Manfred; Van Poppel, Hendrik; Osanto, Susanne
The first therapeutic cancer vaccine demonstrating effectiveness in a phase 3 study was approved by the US Food and Drug Administration on 29 April 2010. The pivotal trial demonstrated overall survival (OS) benefit in patients treated with antigen-loaded leukapheresis cells compared with a control infusion. Results of other prostate cancer (PCa) vaccination strategies are awaited, as this approach may herald a new era in the care for patients with advanced PCa. Consider effectiveness and safety of vaccination strategies in the treatment of PCa. We searched three bibliographic databases (January 1995 through October 2010) for randomised phase 2 and 3 studies of vaccination strategies for PCa based on predetermined relevant Medical Subject Heading terms and free text terms. Data from 3 randomised phase 3 and 10 randomised phase 2 vaccination trials are discussed with respect to clinical outcome in terms of progression-free survival and OS, toxicity, prostate-specific antigen (PSA) response, and immunologic response. Three phase 3 trials (D9901, D9902A, and D9902B) that enrolled a total of 737 patients, all controlled and double-blinded, tested the efficacy of sipuleucel-T. The largest of these three trials, called Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT), has demonstrated safety and effectiveness of sipuleucel-T (now marketed as Provenge) as measured by prolonged survival of 512 asymptomatic patients with metastatic castration-resistant PCa (mCRPC). The study showed a 4.1-mo median survival benefit in the sipuleucel-T vaccine-treated group compared with the control group (25.8 vs 21.7 mo; hazard ratio [HR]: 0.78; 95% confidence interval [CI], 0.62-0.98; p=0.032) and extended 3-yr survival (31.7% vs 23.0%). In contrast, two phase 3 vaccination trials with a whole-tumour-cell mixture of two PCa cell lines (GVAX) and testing GVAX either alone or in combination with chemotherapy versus chemotherapy alone (VITAL1 and 2) were terminated prematurely
As cancer progresses tumor cells dedifferentiate. In the atavistic model this dedifferentiation is interpreted as a reversion to phylogenetically earlier capabilities (Davies & Lineweaver 2011). Since there is an identifiable order to the evolution of capabilities, the more recently evolved capabilities are more likely to be compromised first during cancer progression. A loss of capabilities based on the phylogenetic order of evolution suggests a therapeutic strategy for targeting cancer - design challenges that can only be met by the recently evolved capabilities still intact in normal cells, but lost in cancer cells. Such a target-the-weakness therapeutic strategy contrasts with most current therapies that target the main strength of cancer: cell proliferation. Here, we describe several examples of this target-the-weakness strategy. Our most detailed example involves the immune system. As cancer progresses, the atavistic model suggests that cancer cells lose contact with the more recently evolved adaptive immune system of the host (the basis of vaccination). The absence of adaptive immunity in immunosuppressed tumor environments is an irreversible weakness of cancer that can be exploited by creating a challenge that only the presence of adaptive immunity can meet. Thus, we propose the post-vaccination inoculation of disease at dosages that the recently evolved (and vaccination-primed) adaptive immune system will be able to destroy in normal cells, but not in the immunosuppressed microenvironment of tumor cells. Co-author: Paul Davies (Arizona State University)
Full Text Available Erica Jackson, Hatem SolimanUniversity of South Florida/Moffitt Cancer Center and Research Institute, Tampa, FL, USAAbstract: Breast cancer vaccines are being developed to stimulate adaptive antitumor immune responses in patients. These vaccines have the potential to treat breast cancer with minimal side effects and toxicity. However, many obstacles still need to be overcome to fully realize the vaccines' clinical benefit. A review of the literature was conducted to assess the use of vaccines in targeting transformed cells. Four vaccines currently under study were discussed, each summarizing the different vaccine platforms used to introduce target antigen to the patient's immune system. The advantages and disadvantages of each method were discussed, although no one method was found to be superior. Additional issues addressed included overcoming tumor-induced immunosuppression, immune evasion of transformed cells, the use of vaccines in combination therapy, and the challenges of using these vaccines in various clinical settings. Vaccines may be most effective in patients with minimal residual disease, as opposed to using them in the metastatic setting. Also, specific clinical trial design considerations for the use of vaccines in cancer patients, such as time-to-failure end points, were discussed. Understanding these various elements will be important to the translation of breast cancer vaccine therapy into routine clinical practice.Keywords: breast cancer, vaccine, immunotherapy, immune tolerance, peptide vaccine, dendritic cell vaccine
... Transmitted Diseases NIH Research Leads to Cervical Cancer Vaccine Past Issues / Fall 2008 Table of Contents For ... Douglas Lowy (left) and John Schiller developed the vaccine to prevent HPV infection in women, the cause ...
Ha, Kevin D.; Bidlingmaier, Scott M.; Liu, Bin
Macropinocytosis has long been known as a primary method for cellular intake of fluid-phase and membrane-bound bulk cargo. This review seeks to re-examine the latest studies to emphasize how cancers exploit macropinocytosis to further their tumorigenesis, including details in how macropinocytosis can be adapted to serve diverse functions. Furthermore, this review will also cover the latest endeavors in targeting macropinocytosis as an avenue for novel therapeutics.
Ha, Kevin D; Bidlingmaier, Scott M; Liu, Bin
Macropinocytosis has long been known as a primary method for cellular intake of fluid-phase and membrane-bound bulk cargo. This review seeks to re-examine the latest studies to emphasize how cancers exploit macropinocytosis to further their tumorigenesis, including details in how macropinocytosis can be adapted to serve diverse functions. Furthermore, this review will also cover the latest endeavors in targeting macropinocytosis as an avenue for novel therapeutics.
Kevin D Ha
Full Text Available Macropinocytosis has long been known as a primary method for cellular intake of fluid-phase and membrane-bound bulk cargo. This review seeks to re-examine the latest studies to emphasize how cancers exploit macropinocytosis to further their tumorigenesis, including details in how macropinocytosis can be adapted to serve diverse functions. Furthermore, this review will also cover the latest endeavors in targeting macropinocytosis as an avenue for novel therapeutics.
Full Text Available Abstract With the approval of the first therapeutic cancer vaccines for veterinarian and human use, the field reached a significant milestone after a considerable interval of tumultuous research and development marked by numerous ups and downs. As the mechanism of action and clinical benefit afforded by this class of agents are starkly different from that of conventional or small targeted therapies for cancer, there are still numerous hurdles that need to be overcome to fully unleash their potential. These challenges and efforts are illustrated in a book just published on this subject, a non-exhaustive yet representative synopsis of the latest advances in cancer vaccine technologies in various stages of development. Major lessons resulting from clinical testing of cancer vaccines and other immune interventions, are being integrated in novel, cutting edge platform technologies that blur the distinction between passive and active immunotherapies as well as carry the promise of fundamentally changing and improving the management of patients with cancer.
Roč. 49, č. 5 (2002), s. 285-289 ISSN 0028-2685 Institutional research plan: CEZ:AV0Z5052915 Keywords : human papilloma viruses * tumor vaccines * dendritic cells Subject RIV: FD - Oncology ; Hematology Impact factor: 0.679, year: 2002
Andersen, M.H.; Sorensen, R.B.; Schrama, D.
Harnessing of the immune system by the development of 'therapeutic' vaccines, for the battle against cancer has been the focus of tremendous research efforts over the past two decades. As an illustration of the impressive amounts of data gathered over the past years, numerous antigens expressed...... their escape from cytotoxic therapies represent prime vaccination candidates. The characterization of a high number of tumor antigens allow the concurrent or serial immunological targeting of different proteins associated with such cancer traits. Moreover, while vaccination in itself is a promising new...... approach to fight cancer, the combination with additional therapy could create a number of synergistic effects. Herein we discuss the possibilities and prospects of vaccination when combined with other treatments. In this regard, cell death upon drug exposure may be immunogenic or non-immunogenic depending...
Li, Jianqiang; Bao, Mengru; Ge, Jun; Ren, Sulin; Zhou, Tong; Qi, Fengchun; Pu, Xiuying; Dou, Jia
Hepatitis B virus (HBV) is a member of Hepadnavirus family, which leads to chronic infection in around 5% of patients with a high risk of developing liver cirrhosis, liver failure, and hepatocellular carcinoma. 1 Despite the availability of prophylactic vaccines against hepatitis B for over 3 decades, there are still more than 2 billion people have been infected and 240 million of them were chronic. Antiviral therapies currently used in the treatment of CHB (chronic hepatitis B) infection include peg-interferon, standard α-interferon and nucleos/tide analogs (NAs), but none of them can provide sustained control of viral replication. As an alternative strategy, therapeutic vaccines for CHB patients have been widely studied and showed some promising efficacies in dozens of preclinical and clinical trials. In this article, we review current research progress in several types of therapeutic vaccines for CHB treatment, including protein-based vaccines, DNA-based vaccines, live vector-based vaccines, peptide-based vaccines and cell-based therapies. These researches may provide some clues for developing new treatments in CHB infection.
Full Text Available Paola Cappello, Moitza Principe, Francesco Novelli Department of Molecular Biotechnologies and Health Sciences, Center for Experimental Research and Medical Studies, AOU Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy Abstract: Pancreatic ductal adenocarcinoma (PDA is a lethal disease and is one of the cancers that is most resistant to traditional therapies. Historically, neither chemotherapy nor radiotherapy has provided any significant increase in the survival of patients with PDA. Despite intensive efforts, any attempts to improve the survival in the past 15 years have failed. This holds true even after the introduction of molecularly targeted agents, chosen on the basis of their involvement in pathways that are considered to be important in PDA development and progression. Recently, however, FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin treatment has provided a limited survival advantage in patients with advanced PDA. Therefore, effective therapeutic strategies are urgently needed to improve the survival rate of patients with PDA. Results from the last 10 years of research in the field of PDA have helped to identify new immunological targets and develop new vaccines that are capable of stimulating an immune response. In addition, the information obtained about the role of the tumor microenvironment in suppressing the immune response and the possibility of targeting PDA microenvironment to limit immune suppression and enhance the response of effector T-cells has opened new avenues for treating this incurable disease. The time is ripe for developing new therapeutic approaches that are able to effectively counteract the progression and spreading of PDA. This review discusses the potential prospects in the care of patients with pancreatic cancer through vaccination and its combination therapy with surgery, chemotherapy, targeting of the tumor microenvironment, and inhibition of immunological
Developing personalized cancer therapies based on cancer genomics methodologies forms the basis for future cancer therapeutics. A genomics platform was developed based on canine cancer to produce a proof-of-concept for personalized genomics led therapeutic choices but also developing personalized therapeutics for canine cancer patients themselves. The platform identified the genetic state of a canine cancer patient within two drugable pathways; p53 and HSP90/IRF1. The former ge...
Objective: This article provides an overview of cervical cancer vaccine including safety, efficacy and cost in the primary prevention of cervical cancer. Discussion: The quadrivalent human papilloma virus (HPV) vaccine protects against HPV types 6, 11, 16 and 18. These HPV types are responsible for 70% of cervical cancers ...
WHEELER COSETTE M
Full Text Available The potential use of vaccines for the human papillomavirus (HPV in the prevention and treatment of cervical cancer is a possibility in the near future. Close to 20 genotypes of HPV, of the 75 that have been identified, infect the femine genital tract, but four subtypes (16, 18, 31 and 45 have been associated in close to 80% of cervical cancers. this article proposes that in order to design an effective prophylactic vaccine against HPV infection, an adequate immune response should be guaranteed through four goals; a activation of antigens present in the cell; b overcoming the host response and viral genetic variability in the T cell response; c generation of high levels of T and B memory cells; and d persistence of antigens.
We have vaccines against viruses that cause cancer, but what about vaccines for cancers not caused by viruses? Learn about NCI's development of safe and effective vaccines for cancers not caused by infectious agents.
Plemper, Richard K; Hammond, Anthea L
Introduction Measles virus is a major human pathogen responsible for approximately 150,000 measles deaths annually. The disease is vaccine preventable and eradication of the virus is considered feasible in principle. However, a herd immunity exceeding 95% is required to prevent sporadic viral outbreaks in a population. Declining disease prevalence combined with public anxieties about vaccination safety has increased vaccine refusal especially in the European region, which has resulted in measles resurgence in some areas. Areas covered Here, we discuss whether synergizing effective measles therapeutics with vaccination could contribute to solving an endgame conundrum of measles elimination by accelerating the eradication effort. Based on an anticipated use for protection of high-risk contacts of confirmed measles cases through post-exposure prophylaxis, we identify key elements of the desirable drug profile, review current disease management strategies and the state of experimental inhibitor candidates, evaluate the risk associated with viral escape from inhibition, and consider the potential of measles therapeutics for the management of persistent viral infection of the CNS. Assuming a post-measles world with waning measles immunity, we contemplate the possible impact of therapeutics on controlling the threat imposed by closely related zoonotic pathogens of the same genus as measles virus. Expert opinion Efficacious therapeutics given for post-exposure prophylaxis of high-risk social contacts of confirmed index cases may aid measles eradication by closing herd immunity gaps due to vaccine refusal or failure in populations with overall good vaccination coverage. The envisioned primarily prophylactic application of measles therapeutics to a predominantly pediatric and/or adolescent patient population dictates the drug profile; the article must be safe and efficacious, orally available, shelf-stable at ambient temperature, and amenable to cost-effective manufacture
diseases and accidents observed during treatment period as well as corresponding events during drug-free, pre- and post-treatment periods, under placebo or...2004 49. Culley, JL, Arlen, PM, Bastian, A, et al. Combining a recombinant cancer vaccine with standard definitive radiotherapy in patients with...investigational) product. This will also include intercurrent diseases and accidents observed during treatment period as well as corresponding events
Speiser Daniel E
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.
Awasthi, Sita; Friedman, Harvey M
A half billion people have genital herpes infections worldwide. Approximately one-fifth of American women between ages 14 and 49 are HSV-2 seropositive. The development of an effective genital herpes vaccine is a global health necessity based on the mental anguish genital herpes causes for some individuals, the fact that pregnant women with genital herpes risk transmitting infection to their newborn children, and the observation that HSV-2 infection is associated with a 3-fold to 4-fold increased probability of HIV acquisition. We review the strengths and limitations of preclinical animal models used to assess genital herpes vaccine candidates and the goals of prophylactic and therapeutic vaccines. We also discuss the current pipeline of vaccine candidates and lessons learned from past clinical trials that serve as a stimulus for new strategies, study designs and endpoint determinations. Copyright © 2014 Elsevier B.V. All rights reserved.
Albers, A E; Hoffmann, T K; Klussmann, J P; Kaufmann, A M
Infection with human papilloma virus (HPV) has been identified as the cause of recurrent papillomatosis and of a subgroup of squamous cell carcinomas of the head and neck. A change in prevalence of these lesions, especially for oropharyngeal carcinoma, can be expected as a consequence of the introduction of prophylactic HPV vaccines for young women, targeting the most frequent high- and low-risk HPV subtypes. Vaccination for the major low-risk HPV types has proven to be highly effective against genital warts and activity against papillomatosis can be expected. The possibilities of prophylactic HPV vaccination as well as new developments and the rationale for therapeutic vaccines are discussed on the basis of the current literature.
Grau, Morgan; Walker, Paul R; Derouazi, Madiha
Immunotherapies are increasingly used to treat cancer, with some outstanding results. Immunotherapy modalities include therapeutic vaccination to eliminate cancer cells through the activation of patient's immune system against tumor-derived antigens. Nevertheless, the full potential of therapeutic vaccination has yet to be demonstrated clinically because many early generation vaccines elicited low-level immune responses targeting only few tumor antigens. Cell penetrating peptides (CPPs) are highly promising tools to advance the field towards clinical success. CPPs efficiently penetrate cell membranes, even when linked to antigenic cargos, which can induce both CD8 and CD4 T-cell responses. Pre-clinical studies demonstrated that targeting multiple tumor antigens, even those considered to be poorly immunogenic, led to tumor regression. Therefore, CPP-based cancer vaccines represent a flexible and powerful means to extend therapeutic vaccination to many cancer indications. Here, we review recent findings in CPP development and discuss their use in next generation immunotherapies.
Wu, Chao-Chih; Wu, Fang-Cih; Hsu, Yun-Tin; Hsiao, Yu-Chia; Yang, Yuh-Cheng; Chang, C Allen; Chang, Chih-Long
B-cell-activating factor (BAFF) belongs to the tumor necrosis factor family that not only stimulates B and T cells but also counteracts immune tolerance. BAFF is also a type II membrane protein, which is secreted through the endoplasmic reticulum (ER)-Golgi apparatus pathway. Fusing an antigen to BAFF might enhance the presentation of major histocompatibility complex class I molecules. These characteristics represent an opportunity to enhance the antitumor effects of DNA vaccines. Therefore, we fused BAFF to human papillomavirus type 16 E7 as a DNA vaccine and evaluated its antitumor effects. We found that this vaccine increased E7-specific CD8+ T-cell immune responses, engendered major antitumor effects against E7-expressing tumors, and prolonged the survival of the immunized mice. Interestingly, vaccinating B-cell-deficient mice with BAFF-E7 revealed considerable E7-specific CD8+ T-cell immune responses, suggesting that B cells do not contribute to this immune response. Image analysis through confocal fluorescence microscopy revealed that fusing BAFF to E7 targeted the protein to the ER, but not BAFF lacking 128 N-terminal residues that generated a lower number of E7-specific CD8+ T cells in the vaccinated mice. Our data indicated that the ER-targeting characteristic of BAFF is the main factor improving the potency of DNA vaccines.
Award Number: W81XWH-11-1-0531 TITLE: Radiation-Induced Vaccination to Breast Cancer PRINCIPAL INVESTIGATOR: William H. McBride CONTRACTING...TITLE AND SUBTITLE Radiation-Induced Vaccination to Breast Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-11-1-0531 5c. PROGRAM ELEMENT NUMBER 6...therapy to generate an in situ tumor vaccine and abscopal effects at distant tumor sites (13), giving some rationale for this attempt to examine this
Amelia Sadie Aitken
Full Text Available Vaccines have classically been used for disease prevention. Modern clinical vaccines are continuously being developed for both traditional use as well as for new applications. Typically thought of in terms of infectious disease control, vaccination approaches can alternatively be adapted as a cancer therapy. Vaccines targeting cancer antigens can be used to induce anti-tumour immunity and have demonstrated therapeutic efficacy both pre-clinically and clinically. Various approaches now exist and further establish the tremendous potential and adaptability of anti-cancer vaccination. Classical strategies include ex vivo-loaded immune cells, RNA- or DNA-based vaccines and tumour cell lysates. Recent oncolytic virus development has resulted in a surge of novel viruses engineered to induce powerful tumour-specific immune responses. In addition to their use as cancer vaccines, oncolytic viruses have the added benefit of being directly cytolytic to cancer cells and thus promote antigen recognition within a highly immune-stimulating tumour microenvironment. While oncolytic viruses are perfectly equipped for efficient immunization, this complicates their use upon previous exposure. Indeed, the host’s anti-viral counter-attacks often impair multiple-dosing regimens. In this review we will focus on the use of oncolytic viruses for anti-tumour vaccination. We will explore different strategies as well as ways to circumvent some of their limitations.
Clay, Timothy M; Osada, Takuya; Hartman, Zachary C; Hobeika, Amy; Devi, Gayathri; Morse, Michael A; Lyerly, H Kim
Aberrant signaling pathways are a hallmark of cancer. A variety of strategies for inhibiting signaling pathways have been developed, but monoclonal antibodies against receptor tyrosine kinases have been among the most successful. A challenge for these therapies is therapeutic unresponsiveness and acquired resistance due to mutations in the receptors, upregulation of alternate growth and survival pathways, or inadequate function of the monoclonal antibodies. Vaccines are able to induce polyclonal responses that can have a multitude of affects against the target molecule. We began to explore therapeutic vaccine development to antigens associated with these signaling pathways. We provide an illustrative example in developing therapeutic cancer vaccines inducing polyclonal adaptive immune responses targeting the ErbB family member HER2. Further, we will discuss new strategies to augment the clinical efficacy of cancer vaccines by enhancing vaccine immunogenicity and reversing the immunosuppressive tumor microenvironment.
Brashier, Dick B S; Sharma, Ashok Kumar; Akhoon, Neha
Drug Abuse has become a major challenging problem for the society. It effects people of all countries economical strata's and all ages. According. Monetary loss all over the world regarding drug abuse is in million dollars, it not only has an impact on human productivity and healthcare cost but also on cost of crimes conducted by these drugs and alcohol abuse. Therapeutic vaccine has come as new approach to deal with this problem, after failures in search for a pharmaceutical agent to deal with drug of abuse and alcohol. Research in field of nicotine abuse has gone a way ahead with number of vaccines being tried clinically followed by cocaine, opioids, methamphetamine, phencyclidine and alcohol. All of them have a common mechanism of action by antibody production whereas alcohol acts by genetic intervention. None have being approved yet due to poor results in phase II trials, possibly due to not able to trigger an adequate immunological response. But still quest is on for cracking the ice by developing first successful vaccine against drug of abuse, that would follow for other drugs too. It would be great step in field of therapeutic vaccines for drug abuse after similar successful vaccines being approved for other diseases like cancer.
Schreiber, Taylor H; Raez, Luis; Rosenblatt, Joseph D; Podack, Eckhard R
Despite enormous effort, promising pre-clinical data in animal studies and over 900 clinical trials in the United States, no cancer vaccine has ever been approved for clinical use. Over the past decade a great deal of progress has been in both laboratory and clinical studies defining the interactions between developing tumors and the immune system. The results of these studies provide a rationale that may help explain the failure of recent therapeutic cancer vaccines in terms of vaccine principles, in selecting which tumors are the most appropriate to target and instruct the design and implementation of state-of-the-art cancer vaccines. Copyright 2010 Elsevier Ltd. All rights reserved.
Pontes, Jéssica Etienne Dourado; Tabet, Elaine; Folkmann, Maria Áurea dos Santos; Cunha, Mariana Lucas da Rocha; Almeida, Fabiane de Amorim
ABSTRACT Objective: To identify and compare behaviors of children during vaccination, who were prepared or not for the procedure using an instructional therapeutic play. Methods: A quasi experimental study, with quantitative approach of 60 children aged 3 to 6 years. The child's reactions were recorded in a checklist. Data were analyzed using descriptive and inferential statistics and Fisher's test. Results: The main reactions in the experimental group were stay still (25;83%) and spontaneously collaborate (24;80%). In the control group, the main reactions were cries and cling to parents (15; 50%), flushing (11;36.67%) and moving the body/agitated (10;33.3%). Conclusion: The reactions of cooperation were more frequent in the experimental group, while low acceptance was observed only in the control group. Therapeutic play has proved an important tool in preparing for the vaccine. PMID:26154545
The characteristics of two prophylactic Human Papilloma Virus HPV vaccines and ethical issues related to HPV vaccination are reviewed in this paper. These vaccines have the potential of substantially reducing HPV-related morbidity and mortality, and in particular cervical cancer. The vaccines cannot treat women with current HPV infection or HPV related disease. They should be administered before the commencement of sexual activity. The ideal age group is adolescent girls between the ages 9-13. Both vaccines are highly efficacious and immunogenic and induce high levels of serum antibodies after three doses for all vaccine-related HPV types. School-based vaccination is considered as a costeffective method for its delivery. Adequate education of both clinicians and patients is an essential to ensure effective implementation when considering a national vaccination program. (author)
Garnett, Charlie T; Greiner, John W; Tsang, Kwong-Yok; Kudo-Saito, Chie; Grosenbach, Douglas W; Chakraborty, Mala; Gulley, James L; Arlen, Philip M; Schlom, Jeffrey; Hodge, James W
For the immune system to mount an effective antitumor T-cell response, an adequate number of T-cells specific for the antigens expressed by the malignancy must be activated . Since most antigens expressed by tumors are "self"-antigens, tumor antigens often lack endogenous immunogenicity and thus do not sufficiently activate T-cells to levels that can mediate tumor eradication. In addition, virtually all solid tumor cells lack the costimulatory molecules necessary to activate tumor-specific T-cells. Approaches that stimulate immune responses to these tumor antigens have the potential to alter this poor responsiveness. This theory has promoted the use of active immunotherapy to generate immune responses against tumor-associated antigens (TAAs) for the treatment of cancer. As one such vaccine strategy, we have utilized poxviruses as delivery vehicles for TAAs in combination with T-cell costimulatory molecules. Initial studies have demonstrated that the insertion of costimulatory molecule trangenes into viral vectors, along with a TAA transgene, greatly enhances the immune response to the antigen. Using this approach, a TRIad of COstimulatory Molecules (TRICOM; B7-1, ICAM-1 and LFA-3) has been shown to enhance T-cell responses to TAAs to levels far greater than any one or two of the costimulatory molecules in combination. In this article, preclinical findings and recent clinical applications of TRICOM-based vaccines as a cancer immunotherapy are reviewed.
Comber, Joseph D; Philip, Ramila
Major histocompatibility complex class I (MHC-I) presented peptide epitopes provide a 'window' into the changes occurring in a cell. Conventionally, these peptides are generated by proteolysis of endogenously synthesized proteins in the cytosol, loaded onto MHC-I molecules, and presented on the cell surface for surveillance by CD8(+) T cells. MHC-I restricted processing and presentation alerts the immune system to any infectious or tumorigenic processes unfolding intracellularly and provides potential targets for a cytotoxic T cell response. Therefore, therapeutic vaccines based on MHC-I presented peptide epitopes could, theoretically, induce CD8(+) T cell responses that have tangible clinical impacts on tumor eradication and patient survival. Three major methods have been used to identify MHC-I restricted epitopes for inclusion in peptide-based vaccines for cancer: genetic, motif prediction and, more recently, immunoproteomic analysis. Although the first two methods are capable of identifying T cell stimulatory epitopes, these have significant disadvantages and may not accurately represent epitopes presented by a tumor cell. In contrast, immunoproteomic methods can overcome these disadvantages and identify naturally processed and presented tumor associated epitopes that induce more clinically relevant tumor specific cytotoxic T cell responses. In this review, we discuss the importance of using the naturally presented MHC-I peptide repertoire in formulating peptide vaccines, the recent application of peptide-based vaccines in a variety of cancers, and highlight the pros and cons of the current state of peptide vaccines.
Award Number: W81XWH-11-1-0531 TITLE: Radiation-Induced Vaccination to Breast Cancer PRINCIPAL INVESTIGATOR: William H. McBride CONTRACTING...FORM TO THE ABOVE ADDRESS. 1. REPORT DATE 2. REPORT TYPE Annual 3. DATES COVERED (From - To) 4. TITLE AND SUBTITLE Radiation-Induced Vaccination to...determine abscopal responses that are hypothesized to be due to RT- induced vaccination . RT was started 10 days after the first and 3rd dose of
Morse, Michael A; Lyerly, H Kim
Checkpoint blockade, prevention of inhibitory signaling that limits activation or function of tumor antigen-specific T cells responses, is revolutionizing the treatment of many poor prognosis malignancies. Indeed monoclonal antibodies that modulate signaling through the inhibitory molecules CTLA-4 and PD-1 are now clinically available; however, many tumors, demonstrate minimal response suggesting the need for combinations with other therapeutic strategies. Because an inadequate frequency of activated tumor antigen-specific T cells in the tumor environment, the so-called non-inflamed phenotype, is observed in some malignancies, other rationale partners are modalities that lead to enhanced T cell activation (vaccines, cytokines, toll-like receptor agonists, and other anticancer therapies such as chemo-, radio- or targeted therapies that lead to release of antigen from tumors). This review will focus on preclinical and clinical data supporting the use of cancer vaccines with anti-CTLA-4 and anti-PD-1/PD-L1 antibodies. Preliminary preclinical data demonstrate enhanced antitumor activity although the results in human studies are less clear. Broader combinations of multiple immune modulators are now under study. Copyright © 2015 Elsevier Ltd. All rights reserved.
Gray, Joe W.; Guan, Yinghui; Kuo, Wen-Lin; Fridlyand, Jane; Mills, Gordon B.
Cancer markers may be developed to detect diseases characterized by increased expression of apoptosis-suppressing genes, such as aggressive cancers. Genes in the human chromosomal regions, 8q24, 11q13, 20q11-q13, were found to be amplified indicating in vivo drug resistance in diseases such as ovarian cancer. Diagnosis and assessment of amplification levels certain genes shown to be amplified, including PVT1, can be useful in prediction of poor outcome of patient's response and drug resistance in ovarian cancer patients with low survival rates. Certain genes were found to be high priority therapeutic targets by the identification of recurrent aberrations involving genome sequence, copy number and/or gene expression are associated with reduced survival duration in certain diseases and cancers, specifically ovarian cancer. Therapeutics to inhibit amplification and inhibitors of one of these genes, PVT1, target drug resistance in ovarian cancer patients with low survival rates is described.
Payne, Richard; McDonald, David; Byrne, Scott
Due to changes in glycosyltransferase expression during tumorigenesis, the glycoproteins of cancer cells often carry highly truncated carbohydrate chains compared to those on healthy cells. These glycans are known as tumor-associated carbohydrate antigens, and are prime targets for use in vaccines for the prevention and treatment of cancer. Herein, we review the state-of-the-art in targeting the immune system towards tumor-associated glycopeptide antigens via synthetic self adjuvanting vaccines, in which the antigenic and adjuvanting moieties of the vaccines are present in the same molecule. The majority of the self-adjuvanting glycopeptide cancer vaccines reported to date employ antigens from mucin 1, a protein which is highly over-expressed and aberrantly glycosylated in many forms of cancer. The adjuvants used in these vaccines predominantly include lipopeptide- or lipoamino acid-based TLR2 agonists, although studies investigating stimulation of TLR9 and TLR4 are also discussed. Most of these adjuvants are highly lipophilic, and, upon conjugation to antigenic peptides, provide amphiphilic vaccine molecules. The amphiphilic nature of these vaccine constructs can lead to the formation of higher-order structures by vaccines in solution, which are likely to be important for their efficacy in vivo.
Two researchers leveraged CCR’s unique environment of investigator-driven inquiry to pursue studies of two cancer-causing genes that eventually led to the development of a vaccine against two forms of human papillomavirus.
Full Text Available Chikungunya virus (CHIKV has come to prominence as a global, re-emerging pathogen over the last two decades, progressing from sporadic, remote outbreaks to worldwide explosive epidemics. From contained, though considerable, outbreaks in the southern Indian Ocean, parts of South America and the Caribbean, CHIKV continues to be a significant pathogen in Southeast Asia and India. CHIKV circulates during epidemics through an urban mosquito-to-human transmission cycle, and with no available treatments or licensed vaccines to specifically target CHIKV disease, limiting transmission relies on vector control, which poses significant challenges, especially in developing countries. This review summarizes the current findings and progress in the development of safe, effective and affordable therapeutics and vaccines for CHIKV disease.
Full Text Available Persistent infection with high-risk human papillomavirus (HPV types, most often HPV16 and HPV18, causes all cervical and most anal cancers, and a subset of vulvar, vaginal, penile and oropharyngeal carcinomas. Two prophylactic virus-like particle (VLPs-based vaccines, are available that protect against vaccine type-associated persistent infection and associated disease, yet have no therapeutic effect on existing lesions or infections. We have generated recombinant live-attenuated influenza A viruses expressing the HPV16 oncogenes E6 and E7 as experimental immunotherapeutic vaccine candidates. The influenza A virus life cycle lacks DNA intermediates as important safety feature. Different serotypes were generated to ensure efficient prime and boost immunizations. The immune response to vaccination in C57BL/6 mice was characterized by peptide ELISA and IFN-γ ELISpot, demonstrating induction of cell-mediated immunity to HPV16 E6 and E7 oncoproteins. Prophylactic and therapeutic vaccine efficacy was analyzed in the murine HPV16-positive TC-1 tumor challenge model. Subcutaneous (s.c. prime and boost vaccinations of mice with recombinant influenza A serotypes H1N1 and H3N2, followed by challenge with TC-1 cells resulted in complete protection or significantly reduced tumor growth as compared to control animals. In a therapeutic setting, s.c. vaccination of mice with established TC-1 tumors decelerated tumor growth and significantly prolonged survival. Importantly, intralesional vaccine administration induced complete tumor regression in 25% of animals, and significantly reduced tumor growth in 50% of mice. These results suggest recombinant E6E7 influenza viruses as a promising new approach for the development of a therapeutic vaccine against HPV-induced disease.
Collins, Ian; Workman, Paul
Cancer drug development is leading the way in exploiting molecular biological and genetic information to develop "personalized" medicine. The new paradigm is to develop agents that target the precise molecular pathology driving the progression of individual cancers. Drug developers have benefited from decades of academic cancer research and from investment in genomics, genetics and automation; their success is exemplified by high-profile drugs such as Herceptin (trastuzumab), Gleevec (imatinib), Tarceva (erlotinib) and Avastin (bevacizumab). However, only 5% of cancer drugs entering clinical trials reach marketing approval. Cancer remains a high unmet medical need, and many potential cancer targets remain undrugged. In this review we assess the status of the discovery and development of small-molecule cancer therapeutics. We show how chemical biology approaches offer techniques for interconnecting elements of the traditional linear progression from gene to drug, thereby providing a basis for increasing speed and success in cancer drug discovery.
Full Text Available Breast cancer remains a major public health problem, being the second cause of cancer death in women. There is a marked tendency to restrict the extension of surgical gesture, which directly leads to two different attitudes: radical surgery and conservative surgery, to which, at least in our country, there are still some delays. Prospective and retrospective studies have shown that, in 20 years, conservative and radical therapy had about the same rate of survival and disease-free interval, at least for stage I and II breast cancer, the only real counterargument against conservative surgery being that, in principle, the higher rate of recurrence local constraint can be solved by postoperative radiotherapy. Finally, the survival rate is the main parameter of evaluation, assessing the effectiveness of the treatment in breast cancer, and in all its other forms.
Full Text Available Sperm protein (Sp17 is an attractive target for ovarian cancer (OC vaccines because of its over-expression in primary as well as in metastatic lesions, at all stages of the disease. Our studies suggest that a Sp17-based vaccine can induce an enduring defense against OC development in C57BL/6 mice with ID8 cells, following prophylactic and therapeutic treatments. This is the first time that a mouse counterpart of a cancer testis antigen (Sp17 was shown to be expressed in an OC mouse model, and that vaccination against this antigen significantly controlled tumor growth. Our study shows that the CpG-adjuvated Sp17 vaccine overcomes the issue of immunologic tolerance, the major barrier to the development of effective immunotherapy for OC. Furthermore, this study provides a better understanding of OC biology by showing that Th-17 cells activation and contemporary immunosuppressive T-reg cells inhibition is required for vaccine efficacy. Taken together, these results indicate that prophylactic and therapeutic vaccinations can induce long-standing protection against OC and delay tumor growth, suggesting that this strategy may provide additional treatments of human OC and the prevention of disease onset in women with a family history of OC.
Full Text Available Durante el desarrollo del cáncer cervicouterino se inducen mecanismos para evadir el sistema inmune, como son la disminución de la expresión de moléculas de antígeno mayor de histocompatibilidad I y la secreción de citocinas por las células tumorales. Como consecuencia de ello, la estimulación de linfocitos T citotóxicos (LTC y cooperadores (TC, de células asesinas naturales (AN y macrófagos es muy deficiente. Para inducir una respuesta inmune efectiva contra el tumor, se requiere la estimulación simultánea de múltiples componentes del sistema inmune: por vía sistémica la estimulación de LTC y TC contra epítopos del virus del papiloma humano, y en un nivel local, la inducción de la secreción de citocinas por el tumor, para aumentar el procesamiento y la presentación de blancos tumorales, así como la estimulación de los linfocitos, AN y macrófagos que infiltran el tumor.Several mechanisms to evade the immune system are induced during cervical cancer development, including the decrease of expression of class I HLA molecules and secretion of specific cytokines by tumoral cells. Consequently, the stimulation of cytotoxic (CTL and helper (TH T lymphocytes, as well as the natural killer (NK cells and macrophages is very poor. The induction of immune response against tumors needs the stimulation of multiple components of the immune system: systemic stimulation of CTL and TH against Human Papilloma Virus epitopes and directly in the tumor the secretion of specific cytokines to increase the antigen processing and presentation of tumoral targets, and the stimulation of lymphocyte, NK cells and macrophages that infiltrate tumors.
Megan A. McNamara
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.
Bitterman, Roni; Eliakim-Raz, Noa; Vinograd, Inbal; Zalmanovici Trestioreanu, Anca; Leibovici, Leonard; Paul, Mical
This is an update of the Cochrane review published in 2013, Issue 10.Immunosuppressed cancer patients are at increased risk of serious influenza-related complications. Guidelines, therefore, recommend influenza vaccination for these patients. However, data on vaccine effectiveness in this population are lacking, and the value of vaccination in this population remains unclear. To assess the effectiveness of influenza vaccine in immunosuppressed adults with malignancies. The primary review outcome is all-cause mortality, preferably at the end of the influenza season. Influenza-like illness (ILI, a clinical definition), confirmed influenza, pneumonia, any hospitalisations, influenza-related mortality and immunogenicity were defined as secondary outcomes. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and LILACS databases up to May 2017. We searched the following conference proceedings: ICAAC, ECCMID, IDSA (infectious disease conferences), ASH, ASBMT, EBMT (haematological), and ASCO (oncological) between the years 2006 to 2017. In addition, we scanned the references of all identified studies and pertinent reviews. We searched the websites of the manufacturers of influenza vaccine. Finally, we searched for ongoing or unpublished trials in clinical trial registry databases. Randomised controlled trials (RCTs), prospective and retrospective cohort studies and case-control studies were considered, comparing inactivated influenza vaccines versus placebo, no vaccination or a different vaccine, in adults (16 years and over) with cancer. We considered solid malignancies treated with chemotherapy, haematological cancer patients treated or not treated with chemotherapy, cancer patients post-autologous (up to six months after transplantation) or allogeneic (at any time) haematopoietic stem cell transplantation (HSCT). Two review authors independently assessed the risk of bias and extracted data from included studies adhering to Cochrane
Farsaci, Benedetto; Donahue, Renee N.; Coplin, Michael A.; Grenga, Italia; Lepone, Lauren M.; Molinolo, Alfredo A.; Hodge, James W.
This study investigated the effects on the tumor microenvironment of combining antiangiogenic tyrosine kinase inhibitors (TKI) with therapeutic vaccines, and in particular, how vascular changes affect tumor-infiltrating immune cells. We conducted studies using a TKI (sunitinib or sorafenib) in combination with recombinant vaccines in 2 murine tumor models: colon carcinoma (MC38-CEA) and breast cancer (4T1). Tumor vasculature was measured by immunohistochemistry using 3 endothelial cell markers: CD31 (mature), CD105 (immature/proliferating), and CD11b (monocytic). We assessed oxygenation, tight junctions, compactness, and pressure within tumors, along with the frequency and phenotype of tumor-infiltrating T lymphocytes (TIL), myeloid-derived suppressor cells (MDSC), and tumor-associated macrophages (TAM) following treatment with antiangiogenic TKIs alone, vaccine alone, or the combination of a TKI with vaccine. The combined regimen decreased tumor vasculature, compactness, tight junctions, and pressure, leading to vascular normalization and increased tumor oxygenation. This combination therapy also increased TILs, including tumor antigen-specific CD8 T cells, and elevated the expression of activation markers FAS-L, CXCL-9, CD31, and CD105 in MDSCs and TAMs, leading to reduced tumor volumes and an increase in the number of tumor-free animals. The improved antitumor activity induced by combining antiangiogenic TKIs with vaccine may be the result of activated lymphoid and myeloid cells in the tumor microenvironment, resulting from vascular normalization, decreased tumor-cell density, and the consequent improvement in vascular perfusion and oxygenation. Therapies that alter tumor architecture can thus have a dramatic impact on the effectiveness of cancer immunotherapy. PMID:25092771
Guindon, Josée; Hohmann, Andrea G
The endocannabinoid system is implicated in a variety of physiological and pathological conditions (inflammation, immunomodulation, analgesia, cancer and others). The main active ingredient of cannabis, Δ(9) -tetrahydrocannabinol (Δ(9) -THC), produces its effects through activation of CB(1) and CB(2) receptors. CB(1) receptors are expressed at high levels in the central nervous system (CNS), whereas CB(2) receptors are concentrated predominantly, although not exclusively, in cells of the immune system. Endocannabinoids are endogenous lipid-signalling molecules that are generated in the cell membrane from phospholipid precursors. The two best characterized endocannabinoids identified to date are anandamide (AEA) and 2-arachidonoylglycerol (2-AG). Here we review the relationship between the endocannabinoid system and anti-tumour actions (inhibition of cell proliferation and migration, induction of apoptosis, reduction of tumour growth) of the cannabinoids in different types of cancer. This review will focus on examining how activation of the endocannabinoid system impacts breast, prostate and bone cancers in both in vitro and in vivo systems. The therapeutic potential of cannabinoids for cancer, as identified in clinical trials, is also discussed. Identification of safe and effective treatments to manage and improve cancer therapy is critical to improve quality of life and reduce unnecessary suffering in cancer patients. In this regard, cannabis-like compounds offer therapeutic potential for the treatment of breast, prostate and bone cancer in patients. Further basic research on anti-cancer properties of cannabinoids as well as clinical trials of cannabinoid therapeutic efficacy in breast, prostate and bone cancer is therefore warranted. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.
Klonisch, Thomas; Wiechec, Emilia; Hombach-Klonisch, Sabine
Rapid advance in the cancer stem cell field warrants optimism for the development of more reliable cancer therapies within the next 2-3 decades. Below, we characterize and compare the specific markers that are present on stem cells, cancer cells and cancer stem cells (CSC) in selected tissues...... (colon, breast, liver, pancreas, and prostate). It is becomingevident that successful cancer therapies have to eradicate CSC. Thus, strategies aimed at efficient targeting of CSC are becoming vital for monitoring the progress of cancer therapy and evaluating new therapeutic approaches. Therefore...
Ip, P. P.; Boerma, A.; Walczak, M.; Oosterhuis, K.; Haanen, J. B.; Schumacher, T. N.; Nijman, H. W.; Daemen, T.
Cellular immunity against cancer can be achieved with viral vector-and DNA-based immunizations. In preclinical studies, cancer vaccines are very potent, but in clinical trials these potencies are not achieved yet. Thus, a rational approach to improve cancer vaccines is warranted. We previously
Berntsen, A.; Trepiakas, R.; Wenandy, L.
Therapeutic dendritic cell (DC) vaccination against cancer is a strategy aimed at activating the immune system to recognize and destroy tumor cells. In this nonrandomized phase 1/2 trial, we investigated the safety, feasibility, induction of T-cell response, and clinical response after treatment...... with a DC- based vaccine in patients with metastatic renal cell carcinoma. Twenty-seven patients with progressive cytokine-refractory metastatic renal cell carcinoma were vaccinated with DCs loaded with either a cocktail of survivin and telomerase peptides or tumor lysate depending on their HLA-A2 haplotype......, and low-dose IL-2 was administered concomitantly. Tumor response, immune response, and serum IL-6 and YKL-40 were measured during treatment. Vaccine generation was Successful in all patients and no serious adverse events were observed. None of the patients had an objective response but 13/27 patients...
Draghiciu, Oana; Boerma, Annemarie; Hoogeboom, Baukje Nynke; Nijman, Hans W.; Daemen, Toos
The clinical efficacy of therapeutic cancer vaccines remains limited. For effective immunotherapeutic responses in cancer patients, multimodal approaches capable of both inducing antitumor immune responses and bypassing tumor-mediated immune escape seem essential. Here, we report on a combination
Renaissance Eden Roc Beach Resort & Spa Miami Beach, FL Conference Co-Chairpersons: Olivera J. Finn University of Pittsburgh School of Medicine, Pittsburgh...150- pair case-control cohort. The cases (progression to systemic disease within five years of surgery ) and controls (no progression within seven...Loyola University Chicago, Stritch School of Medicine, Department of Cell Biology, Neurobiology and Anatomy and Department of Surgery , Maywood, IL
Kelleher, Fergal C
OBJECTIVE: To conduct a systematic review of the role that the hedgehog signaling pathway has in pancreatic cancer tumorigenesis. METHOD: PubMed search (2000-2010) and literature based references. RESULTS: Firstly, in 2009 a genetic analysis of pancreatic cancers found that a core set of 12 cellular signaling pathways including hedgehog were genetically altered in 67-100% of cases. Secondly, in vitro and in vivo studies of treatment with cyclopamine (a naturally occurring antagonist of the hedgehog signaling pathway component; Smoothened) has shown that inhibition of hedgehog can abrogate pancreatic cancer metastasis. Thirdly, experimental evidence has demonstrated that sonic hedgehog (Shh) is correlated with desmoplasia in pancreatic cancer. This is important because targeting the Shh pathway potentially may facilitate chemotherapeutic drug delivery as pancreatic cancers tend to have a dense fibrotic stroma that extrinsically compresses the tumor vasculature leading to a hypoperfusing intratumoral circulation. It is probable that patients with locally advanced pancreatic cancer will derive the greatest benefit from treatment with Smoothened antagonists. Fourthly, it has been found that ligand dependent activation by hedgehog occurs in the tumor stromal microenvironment in pancreatic cancer, a paracrine effect on tumorigenesis. Finally, in pancreatic cancer, cells with the CD44+CD24+ESA+ immunophenotype select a population enriched for cancer initiating stem cells. Shh is increased 46-fold in CD44+CD24+ESA+ cells compared with normal pancreatic epithelial cells. Medications that destruct pancreatic cancer initiating stem cells are a potentially novel strategy in cancer treatment. CONCLUSIONS: Aberrant hedgehog signaling occurs in pancreatic cancer tumorigenesis and therapeutics that target the transmembrane receptor Smoothened abrogate hedgehog signaling and may improve the outcomes of patients with pancreatic cancer.
de Goede, A L; Vulto, A G; Osterhaus, A D M E; Gruters, R A
HIV infection leads to a gradual loss CD4(+) T lymphocytes comprising immune competence and progression to AIDS. Effective treatment with combined antiretroviral drugs (cART) decreases viral load below detectable levels but is not able to eliminate the virus from the body. The success of cART is frustrated by the requirement of expensive lifelong adherence, accumulating drug toxicities and chronic immune activation resulting in increased risk of several non-AIDS disorders, even when viral replication is suppressed. Therefore, there is a strong need for therapeutic strategies as an alternative to cART. Immunotherapy, or therapeutic vaccination, aims to increase existing immune responses against HIV or induce de novo immune responses. These immune responses should provide a functional cure by controlling viral replication and preventing disease progression in the absence of cART. The key difficulty in the development of an HIV vaccine is our ignorance of the immune responses that control of viral replication, and thus how these responses can be elicited and how they can be monitored. Part one of this review provides an extensive overview of the (patho-) physiology of HIV infection. It describes the structure and replication cycle of HIV, the epidemiology and pathogenesis of HIV infection and the innate and adaptive immune responses against HIV. Part two of this review discusses therapeutic options for HIV. Prevention modalities and antiretroviral therapy are briefly touched upon, after which an extensive overview on vaccination strategies for HIV is provided, including the choice of immunogens and delivery strategies. Copyright © 2014. Published by Elsevier Masson SAS.
Fu, Biao; Huang, Xiaomei; Deng, Jiaqi; Gu, Daijiao; Mei, Qibing; Deng, Mingming; Tang, Shixiao; Lü, Muhan
Tumor immunotherapy has been in development for more than a century. With the rapid developments in biotechnology research in recent years, immunotherapy has become a promising oncotherapy strategy after surgery, chemotherapy and radiotherapy. Cancer vaccines are a promising new treatment strategy and the application of nanotechnology in cancer vaccines, greatly enhances their effectiveness. Such applications indicate the bright prospects of tumor immunotherapy. The multifunctional nanomaterials used in cancer vaccines and their practical application in specific cancer vaccines are hereby reviewed. In addition, a preliminary analysis of the current and prospective use of nanotechnology with the purpose of providing solutions to cancer vaccine challenges is presented.
Postow, Michael; Callahan, Margaret K; Wolchok, Jedd D
Despite significant scientific knowledge in the field of cancer immunology, therapeutic strategies using cancer vaccines to generate anti-tumor immunity have historically resulted in only modest clinical benefit. Disappointing results from prior cancer vaccine trials are likely due to multifactorial causes. Perhaps the most important is the role of inherent tumor-induced immune suppression and enhanced immunologic tolerance. Current research directed toward understanding the mechanisms of immunologic tolerance has led to the development of promising therapeutic immune regulatory antibodies that inhibit immunologic checkpoints and subsequently enhance immunologic anti-tumor activity. This review discusses the prior challenges associated with cancer vaccines and describes how, by breaking immune inhibition and facilitating immune stimulation, immune regulatory antibodies show great promise in the treatment of a variety of tumors.
Patel, Sunny C; Lee, Stephen; Lalwani, Gaurav; Suhrland, Cassandra; Chowdhury, Sayan Mullick; Sitharaman, Balaji
Graphene is a multifunctional carbon nanomaterial and could be utilized to develop platform technologies for cancer therapies. Its surface can be covalently and noncovalently functionalized with anticancer drugs and functional groups that target cancer cells and tissue to improve treatment efficacies. Furthermore, its physicochemical properties can be harnessed to facilitate stimulus responsive therapeutics and drug delivery. This review article summarizes the recent literature specifically focused on development of graphene technologies to treat cancer. We will focus on advances at the interface of graphene based drug/gene delivery, photothermal/photodynamic therapy and combinations of these techniques. We also discuss the current understanding in cytocompatibility and biocompatibility issues related to graphene formulations and their implications pertinent to clinical cancer management. PMID:26769305
Goossen, Ginette M.; Kremer, Leontien C. M.; van de Wetering, Marianne D.
Influenza infection is a potential cause of severe morbidity in children with cancer, therefore vaccination against influenza is recommended. However, there are conflicting data concerning the immune response to influenza vaccination in children with cancer and the value of vaccination remains
Goossen, Ginette M.; Kremer, Leontien C. M.; van de Wetering, Marianne D.
Influenza infection is a potential cause of severe morbidity in children with cancer; therefore vaccination against influenza is recommended. However, data are conflicting regarding the immune response to influenza vaccination in children with cancer, and the value of vaccination remains unclear. 1.
To investigate vaccination with apoptosis colorectal cancer (CRC) cell pulsed autologous dendritic cells (DCs) in advanced CRC, 14 patients with advanced colorectal cancer (CRC) were enrolled and treated with DCs vaccine to assess toxicity, tolerability, immune and clinical responses to the vaccine. No severe toxicity ...
Technical advances that has been achieved during the past two decades have not dramatically improved the 35 % five-year rate observed in patients with colorectal cancer. These tumours remain one of the most challenging problems in public health policies in western countries. Screening applies to some subgroups of high-risk individuals and the general population aged over 50. In order to improve their efficacy, such screening programs imply large-scale information campaigns and a strong cooperation with the general physicians. The diagnosis is strongly suggested by any recent modification of bowel habits ad by rectal bleeding. It has to be confirmed by rectal examination and by colonoscopy which allows sampling to the tumour. Loco-regional and distant metastatic tumour spread must be assessed precisely before any therapeutic strategy is decided. Surgery, which resects the tumour en bloc with the corresponding lymphatic territories, is the only treatment that can achieve long term cure. In localized tumours, surgery alone can provide patients with 5-years survival rates close to 95 %. On the other hand, surgery alone is not sufficient to cure patients with advances cancers. In recent years, several adjuvant therapeutic modalities have been shown to improve the results of surgery in these cases (rectal cancer: pre-operative radiotherapy or post-operative radio-chemotherapy, colon cancer with nodal metastases: post-operative chemotherapy). There is a hope that a better use of our diagnostic and therapeutic armementarium would be able to avoid or to cure up to 75 % of the colorectal cancers we are dealing with. (author)
performed with SP6 RNA polymerase (mMessage mMachine SP6 kit; Ambion). Agarose gel electrophoresis confirmed production of full-length capped mRNA, and...therefore offers a promising strategy to improve vaccine efficacy. The rational design of therapeutic cancer vaccines using this approach mandates a...Materials and Methods Human blood samples Collection and use of
Xu, Wen; Rush, Jack; Rickett, Kirsty; Coward, Jermaine I G
Mucinous ovarian cancer represents approximately 3% of epithelial ovarian cancers (EOC). Despite this seemingly low prevalence, it remains a diagnostic and therapeutic conundrum that has resulted in numerous attempts to adopt novel strategies in managing this disease. Anecdotally, there has been a prevailing notion that established gold standard systemic regimens should be substituted for those utilised in cancers such as gastrointestinal (GI) malignancies; tumours that share more biological similarities than other EOC subtypes. This review summarises the plethora of small studies which have adopted this philosophy and influenced the design of the multinational GOG142 study, which was ultimately terminated due to poor accrual. To date, there is a paucity of evidence to support delivering 'GI style' chemotherapy for mucinous ovarian cancer over and above carboplatin-paclitaxel doublet therapy. Hence there is an urge to develop studies focused on targeted therapeutic agents driven by refined mutational analysis and conducted within the context of harmonised international collaborations. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
HPV) vaccination, as well as the information provided, methods of obtaining consent and assent, and completion rates achieved. Methods. Information on cervical cancer and HPV vaccination was provided to 19 primary schools in Western Cape ...
Brinkman, J A; Caffrey, A S; Muderspach, L I; Roman, L D; Kast, W M
Cervical cancer is the second most common cause of cancer-related deaths in women worldwide. Screening for cervical cancer is accomplished utilizing a Pap smear and pelvic exam. While this technology is widely available and has reduced cervical cancer incidence in industrialized nations, it is not readily available in third world countries in which cervical cancer incidence and mortality is high. Development of cervical cancer is associated with infection with high risk types of human papillomavirus (HPV) creating a unique opportunity to prevent or treat cervical cancer through anti-viral vaccination strategies. Several strategies have been examined in clinical trials for both the prevention of HPV infection and the treatment of pre-existing HPV-related disease. Clinical trials utilizing prophylactic vaccines containing virus-like particles (VLPs) indicate good vaccine efficacy and it is predicted that a prophylactic vaccine may be available within the next five years. But, preclinical research in this area continues in order to deal with issues such as cost of vaccination in underserved third world populations. A majority of clinical trials using therapeutic agents which aim to prevent the progression of pre-existing HPV associated lesions or cancers have shown limited efficacy in eradicating established tumors in humans possibly due to examining patients with more advanced-stage cancer who tend to have decreased immune function. Future trends in clinical trials with therapeutic agents will examine patients with early stage cancers or pre-invasive lesions in order to prevent invasive cervical cancer. Meanwhile, preclinical studies in this field continue and include the further exploration of peptide or protein vaccination, and the delivery of HPV antigens in DNA-based vaccines or in viral vectors. Given that cervical cancers are caused by the human papillomavirus, the prospect of therapeutic vaccination to treat existing lesions and prophylactic vaccination to
Yallapu, Murali M.; Jaggi, Meena; Chauhan, Subhash C.
Cancer is the second leading cause of death in the United States. Conventional therapies cause widespread systemic toxicity and lead to serious side effects which prohibit their long term use. Additionally, in many circumstances tumor resistance and recurrence is commonly observed. Therefore, there is an urgent need to identify suitable anticancer therapies that are highly precise with minimal side effects. Curcumin is a natural polyphenol molecule derived from the Curcuma longa plant which exhibits anticancer, chemo-preventive, chemo- and radio-sensitization properties. Curcumin’s widespread availability, safety, low cost and multiple cancer fighting functions justify its development as a drug for cancer treatment. However, various basic and clinical studies elucidate curcumin’s limited efficacy due to its low solubility, high rate of metabolism, poor bioavailability and pharmacokinetics. A growing list of nanomedicine(s) using first line therapeutic drugs have been approved or are under consideration by the Food and Drug Administration (FDA) to improve human health. These nanotechnology strategies may help to overcome challenges and ease the translation of curcumin from bench to clinical application. Prominent research is reviewed which shows that advanced drug delivery of curcumin (curcumin nanoformulations or curcumin nanomedicine) is able to leverage therapeutic benefits by improving bioavailability and pharmacokinetics which in turn improves binding, internalization and targeting of tumor(s). Outcomes using these novel drug delivery systems have been discussed in detail. This review also describes the tumor-specific drug delivery system(s) that can be highly effective in destroying tumors. Such new approaches are expected to lead to clinical trials and to improve cancer therapeutics. PMID:23116309
Li, Lijin; Goedegebuure, Peter; Mardis, Elaine R.; Ellis, Matthew J.C.; Zhang, Xiuli; Herndon, John M.; Fleming, Timothy P.; Carreno, Beatriz M.; Hansen, Ted H.; Gillanders, William E.
New DNA sequencing platforms have revolutionized human genome sequencing. The dramatic advances in genome sequencing technologies predict that the $1,000 genome will become a reality within the next few years. Applied to cancer, the availability of cancer genome sequences permits real-time decision-making with the potential to affect diagnosis, prognosis, and treatment, and has opened the door towards personalized medicine. A promising strategy is the identification of mutated tumor antigens, and the design of personalized cancer vaccines. Supporting this notion are preliminary analyses of the epitope landscape in breast cancer suggesting that individual tumors express significant numbers of novel antigens to the immune system that can be specifically targeted through cancer vaccines
William E. Gillanders
Full Text Available New DNA sequencing platforms have revolutionized human genome sequencing. The dramatic advances in genome sequencing technologies predict that the $1,000 genome will become a reality within the next few years. Applied to cancer, the availability of cancer genome sequences permits real-time decision-making with the potential to affect diagnosis, prognosis, and treatment, and has opened the door towards personalized medicine. A promising strategy is the identification of mutated tumor antigens, and the design of personalized cancer vaccines. Supporting this notion are preliminary analyses of the epitope landscape in breast cancer suggesting that individual tumors express significant numbers of novel antigens to the immune system that can be specifically targeted through cancer vaccines.
Li, Lijin [Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110 (United States); Goedegebuure, Peter [Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110 (United States); The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, MO 63110 (United States); Mardis, Elaine R. [The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, MO 63110 (United States); The Genome Institute at Washington University School of Medicine, St. Louis, MO 63108 (United States); Ellis, Matthew J.C. [The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, MO 63110 (United States); Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110 (United States); Zhang, Xiuli; Herndon, John M. [Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110 (United States); Fleming, Timothy P. [Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110 (United States); The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, MO 63110 (United States); Carreno, Beatriz M. [The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, MO 63110 (United States); Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110 (United States); Hansen, Ted H. [The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, MO 63110 (United States); Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110 (United States); Gillanders, William E., E-mail: firstname.lastname@example.org [Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110 (United States); The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, MO 63110 (United States)
New DNA sequencing platforms have revolutionized human genome sequencing. The dramatic advances in genome sequencing technologies predict that the $1,000 genome will become a reality within the next few years. Applied to cancer, the availability of cancer genome sequences permits real-time decision-making with the potential to affect diagnosis, prognosis, and treatment, and has opened the door towards personalized medicine. A promising strategy is the identification of mutated tumor antigens, and the design of personalized cancer vaccines. Supporting this notion are preliminary analyses of the epitope landscape in breast cancer suggesting that individual tumors express significant numbers of novel antigens to the immune system that can be specifically targeted through cancer vaccines.
Fernández-Tejada, Alberto; Cañada, F Javier; Jiménez-Barbero, Jesús
Glycans are everywhere in biological systems, being involved in many cellular events with important implications for medical purposes. Building upon a detailed understanding of the functional roles of carbohydrates in molecular recognition processes and disease states, glycans are increasingly being considered as key players in pharmacological research. On the basis of the important progress recently made in glycochemistry, glycobiology, and glycomedicine, we provide a complete overview of successful applications and future perspectives of carbohydrates in the biopharmaceutical and medical fields. This review highlights the development of carbohydrate-based diagnostics, exemplified by glycan imaging techniques and microarray platforms, synthetic oligosaccharide vaccines against infectious diseases (e.g., HIV) and cancer, and finally carbohydrate-derived therapeutics, including glycomimetic drugs and glycoproteins. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Mair, Barbara; Kubicek, Stefan; Nijman, Sebastian M B
Epigenetic deregulation is a hallmark of cancer, and there has been increasing interest in therapeutics that target chromatin-modifying enzymes and other epigenetic regulators. The rationale for applying epigenetic drugs to treat cancer is twofold. First, epigenetic changes are reversible, and drugs could therefore be used to restore the normal (healthy) epigenetic landscape. However, it is unclear whether drugs can faithfully restore the precancerous epigenetic state. Second, chromatin regulators are often mutated in cancer, making them attractive drug targets. However, in most instances it is unknown whether cancer cells are addicted to these mutated chromatin proteins, or whether their mutation merely results in epigenetic instability conducive to the selection of secondary aberrations. An alternative incentive for targeting chromatin regulators is the exploitation of cancer-specific vulnerabilities, including synthetic lethality, caused by epigenetic deregulation. We review evidence for the hypothesis that mechanisms other than oncogene addiction are a basis for the application of epigenetic drugs, and propose future research directions. Copyright © 2014 Elsevier Ltd. All rights reserved.
Kitagawa, Koichi; Oda, Tsugumi; Saito, Hiroki; Araki, Ayame; Gonoi, Reina; Shigemura, Katsumi; Hashii, Yoshiko; Katayama, Takane; Fujisawa, Masato; Shirakawa, Toshiro
Several types of vaccine-delivering tumor-associated antigens (TAAs) have been developed in basic and clinical research. Wilms' tumor 1 (WT1), identified as a gene responsible for pediatric renal neoplasm, is one of the most promising TAA for cancer immunotherapy. Peptide and dendritic cell-based WT1 cancer vaccines showed some therapeutic efficacy in clinical and pre-clinical studies but as yet no oral WT1 vaccine can be administrated in a simple and easy way. In the present study, we constructed a novel oral cancer vaccine using a recombinant Bifidobacterium longum displaying WT1 protein. B. longum 420 was orally administered into mice inoculated with WT1-expressing tumor cells for 4 weeks to examine anti-tumor effects. To analyze the WT1-specific cellular immune responses to oral B. longum 420, mice splenocytes were isolated and cytokine production and cytotoxic activities were determined. Oral administrations of B. longum 420 significantly inhibited WT1-expressing tumor growth and prolonged survival in mice. Immunohistochemical study and immunological assays revealed that B. longum 420 substantially induced tumor infiltration of CD4 + T and CD8 + T cells, systemic WT1-specific cytokine production, and cytotoxic activity mediated by WT1-epitope specific cytotoxic T lymphocytes, with no apparent adverse effects. Our novel oral cancer vaccine safely induced WT1-specific cellular immunity via activation of the gut mucosal immune system and achieved therapeutic efficacy with several practical advantages over existing non-oral vaccines.
Vaccine - HPV; Immunization - HPV; Gardasil; HPV2; HPV4; Vaccine to prevent cervical cancer; Genital warts - HPV vaccine; Cervical dysplasia - HPV vaccine; Cervical cancer - HPV vaccine; Cancer of the cervix - HPV vaccine; Abnormal ...
Shih, Ting-Yu; Blacklow, Serena O; Li, Aileen W; Freedman, Benjamin R; Bencherif, Sidi; Koshy, Sandeep T; Darnell, Max C; Mooney, David J
A covalently crosslinked methacrylated (MA)-alginate cryogel vaccine has been previously shown to generate a potent response against murine melanoma, but is not mechanically robust and requires a large 16G needle for delivery. Here, covalent and ionic crosslinking of cryogels are combined with the hypothesis that this will result in a tough MA-alginate cryogel with improved injectability. All tough cryogels can be injected through a smaller, 18G needle without sustaining any damage, while covalently crosslinked-only cryogels break after injection. Cytosine-phosphodiester-guanine (CpG)-delivering tough cryogels effectively activate dendritic cells (DCs). Granulocyte macrophage colony-stimulating factor releasing tough cryogels recruit four times more DCs than blank gels by day 7 in vivo. The tough cryogel vaccine induces strong antigen-specific cytotoxic T-lymphocyte and humoral responses. These vaccines prevent tumor formation in 80% of mice inoculated with HER2/neu-overexpressing DD breast cancer cells. The MA-alginate tough cryogels provide a promising minimally invasive delivery platform for cancer vaccinations. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Full Text Available Integrins are transmembrane receptors that are central to the biology of many human pathologies. Classically mediating cell-extracellular matrix and cell-cell interaction, and with an emerging role as local activators of TGFβ, they influence cancer, fibrosis, thrombosis and inflammation. Their ligand binding and some regulatory sites are extracellular and sensitive to pharmacological intervention, as proven by the clinical success of seven drugs targeting them. The six drugs on the market in 2016 generated revenues of some US$3.5 billion, mainly from inhibitors of α4-series integrins. In this review we examine the current developments in integrin therapeutics, especially in cancer, and comment on the health economic implications of these developments.
Idorn, Manja; Thor Straten, Per
Exercise improves functional capacity and patient-reported outcomes across a range of cancer diagnoses. The mechanisms behind this protection have been largely unknown, but exercise-mediated changes in body composition, sex hormone levels, systemic inflammation, and immune cell function have been suggested to play a role. We recently demonstrated that voluntary exercise leads to an influx of immune cells in tumors, and a more than 60% reduction in tumor incidence and growth across several mouse models. Given the common mechanisms of immune cell mobilization in mouse and man during exercise, we hypothesize that this link between exercise and the immune system can be exploited in cancer therapy in particular in combination with immunotherapy. Thus, we believe that exercise may not just be "healthy" but may in fact be therapeutic.
Luttjeboer, Jos; Setiawan, Didik; Cao, Qi; Daemen, Toos CAHH; Postma, Maarten J.
In this study, the potential price for a therapeutic vaccine against Human Papilloma Virus (HPV)-16 & 18 (pre)-malignant cervical lesions is examined. A decision tree model was built in the context of the new Dutch cervical cancer-screening program and includes a primary test for the presence of
Glycosylation changes are universal hallmarks of malignant transformation and tumour progression in human cancer, which take place on the whole cells or some specific molecules. Accordingly, those changes make them prominent candidates for cancer biomarkers in the meantime. This review mainly focuses on the ...
Anastasopoulou, Eleftheria A; Voutsas, Ioannis F; Papamichail, Michael; Baxevanis, Constantin N; Perez, Sonia A
Realizing the basis for generating long-lasting clinical responses in cancer patients after therapeutic vaccinations provides the means to further ameliorate clinical efficacy. Peptide cancer vaccines stimulating CD4(+) T helper cells are often promising for inducing immunological memory and persistent CD8(+) cytotoxic T cell responses. Recent reports from our clinical trial with the AE37 vaccine, which is a HER2 hybrid polypeptide, documented its efficacy to induce CD4(+) T cell immunity, which was associated with clinical improvements preferentially among HLA-DRB1*11(+) prostate cancer patients. Here, we performed in-depth investigation of the CD4(+) T cell response against the AE37 vaccine. We used the DR11/AE37 tetramer in combination with multicolor flow cytometry to identify and characterize AE37-specific CD4(+) T cells regarding memory and Tregs phenotype in HLA-DRB1*11(+) vaccinated patients. To verify vaccine-specific immunological memory in vivo, we also assessed AE37-specific CD4(+) T cells in defined CD4(+) memory subsets by cell sorting. Finally, vaccine-induced AE37-specific CD4(+) T cells were assessed regarding their functional profile. AE37-specific memory CD4(+) T cells could be detected in peptide-stimulated cultures from prostate cancer patients following vaccination even 4 y post-vaccination. The vast majority of vaccine-induced AE37-specific CD4(+) T cells exhibited a multifunctional, mostly Th1 cytokine signature, with the potential of granzyme B production. In contrast, we found relatively low frequencies of Tregs among AE37-specific CD4(+) T cells. This is the first report on the identification of vaccine-induced HER2-specific multifunctional long-lasting CD4(+) T cells in vaccinated prostate cancer patients.
Weinert, Brian T; Krishnadath, Kausilia K; Milano, Francesca
Tumor antigens are the primary target of therapeutic cancer vaccines. We set out to define and compare the expression pattern of tumor antigen genes in esophagus carcinoma biopsies and in an allogeneic tumor lysate-based cancer vaccine, MelCancerVac. Cells used for vaccine production were treated...... with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-aza-CdR) to determine whether this treatment could improve the profile of tumor antigen genes expressed in these cells. In addition, the presence of MAGE-A tumor antigen protein was evaluated in the purified tumor cell lysate used...
Batra, Surabhi; Adekola, Kehinde U A; Rosen, Steven T; Shanmugam, Mala
Cancer is now recognized to be a disease arising from both genetic and metabolic abnormalities. In the mid-1900s, Otto Warburg described the phenomenon of elevated glucose consumption and aerobic glycolysis, and the dependence of cancer cells on this phenomenon for proliferation and growth. The Warburg effect has formed the basis of such diagnostic and prognostic imaging modalities as positron emission tomography (PET); however, we have not yet capitalized on this phenomenon for therapy. Several mechanisms have now been shown to contribute to the Warburg effect.Ongoing studies are attempting to understand the reasons that tumor cells engage in aerobic glycolysis in lieu of oxidative phosphorylation, and the advantages that accrue to them as a result. In this review, we discuss known benefits to tumor cells from this metabolic switch, and we highlight key enzymes that play a role in aerobic glycolysis. We also describe novel therapeutic options targeting glucose metabolism and the importance of continuing to understand the metabolic plasticity of cancer.
Kuai, Rui; Ochyl, Lukasz J.; Bahjat, Keith S.; Schwendeman, Anna; Moon, James J.
Despite the tremendous potential of peptide-based cancer vaccines, their efficacy has been limited in humans. Recent innovations in tumour exome sequencing have signalled the new era of personalized immunotherapy with patient-specific neoantigens, but a general methodology for stimulating strong CD8α+ cytotoxic T-lymphocyte (CTL) responses remains lacking. Here we demonstrate that high-density lipoprotein-mimicking nanodiscs coupled with antigen (Ag) peptides and adjuvants can markedly improve Ag/adjuvant co-delivery to lymphoid organs and sustain Ag presentation on dendritic cells. Strikingly, nanodiscs elicited up to 47-fold greater frequencies of neoantigen-specific CTLs than soluble vaccines and even 31-fold greater than perhaps the strongest adjuvant in clinical trials (that is, CpG in Montanide). Moreover, multi-epitope vaccination generated broad-spectrum T-cell responses that potently inhibited tumour growth. Nanodiscs eliminated established MC-38 and B16F10 tumours when combined with anti-PD-1 and anti-CTLA-4 therapy. These findings represent a new powerful approach for cancer immunotherapy and suggest a general strategy for personalized nanomedicine.
Full Text Available The recognition that the development of cancer is associated with acquired immunodeficiency, mostly against cancer cells themselves, and understanding pathways inducing this immunosuppression, has led to a tremendous development of new immunological approaches, both vaccines and drugs, which overcome this inhibition. Both “passive” (e.g. strategies relying on the administration of specific T cells and “active” vaccines (e.g. peptide-directed or whole-cell vaccines have become attractive immunological approaches, inducing cell death by targeting tumor-associated antigens. Whereas peptide-targeted vaccines are usually directed against a single antigen, whole-cell vaccines (e.g. dendritic cell vaccines are aimed to induce robust responsiveness by targeting several tumor-related antigens simultaneously. The combination of vaccines with new immuno-stimulating agents which target “immunosuppressive checkpoints” (anti-CTLA-4, PD-1, etc. is likely to improve and maintain immune response induced by vaccination.
Saslow, Debbie; Andrews, Kimberly S.; Manassaram-Baptiste, Deana; Loomer, Lacey; Lam, Kristina E.; Fisher-Borne, Marcie; Smith, Robert A.; Fontham, Elizabeth T. H.
The American Cancer Society (ACS) reviewed and updated its guideline on human papillomavirus (HPV) vaccination based on a methodologic and content review of the Advisory Committee on Immunization Practices (ACIP) HPV vaccination recommendations. A literature review was performed to supplement the evidence considered by the ACIP and to address new vaccine formulations and recommendations as well as new data on population outcomes since publication of the 2007 ACS guideline. The ACS Guideline Development Group determined that the evidence supports ACS endorsement of the ACIP recommendations, with one qualifying statement related to late vaccination. The ACS recommends vaccination of all children at ages 11 and 12 years to protect against HPV infections that lead to several cancers and precancers. Late vaccination for those not vaccinated at the recommended ages should be completed as soon as possible, and individuals should be informed that vaccination may not be effective at older ages. PMID:27434803
Jönsson, Bengt; Wilking, Nils
Public payment is key to market access for new therapeutics including cancer vaccines and cancer immunotherapeutics. However, the methodology for economic evaluation aimed at informing decisions about pricing and reimbursement is different for cancer vaccines, such as HPV for preventing the occurrence or incidence of cancer, and immunotherapeutics for treatment of patients with manifest cancer. Vaccination against HPV is a traditional public health intervention, where the role of economic evaluation is to inform decisions about optimal vaccination strategies. The decision is about funding for a vaccination program, aimed at vaccinating a defined population at risk, either at a national or regional level. The methodology of economic evaluation is based on statistical modeling of number of cases prevented over a long time period, and the costs and health outcome related to this, for different vaccination strategies For immunotherapeutics, the role of economic evaluation is to assist decisions about reimbursement and guidelines for treatment of patients with establish disease, very often at advanced stages with short life expectancy. The focus is on alternative treatment options, and the costs and outcomes associated with these. Alternatives may be best supportive care, immunotherapeutics or other treatments like surgery, radiotherapy and other anti-cancer drugs. From an economic perspective the type of therapy does not matter, only costs and outcome associated with the relevant alternatives. The main controversy about reimbursement of immunotherapeutics, as with other new cancer drugs, has been the cost of treatment, mainly determined by the price of the therapy, in relation to the expected benefits in terms of survival and quality of life. This paper reviews the evidence on cost-effectiveness, the reimbursement decisions made, and the impact on market access for new immunotherapeutics. Sipuleucel-T (Provenge(®)) and abiraterone (Zytiga(®)) for treatment of
This study aims to elucidate the signaling pathway of TRAIL-mediated apoptosis in prostate cancer cells, and to examine the therapeutic effect of TRAIL on prostate cancer cells in vitro and in vivo...
This study aims to elucidate the signaling pathway of TRAIL-mediated apoptosis in prostate cancer cells, and to examine the therapeutic effect of TRAIL on prostate cancer cells in vitro and in vivo...
This study aims to elucidate the signaling pathway of TRAIL-mediated apoptosis in prostate cancer cells, and to examine the therapeutic effect of TRAIL on prostate cancer cells in vitro and in vivo...
Abalaka, Jeremiah O A
It is generally held that HIV, the causative agent of the rampaging global HIV/AIDS pandemic, is incurable and uniformly fatal. Since the discovery and isolation of the virus over two decades ago, global efforts at producing preventive and curative vaccines against it have so far resulted in failure. Working single-handedly with only his family's meagre resources and against the tide of universally accepted dogmas on HIV/AIDS, the author designed, developed and applied new HIV therapeutic and preventive vaccines in Nigeria, and has been using them on willing HIV-infected and normal persons respectively with their informed and written consent since their development. In many cases, the therapeutic vaccine produced rapid improvement not only in the symptoms and signs attributable to HIV infection, but also in various laboratory parameters with a sustained seroconversion to HIV antibody negative status in a number of the patients. In those HIV-infected patients with concomitant hepatitis B (HBV) and/or C (HCV) infection(s), the therapeutic vaccine has resulted in maintained seroconversion to negative (normal) for the HBsAg and HCV antibodies also. No significant adverse or side effect has been observed yet with the use of these vaccines. The vaccines do not cause the production of any detectable levels of stigmatizing anti-HIV antibodies. It is postulated that the vaccines elicit effective but selective cell-mediated cytotoxic immune responses against HIV, HBV and HCV-infected cells.
Background: Cervical cancer is a preventable disease with a high prevalence in South Africa (SA), where screening is opportunistic. Primary prevention is now possible through HPV vaccination. In VACCS 1 the feasibility of linking cervical cancer with HPV vaccination was demonstrated. Objectives: To investigate the ...
Mary R. Doherty
Full Text Available The connection between epithelial-mesenchymal (E-M plasticity and cancer stem cell (CSC properties has been paradigm-shifting, linking tumor cell invasion and metastasis with therapeutic recurrence. However, despite their importance, the molecular pathways involved in generating invasive, metastatic, and therapy-resistant CSCs remain poorly understood. The enrichment of cells with a mesenchymal/CSC phenotype following therapy has been interpreted in two different ways. The original interpretation posited that therapy kills non-CSCs while sparing pre-existing CSCs. However, evidence is emerging that suggests non-CSCs can be induced into a transient, drug-tolerant, CSC-like state by chemotherapy. The ability to transition between distinct cell states may be as critical for the survival of tumor cells following therapy as it is for metastatic progression. Therefore, inhibition of the pathways that promote E-M and CSC plasticity may suppress tumor recurrence following chemotherapy. Here, we review the emerging appreciation for how plasticity confers therapeutic resistance and tumor recurrence.
Cadena, Alexandra; Cushman, Taylor R; Anderson, Clark; Barsoumian, Hampartsoum B; Welsh, James W; Cortez, Maria Angelica
The emerging combination of radiation therapy with vaccines is a promising new treatment plan in the fight against cancer. While many cancer vaccines such as MUC1, p53 CpG oligodeoxynucleotide, and SOX2 may be great candidates for antitumor vaccination, there still remain many investigations to be done into possible vaccine combinations. One fruitful partnership that has emerged are anti-tumor vaccines in combination with radiation. Radiation therapy was previously thought to be only a tool for directly or indirectly damaging DNA and therefore causing cancer cell death. Now, with much preclinical and clinical data, radiation has taken on the role of an in situ vaccine. With both cancer vaccines and radiation at our disposal, more and more studies are looking to combining vaccine types such as toll-like receptors, viral components, dendritic-cell-based, and subunit vaccines with radiation. While the outcomes of these combinatory efforts are promising, there is still much work to be covered. This review sheds light on the current state of affairs in cancer vaccines and how radiation will bring its story into the future.
Winkler, Gian C; Barle, Ester Lovsin; Galati, Giuseppe; Kluwe, William M
There is no nationally or internationally binding definition of the term "cytotoxic drug" although this term is used in a variety of regulations for pharmaceutical development and manufacturing of drugs as well as in regulations for protecting medical personnel from occupational exposure in pharmacy, hospital, and other healthcare settings. The term "cytotoxic drug" is frequently used as a synonym for any and all oncology or antineoplastic drugs. Pharmaceutical companies generate and receive requests for assessments of the potential hazards of drugs regularly - including cytotoxicity. This publication is intended to provide functional definitions that help to differentiate between generically-cytotoxic cancer drugs of significant risk to normal human tissues, and targeted cancer therapeutics that pose much lesser risks. Together with specific assessments, it provides comprehensible guidance on how to assess the relevant properties of cancer drugs, and how targeted therapeutics discriminate between cancer and normal cells. The position of several regulatory agencies in the long-term is clearly to regulate all drugs regardless of classification, according to scientific risk based data. Despite ongoing discussions on how to replace the term "cytotoxic drugs" in current regulations, it is expected that its use will continue for the near future. Copyright © 2014 Elsevier Inc. All rights reserved.
Full Text Available Abstract Cancer vaccines are the promising tools in the hands of the clinical oncologist. Many tumor-associated antigens are excellent targets for immune therapy and vaccine design. Optimally designed cancer vaccines should combine the best tumor antigens with the most effective immunotherapy agents and/or delivery strategies to achieve positive clinical results. Various vaccine delivery systems such as different routes of immunization and physical/chemical delivery methods have been used in cancer therapy with the goal to induce immunity against tumor-associated antigens. Two basic delivery approaches including physical delivery to achieve higher levels of antigen production and formulation with microparticles to target antigen-presenting cells (APCs have demonstrated to be effective in animal models. New developments in vaccine delivery systems will improve the efficiency of clinical trials in the near future. Among them, nanoparticles (NPs such as dendrimers, polymeric NPs, metallic NPs, magnetic NPs and quantum dots have emerged as effective vaccine adjuvants for infectious diseases and cancer therapy. Furthermore, cell-penetrating peptides (CPP have been known as attractive carrier having applications in drug delivery, gene transfer and DNA vaccination. This review will focus on the utilization of different vaccine delivery systems for prevention or treatment of cancer. We will discuss their clinical applications and the future prospects for cancer vaccine development.
Full Text Available The MB49 bladder cancer cell vaccine was effective against bladder cancer in the mice model in previous studies. However, part of the tumors regrew as the vaccine could not eliminate the cancer stem cells (CSCs. MB49 bladder cancer stem cells (MCSCs were isolated by a combination of the limited dilution method and the serum free culture medium method. MCSCs possessed higher expression of CD133, CD44, OCT4, NANOG, and ABCG2, the ability of differentiation, higher proliferative abilities, lower susceptibility to chemotherapy, greater migration in vitro, and stronger tumorigenic abilities in vivo. Then streptavidin–mouse granulocyte macrophage–colony stimulating factor (SA–mGM–CSF MCSCs vaccine was prepared. SA–mGM–CSF MCSCs vaccine extended the survival of the mice and inhibited the growth of tumor in protective, therapeutic, memorial and specific immune response experiments. The level of immunoglobulin G and the ratio of dendritic cells and CD4+ and CD8+ T cells were highest in the experimental group when compared to those in other four control groups, as well as for the cytotoxicity assay. We demonstrated that SA–mGM–CSF MCSCs vaccine induces an antitumor immune response to metastatic bladder cancer.
Berntsen, Annika; Trepiakas, Redas; Wenandy, Lynn
Therapeutic dendritic cell (DC) vaccination against cancer is a strategy aimed at activating the immune system to recognize and destroy tumor cells. In this nonrandomized phase 1/2 trial, we investigated the safety, feasibility, induction of T-cell response, and clinical response after treatment...... toxicity. Almost half of the patients obtained SD, and in more than 1/3 of the patients, SD persisted for more than 6 months. However, the evaluation of SD is difficult to interpret in the absence of a randomized trial and, therefore, these results should be interpreted with caution. Antigen...
Wieërs, Grégoire; Demotte, Nathalie; Godelaine, Danièle; Bruggen, Pierre van der, E-mail: email@example.com [Ludwig Institute for Cancer Research and Université catholique de Louvain, de Duve Institute, 74 av. Hippocrate, P.O. Box B1-7403, B-1200 Brussels (Belgium)
Human tumors are usually not spontaneously eliminated by the immune system and therapeutic vaccination of cancer patients with defined antigens is followed by tumor regressions only in a small minority of the patients. The poor vaccination effectiveness could be explained by an immunosuppressive tumor microenvironment. Because T cells that infiltrate tumor metastases have an impaired ability to lyse target cells or to secrete cytokine, many researchers are trying to decipher the underlying immunosuppressive mechanisms. We will review these here, in particular those considered as potential therapeutic targets. A special attention will be given to galectins, a family of carbohydrate binding proteins. These lectins have often been implicated in inflammation and cancer and may be useful targets for the development of new anti-cancer therapies.
Wieërs, Grégoire; Demotte, Nathalie; Godelaine, Danièle; Bruggen, Pierre van der
Human tumors are usually not spontaneously eliminated by the immune system and therapeutic vaccination of cancer patients with defined antigens is followed by tumor regressions only in a small minority of the patients. The poor vaccination effectiveness could be explained by an immunosuppressive tumor microenvironment. Because T cells that infiltrate tumor metastases have an impaired ability to lyse target cells or to secrete cytokine, many researchers are trying to decipher the underlying immunosuppressive mechanisms. We will review these here, in particular those considered as potential therapeutic targets. A special attention will be given to galectins, a family of carbohydrate binding proteins. These lectins have often been implicated in inflammation and cancer and may be useful targets for the development of new anti-cancer therapies
Lobaina, Yadira; Michel, Marie-Louise
More than 250million people worldwide are chronically infected with hepatitis B virus (CHB), and over half a million die each year due to CHB-associated liver complications such as cirrhosis and hepatocellular carcinoma. The translation of immunological knowledge about CHB into therapeutic strategies aiming to a sustainable hepatitis B virus (HBV) clearance has been challenging. In recent years, however, the understanding on the immune effectors required to overcome chronicity has notably increased thanks to preclinical and clinical research. Therapeutic vaccination may prove to be useful for treating CHB patients when coupled with current antiviral agents and other immunomodulatory strategies. This review summarizes current data and future perspectives on therapeutic vaccination. Other treatment alternatives that could be combined with vaccines for a complete cure from hepatitis B virus infection are also discussed. Copyright © 2017 Elsevier Ltd. All rights reserved.
Roč. 20, č. 1 (2002), s. 207-212 ISSN 1019-6439 Institutional research plan: CEZ:AV0Z5052915 Keywords : human papilloma viruses * tumour vaccines Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.931, year: 2002
Milacic, Marija; Haw, Robin; Rothfels, Karen; Wu, Guanming; Croft, David; Hermjakob, Henning; D'Eustachio, Peter; Stein, Lincoln
Reactome describes biological pathways as chemical reactions that closely mirror the actual physical interactions that occur in the cell. Recent extensions of our data model accommodate the annotation of cancer and other disease processes. First, we have extended our class of protein modifications to accommodate annotation of changes in amino acid sequence and the formation of fusion proteins to describe the proteins involved in disease processes. Second, we have added a disease attribute to reaction, pathway, and physical entity classes that uses disease ontology terms. To support the graphical representation of "cancer" pathways, we have adapted our Pathway Browser to display disease variants and events in a way that allows comparison with the wild type pathway, and shows connections between perturbations in cancer and other biological pathways. The curation of pathways associated with cancer, coupled with our efforts to create other disease-specific pathways, will interoperate with our existing pathway and network analysis tools. Using the Epidermal Growth Factor Receptor (EGFR) signaling pathway as an example, we show how Reactome annotates and presents the altered biological behavior of EGFR variants due to their altered kinase and ligand-binding properties, and the mode of action and specificity of anti-cancer therapeutics.
Casper, Monica J; Carpenter, Laura M
HPV is the most common sexually transmitted infection in the world. While most strains are relatively harmless, some increase a woman's risk of developing cervical cancer. This article explores the intimate, contested relationships among etiologies of cervical cancer, development and use of the new HPV vaccine, and contested notions of sexuality. We particularly focus on shifts in US health care and sexual politics, where the vaccine has animated longstanding concerns about vaccination (e.g. parental rights, cost, specialisation) and young women's bodies and behaviour. We conclude that vaccines are a distinctive kind of pharmaceutical, invoking notions of contagion and containment, and that politics shape every aspect of the pharmaceutical life course.
Balfour, Louise; Corace, Kimberly; Tasca, Giorgio A; Tremblay, Cecile; Routy, Jean-Pierre; Angel, Jonathan B
This is the first study examining motivation to participate in an HIV therapeutic vaccine trial of Remune and ALVAC. Trial participants (N=49) completed psychological measures at baseline. While 69% reported some personal risk in participating, 100% felt hopeful for societal benefits. Trial participants also reported high levels of existential well-being (e.g., "I believe there is some real purpose for my life"). Results suggest that HIV therapeutic vaccine trial participants are highly motivated by altruism and that participating in research may contribute meaning to living with HIV. Fostering altruism and responsibly promoting the societal benefits of research may facilitate trial participation.
Licari, Amelia; Castagnoli, Riccardo; De Sando, Elisabetta; Marseglia, Gian Luigi
Given the multifaceted effector functions of IgE in immediate hypersensitivity, late-phase reactions, regulation of IgE receptor expression and immune modulation, IgE antibodies have long represented an attractive target for therapeutic agents in asthma and other allergic diseases. Effective pharmacologic blockade of the binding of IgE to its receptors has become one of most innovative therapeutic strategies in the field of allergic diseases in the last 10 years. Areas covered: The latest strategies targeting IgE include the development of a therapeutic vaccine, able to trigger our own immune systems to produce therapeutic anti-IgE antibodies, potentially providing a further step forward in the treatment of allergic diseases. The aim of this review is to discuss the discovery strategy, preclinical and early clinical development of a peptide conjugate vaccine for inducing therapeutic anti-IgE antibodies. Expert opinion: Outside the area of development of humanized anti-IgE monoclonal antibodies, the research field of therapeutic IgE-targeted vaccines holds potential benefits for the treatment of allergic diseases. However, most of the experimental observations in animal models have not yet been translated into new treatments and evidence of human efficacy and safety of this new therapeutic strategy are still lacking.
Milacic, Marija; Haw, Robin, E-mail: firstname.lastname@example.org; Rothfels, Karen; Wu, Guanming [Informatics and Bio-computing Platform, Ontario Institute for Cancer Research, Toronto, ON, M5G0A3 (Canada); Croft, David; Hermjakob, Henning [European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD (United Kingdom); D’Eustachio, Peter [Department of Biochemistry, NYU School of Medicine, New York, NY 10016 (United States); Stein, Lincoln [Informatics and Bio-computing Platform, Ontario Institute for Cancer Research, Toronto, ON, M5G0A3 (Canada)
Reactome describes biological pathways as chemical reactions that closely mirror the actual physical interactions that occur in the cell. Recent extensions of our data model accommodate the annotation of cancer and other disease processes. First, we have extended our class of protein modifications to accommodate annotation of changes in amino acid sequence and the formation of fusion proteins to describe the proteins involved in disease processes. Second, we have added a disease attribute to reaction, pathway, and physical entity classes that uses disease ontology terms. To support the graphical representation of “cancer” pathways, we have adapted our Pathway Browser to display disease variants and events in a way that allows comparison with the wild type pathway, and shows connections between perturbations in cancer and other biological pathways. The curation of pathways associated with cancer, coupled with our efforts to create other disease-specific pathways, will interoperate with our existing pathway and network analysis tools. Using the Epidermal Growth Factor Receptor (EGFR) signaling pathway as an example, we show how Reactome annotates and presents the altered biological behavior of EGFR variants due to their altered kinase and ligand-binding properties, and the mode of action and specificity of anti-cancer therapeutics.
Milacic, Marija; Haw, Robin; Rothfels, Karen; Wu, Guanming; Croft, David; Hermjakob, Henning; D’Eustachio, Peter; Stein, Lincoln
Reactome describes biological pathways as chemical reactions that closely mirror the actual physical interactions that occur in the cell. Recent extensions of our data model accommodate the annotation of cancer and other disease processes. First, we have extended our class of protein modifications to accommodate annotation of changes in amino acid sequence and the formation of fusion proteins to describe the proteins involved in disease processes. Second, we have added a disease attribute to reaction, pathway, and physical entity classes that uses disease ontology terms. To support the graphical representation of “cancer” pathways, we have adapted our Pathway Browser to display disease variants and events in a way that allows comparison with the wild type pathway, and shows connections between perturbations in cancer and other biological pathways. The curation of pathways associated with cancer, coupled with our efforts to create other disease-specific pathways, will interoperate with our existing pathway and network analysis tools. Using the Epidermal Growth Factor Receptor (EGFR) signaling pathway as an example, we show how Reactome annotates and presents the altered biological behavior of EGFR variants due to their altered kinase and ligand-binding properties, and the mode of action and specificity of anti-cancer therapeutics
Oh, Jisun; Hlatky, Lynn; Jeong, Yong-Seob; Kim, Dohoon
Understanding how to target cancer stem cells (CSCs) may provide helpful insights for the development of therapeutic or preventive strategies against cancers. Dietary phytochemicals with anticancer properties are promising candidates and have selective impact on CSCs. This review summarizes the influence of phytochemicals on heterogeneous cancer cell populations as well as on specific targeting of CSCs.
Full Text Available Dendritic cells (DCs are potent antigen-presenting cells and play a central role in the initiation and regulation of primary immune responses. Therefore, their use for the active immunotherapy against cancers has been studied with considerable interest. The fusion of DCs with whole tumor cells represents in many ways an ideal approach to deliver, process, and subsequently present a broad array of tumor-associated antigens, including those yet to be unidentified, in the context of DCs-derived costimulatory molecules. DCs/tumor fusion vaccine stimulates potent antitumor immunity in the animal tumor models. In the human studies, T cells stimulated by DC/tumor fusion cells are effective in lysis of tumor cells that are used as the fusion partner. In the clinical trials, clinical and immunological responses were observed in patients with advanced stage of malignant tumors after being vaccinated with DC/tumor fusion cells, although the antitumor effect is not as vigorous as in the animal tumor models. This review summarizes recent advances in concepts and techniques that are providing new impulses to DCs/tumor fusions-based cancer vaccination.
Weir, Genevieve M.; Liwski, Robert S.; Mansour, Marc
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
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)
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.
Ragonnaud, Emeline; Andersson, Anne-Marie C; Mariya, Silmi
oncogenic HPV strains. This antigen was found to be as related to circulating oncogenic Macaca fascicularis papillomaviruses (MfPVs) as to oncogenic HPVs. The CDSE1E2 antigen was fused to a T-cell adjuvant and encoded in chimpanzee 3 and 63 adenoviral vectors. We first showed that the combination of these 2....... Preexisting MfPV infections did not prime vaccine inducible immune responses. Importantly, immunized oncogenic MfPV type 3 (MfPV3) infected animals that responded toward MfPV3 were able to diminish cervical MfPV3 DNA content. Although insufficient breadth was achieved, our results suggest that a relevant...
João Henrique Campos
Full Text Available Almost all cells and organisms release membrane structures containing proteins, lipids, and nucleic acids called extracellular vesicles (EVs, which have a wide range of functions concerning intercellular communication and signaling events. Recently, the characterization and understanding of their biological role have become a main research area due to their potential role in vaccination, as biomarkers antigens, early diagnostic tools, and therapeutic applications. Here, we will overview the recent advances and studies of Evs shed by tumor cells, bacteria, parasites, and fungi, focusing on their inflammatory role and their potential use in vaccination and diagnostic of cancer and infectious diseases.
Campos, João Henrique; Soares, Rodrigo Pedro; Ribeiro, Kleber; Cronemberger Andrade, André; Batista, Wagner Luiz; Torrecilhas, Ana Claudia
Almost all cells and organisms release membrane structures containing proteins, lipids, and nucleic acids called extracellular vesicles (EVs), which have a wide range of functions concerning intercellular communication and signaling events. Recently, the characterization and understanding of their biological role have become a main research area due to their potential role in vaccination, as biomarkers antigens, early diagnostic tools, and therapeutic applications. Here, we will overview the recent advances and studies of Evs shed by tumor cells, bacteria, parasites, and fungi, focusing on their inflammatory role and their potential use in vaccination and diagnostic of cancer and infectious diseases. PMID:26380326
Marian E. Major
Full Text Available Studies in patients and chimpanzees that spontaneously clear Hepatitis C Virus (HCV have demonstrated that natural immunity to the virus is induced during primary infections and that this immunity can be cross protective. These discoveries led to optimism regarding prophylactic HCV vaccines and a number of studies in the chimpanzee model have been performed, all of which resulted in modified infections after challenge but did not always prevent persistence of the virus. Therapeutic vaccine strategies have also been pursued in an effort to reduce the costs and side effects associated with anti-viral drug treatment. This review summarizes the studies performed thus far in both patients and chimpanzees for prophylactic and therapeutic vaccination, assesses the progress made and future perspectives.
Roč. 10, č. 5 (2008), s. 526-534 ISSN 1464-8431 Institutional research plan: CEZ:AV0Z50520514 Keywords : B-cell lymphomas * tumor antigen * therapeutic vaccine Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.913, year: 2008
Lee, Sung Yong; Huang, Zhuomin; Kang, Tae Heung; Soong, Ruey-Shyang; Knoff, Jayne; Axenfeld, Ellen; Wang, Chenguang; Alvarez, Ronald D; Chen, Ching-Shih; Hung, Chien-Fu; Wu, T-C
We have previously created a potent DNA vaccine encoding calreticulin linked to the human papillomavirus (HPV) oncogenic protein E7 (CRT/E7). While treatment with the CRT/E7 DNA vaccine generates significant tumor-specific immune responses in vaccinated mice, the potency with the DNA vaccine could potentially be improved by co-administration of a histone deacetylase inhibitor (HDACi) as HDACi has been shown to increase the expression of MHC class I and II molecules. Thus, we aimed to determine whether co-administration of a novel HDACi, AR-42, with therapeutic HPV DNA vaccines could improve the activation of HPV antigen-specific CD8(+) T cells, resulting in potent therapeutic antitumor effects. To do so, HPV-16 E7-expressing murine TC-1 tumor-bearing mice were treated orally with AR-42 and/or CRT/E7 DNA vaccine via gene gun. Mice were monitored for E7-specific CD8(+) T cell immune responses and antitumor effects. TC-1 tumor-bearing mice treated with AR-42 and CRT/E7 DNA vaccine experienced longer survival, decreased tumor growth, and enhanced E7-specific immune response compared to mice treated with AR-42 or CRT/E7 DNA vaccine alone. Additionally, treatment of TC-1 cells with AR-42 increased the surface expression of MHC class I molecules and increased the susceptibility of tumor cells to the cytotoxicity of E7-specific T cells. This study indicates the ability of AR-42 to significantly enhance the potency of the CRT/E7 DNA vaccine by improving tumor-specific immune responses and antitumor effects. Both AR-42 and CRT/E7 DNA vaccines have been used in independent clinical trials; the current study serves as foundation for future clinical trials combining both treatments in cervical cancer therapy. AR-42, a novel HDAC inhibitor, enhances potency of therapeutic HPV DNA vaccines AR-42 treatment leads to strong E7-specific CD8+ T cell immune responses AR-42 improves tumor-specific immunity and antitumor effects elicited by HPV DNA vaccine AR-42 is more potent than
Jan 31, 2017 ... 5. Molecular mechanism of action of. DC-based cancer vaccines. DC-based vaccines aim to load DCs with tumour antigens ex vivo or in vivo followed by maturation of DCs that leads to their activation. Upon infusion into the patient, the ex vivo mature DCs generate anti-tumour T-cell responses resulting.
CHEUK MAN CHERIE AU
The human cell studies and the live mouse studies are intended to provide the information that is needed to apply therapies to treat breast cancer patients, based on our novel discoveries. We believe that des-acyl ghrelin-like compounds will be novel breast cancer therapeutics while avoiding well-documented serious side effects, including joint pain, osteoporosis or endometrial cancer. Our findings could therefore improve the quality of life of women treated for breast cancer, improve complia...
Sidana, Abhinav; Srinivasan, Ramaprasad
The study of hereditary forms of kidney cancer has vastly increased our understanding of metabolic and genetic pathways involved in the development of both inherited and sporadic kidney cancers. The recognition that diverse molecular events drive different forms of kidney cancers has led to the preclinical and clinical development of specific pathway-directed strategies tailored to treat distinct subgroups of kidney cancer. Here, we describe the molecular mechanisms underlying the pathogenesis of several different types of hereditary renal cancers, review their clinical characteristics, and summarize the treatment strategies for the management of these cancers.
Sehnal, B; Vojáčková, N; Driák, D; Kmoníčková, E; Vaňousová, D; Maxová, K; Neumannová, H; Sláma, J
There is a considerable number of studies on the efficacy HPV (human papillomavirus) vaccination against different cancers but relevant information is scattered in diverse journals. This paper is a review summarizing current knowledge of the potential of HPV vaccination against all HPV related cancers. HPV infection is probably the most frequent sexually transmitted disease. At least 13 HPV genotypes are classified as carcinogenic or probably carcinogenic in respect to cervical cancer. Almost 100% of cervical cancers are linked to HPV infection. HPV 16 and HPV 18 are the most frequently involved genotypes and account together for approximately 70% of cervical cancer in the world. Persistent high risk HPV infection is responsible for a significant proportion of vulvar, vaginal, anal and penile carcinomas. The virus has also been implicated in oncogenesis of head and neck cancers, including oropharyngeal cancers. HPV infection can play an important role in cancerogenesis of lung, esophagus, breast, and colon and rectum. On the contrary, published results indicate that HPV infection is not associated with prostate oncogenesis. Strong predominance of HPV 16 has been reported for all HPV associated cancer sites. Generally, it is estimated that approximately 5.2% of all cancers are associated with oncogenic HPV infection. Currently, there are two vaccines on the market; quadrivalent Silgard® (Gardasil®) and bivalent CervarixTM. Large trials for both vaccines have shown efficacy against HPV related infection and disease. Efficacy has been very high in HPV naive subjects to vaccine related types. While HPV vaccination is currently approved for the prevention of cervical cancer, it also has the potential in the prevention of all HPV associated malignancies. The Czech republic belongs to countries that cover HPV vaccination of girls at the age of 13- 14 years by general health insurance. Overall impact of this vaccination remains to be evaluated. The new issues of the
AWARD NUMBER: W81XWH-13-1-0423 TITLE: Novel Immune-Modulating Cellular Vaccine for Prostate Cancer Immunotherapy PRINCIPAL INVESTIGATOR: Smita...SUBTITLE 5a. CONTRACT NUMBER W81XWH-13-1-0423 Novel Immune-Modulating Cellular Vaccine for Prostate Cancer Immunotherapy 5b. GRANT NUMBER 5c...Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT We have developed a novel strategy that combines tumor immunotherapy targeting PAP and targeted
Jul 13, 2016 ... Cancer recurrence is believed to be one of the major reasons for the failure of cancer treatment strategies. This biological phenomenon could arise from the incomplete eradication of tumour cells after chemo- and radiotherapy. Recent developments in the design of models reflecting cancer recurrence and ...
Cancer recurrence is believed to be one of the major reasons for the failure of cancer treatment strategies. Thisbiological phenomenon could arise from the incomplete eradication of tumour cells after chemo- and radiotherapy.Recent developments in the design of models reflecting cancer recurrence and in vivo imaging ...
Cancer recurrence is believed to be one of the major reasons for the failure of cancer treatment strategies. Thisbiological phenomenon could arise from the incomplete eradication of tumour cells after chemo- and radiotherapy.Recent developments in the design of models reflecting cancer recurrence and in vivo imaging ...
Conclusion: This study revealed a dramatic figure of cervical cancer in Butembo city. Effort should be made by the government and other health agencies to organize mass campaign to practice cervical screening as well as education on the various risk factors. Access to the vaccines (anti-HPV 16-18) and the precocious ...
Assis, J L
The author studied especially the clinical aspects and therapeutic results in 73 patients with neurological complication of anti-rabies vaccination. The neuroparalytic accidents and the most constant neurologic signs and symptoms were emphasized. The most common clinical syndrome was thoraco-lumbar meningomyelitis and there were CSF alterations in 88% of the cases studied. Eighteen patients presented neurologic complications after Fuenzalida vaccine: only 1 of them had Guillain-Barré syndrome, 1 had meningoradiculitis, 4 had myelitis and in the other 12 cases there was diffuse involvement of the nervous system especially of the spinal cord and meninges (meningomyelitis and meningoencephalomyelitis).
Annual Retreat, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky (2nd Place, Roving Research Prize) Kenneth...based HIV Microbicides and Vaccines by targeting the High-mannose Cluster on the Env 19 Glycoprotein gp120. James Graham Brown Cancer Center 8th...Mitochondrial Integrity and Preventing Autophagic Cell Death. Keystone Symposium on Mitochondrial Dynamics and Physiology, March 22-27, 2009, Whistler , British
Full Text Available The antigenic similarity between tumors and embryos has been appreciated for many years and reflects the expression of embryonic gene products by cancer cells and/or cancer-initiating stem cells. Taking advantage of this similarity, we have tested a prophylactic lung cancer vaccine composed of allogeneic murine embryonic stem cells (ESC. Naïve C57BL/6 mice were vaccinated with ESC along with a source of granulocyte macrophage-colony stimulating factor (GM-CSF in order to provide immunostimulatory adjuvant activity. Vaccinated mice were protected against subsequent challenge with implantable Lewis lung carcinoma (LLC. ESC-induced anti-tumor immunity was not due to a non-specific "allo-response" as vaccination with allogeneic murine embryonic fibroblasts did not protect against tumor outgrowth. Vaccine efficacy was associated with robust tumor-reactive primary and memory CD8(+ T effector responses, Th1 cytokine response, higher intratumoral CD8(+ T effector/CD4(+CD25(+Foxp3(+ T regulatory cell ratio, and reduced myeloid derived suppressor cells in the spleen. Prevention of tumorigenesis was found to require a CD8-mediated cytotoxic T lymphocyte (CTL response because in vivo depletion of CD8(+ T lymphocytes completely abrogated the protective effect of vaccination. Importantly, this vaccination strategy also suppressed the development of lung cancer induced by the combination of carcinogen administration and chronic pulmonary inflammation. Further refinement of this novel vaccine strategy and identification of shared ESC/tumor antigens may lead to immunotherapeutic options for lung cancer patients and, perhaps more importantly, could represent a first step toward the development of prophylactic cancer vaccines.
.... Our approach initially involves investigation of EBV sequences in breast cancer cell lines and specimens, determination of whether treatment with Arginine Butyrate will induce the viral thymidine...
Full Text Available In spite of huge concerted efforts, the treatment of cancer, a disease frequently associated with genetic alterations caused due to hereditary or environmental factors, remains a challenge. The last few years have witnessed emergence of several innovative and effective modalities for the treatment of solid tumours and hematological malignancies. Gene therapy has shown enormous potential for cancer treatment, especially for metastatic cancers which unlike localized solid tumours, may not be amenable to surgery or other treatment options. Gene therapy aims to introduce a correct copy of the malfunctioning gene in the tumour environment by using viral or non-viral methods to impede or inhibit its growth. This review provides an overview of three main approaches for cancer gene therapy namely immunotherapy, oncolytic therapy and gene transfer therapy. Immunotherapy augments the host immune system in order to destroy cancer cells while oncolytic therapy uses genetically engineered viruses such as to effectively kill cancer cells. Clinical studies so far have shown that cells can be engineered to express gene products that can specifically target cancer cells and prevents their growth and metastasis. Though gene therapy for cancer is yet to see extensive clinical use, it is likely that in combination with other treatment modalities, it will help in controlling and possibly curing cancer in the near future.
Guo, Theresa; Eisele, David W.; Fakhry, Carole
Oropharyngeal cancer (OPC) is significantly increasing in incidence in the United States. Given that these epidemiologic trends are driven by HPV, the potential impact of prophylactic HPV vaccines on the prevention of OPC is of interest. To date, the primary evidence supporting the approval of current prophylactic HPV vaccines are large phase III clinical trials focused on prevention of genital disease (cervical and anal cancer, as well as genital warts). These trials reported 89-98% vaccine efficacy for prevention of both premalignant lesions and persistent genital infection. However, these trials were designed before the etiologic relationship between HPV and oropharyngeal cancer was established. There are differences in the epidemiology of oral and genital HPV infection, such as differences in age and gender distributions, which suggest that the vaccine efficacy shown in genital cancers may not be directly translatable to the oropharynx. Evaluation of vaccine efficacy is challenging in the oropharynx because no premalignant lesions analogous to cervical intraepithelial neoplasia (CIN) in cervical cancer has been identified. In order to truly investigate the efficacy of these vaccines in the oropharynx, additional clinical trials with feasible endpoints are needed. PMID:27152637
Wilken Jason A
Full Text Available Abstract Background Early studies have demonstrated comparable levels of HER2/ErbB2 expression in both breast and ovarian cancer. Trastuzumab (Herceptin, a therapeutic monoclonal antibody directed against HER2, is FDA-approved for the treatment of both early and late stage breast cancer. However, clinical studies of trastuzumab in epithelial ovarian cancer (EOC patients have not met the same level of success. Surprisingly, however, no reports have examined either the basis for primary trastuzumab resistance in ovarian cancer or potential ways of salvaging trastuzumab as a potential ovarian cancer therapeutic. Methods An in vitro model of primary trastuzumab-resistant ovarian cancer was created by long-term culture of HER2-positive ovarian carcinoma-derived cell lines with trastuzumab. Trastuzumab treated vs. untreated parental cells were compared for HER receptor expression, trastuzumab sensitivity, and sensitivity to other HER-targeted therapeutics. Results In contrast to widely held assumptions, here we show that ovarian cancer cells that are not growth inhibited by trastuzumab are still responsive to trastuzumab. Specifically, we show that responsiveness to alternative HER-targeted inhibitors, such as gefitinib and cetuximab, is dramatically potentiated by long-term trastuzumab treatment of ovarian cancer cells. HER2-positive ovarian carcinoma-derived cells are, therefore, not "unresponsive" to trastuzumab as previously assumed, even when they not growth inhibited by this drug. Conclusions Given the recent success of EGFR-targeted therapeutics for the treatment of other solid tumors, and the well-established safety profile of trastuzumab, results presented here provide a rationale for re-evaluation of trastuzumab as an experimental ovarian cancer therapeutic, either in concert with, or perhaps as a "primer" for EGFR-targeted therapeutics.
Akhter, S.; Ahmad, M; Ramzani, F.; Singh, A.; Ahmad, I.; Rahman, Z.; Ahmad, F.J.; Storm, Gerrit; Kok, R.J.
As of 21st century, cancer is arguably the most complex and challenging disease known to mankind and an inevitable public health concern of this millennium. Nanotechnology, suitably amalgamated with cancer research, has ushered an era of highly personalized and safer medicines which can improve
Eunice Yuen-Ting Lau
Full Text Available Tumor consists of heterogeneous cancer cells including cancer stem cells (CSCs that can terminally differentiate into tumor bulk. Normal stem cells in normal organs regulate self-renewal within a stem cell niche. Likewise, accumulating evidence has also suggested that CSCs are maintained extrinsically within the tumor microenvironment, which includes both cellular and physical factors. Here, we review the significance of stromal cells, immune cells, extracellular matrix, tumor stiffness, and hypoxia in regulation of CSC plasticity and therapeutic resistance. With a better understanding of how CSC interacts with its niche, we are able to identify potential therapeutic targets for the development of more effective treatments against cancer.
Full Text Available The effective treatment of castrate-resistant prostate cancer (CRPC has proven to be very challenging. Until recently, docetaxel was the only therapeutic demonstrated to extend overall patient survival. Yet recently, a considerable number of new therapeutics have been approved to treat CRPC patients. These remarkable advances now give new tools for the therapeutic management of late-stage prostate cancer. In this review, we will examine mechanistic and clinical data of several newly approved therapeutics including the chemotherapeutic cabazitaxel, antiandrogen enzalutamide, endocrine disruptor abiraterone acetate, immunotherapy sipuleucel-T, and bone-targeting radiopharmaceutical alpharadin. In addition, we will examine other promising therapeutics that are currently in Phase III trials.
Yoana Herrera Leiva
Full Text Available In 2016, the EGF-Predictor Phase IV Clinical Trial Opening Workshop was held in Cienfuegos, sponsored by the Center for Molecular Immunology of Havana which coexist with other clinical trials. The overall objective of the study is to evaluate the safety and efficacy of the CIMAVAX-EGF therapeutic vaccine for the treatment of patients diagnosed with lung cancer in advanced stages of the disease and, within its specific objectives, to assess overall survival and the treated patients’ life quality.
Raza, Muhammad Hassan; Siraj, Sami; Arshad, Abida; Waheed, Usman; Aldakheel, Fahad; Alduraywish, Shatha; Arshad, Muhammad
Reactive oxygen species (ROS) are produced in cancer cells as a result of increased metabolic rate, dysfunction of mitochondria, elevated cell signaling, expression of oncogenes and increased peroxisome activities. Certain level of ROS is required by cancer cells, above or below which lead to cytotoxicity in cancer cells. This biochemical aspect can be exploited to develop novel therapeutic agents to preferentially and selectively target cancer cells. We searched various electronic databases including PubMed, Web of Science, and Google Scholar for peer-reviewed english-language articles. Selected articles ranging from research papers, clinical studies, and review articles on the ROS production in living systems, its role in cancer development and cancer treatment, and the role of microbiota in ROS-dependent cancer therapy were analyzed. This review highlights oxidative stress in tumors, underlying mechanisms of different relationships of ROS and cancer cells, different ROS-mediated therapeutic strategies and the emerging role of microbiota in cancer therapy. Cancer cells exhibit increased ROS stress and disturbed redox homeostasis which lead to ROS adaptations. ROS-dependent anticancer therapies including ROS scavenging anticancer therapy and ROS boosting anticancer therapy have shown promising results in vitro as well as in vivo. In addition, response to cancer therapy is modulated by the human microbiota which plays a critical role in systemic body functions.
McArthur, Monica A
Zika is a rapidly emerging public health threat. Although clinical infection is frequently mild, significant neurological manifestations have been demonstrated in infants born to Zika virus (ZIKV) infected mothers. Due to the substantial ramifications of intrauterine infection, effective counter-measures are urgently needed. In order to develop effective anti-ZIKV vaccines and therapeutics, improved animal models and a better understanding of immunological correlates of protection against ZIKV are required. This review will summarize what is currently known about ZIKV, the clinical manifestations and epidemiology of Zika as well as, the development of animal models to study ZIKV infection, host immune responses against ZIKV, and the current state of development of vaccines and therapeutics against ZIKV.
McArthur, Monica A.
Zika is a rapidly emerging public health threat. Although clinical infection is frequently mild, significant neurological manifestations have been demonstrated in infants born to Zika virus (ZIKV) infected mothers. Due to the substantial ramifications of intrauterine infection, effective counter-measures are urgently needed. In order to develop effective anti-ZIKV vaccines and therapeutics, improved animal models and a better understanding of immunological correlates of protection against ZIKV are required. This review will summarize what is currently known about ZIKV, the clinical manifestations and epidemiology of Zika as well as, the development of animal models to study ZIKV infection, host immune responses against ZIKV, and the current state of development of vaccines and therapeutics against ZIKV. PMID:28608813
Maroof, Asher; Brown, Najmeeyah; Smith, Barbara; Hodgkinson, Michael R.; Maxwell, Alice; Losch, Florian O.; Fritz, Ulrike; Walden, Peter; Lacey, Charles N. J.; Smith, Deborah F.; Aebischer, Toni
Therapeutic vaccines, when used alone or in combination therapy with antileishmanial drugs, may have an important place in the control of a variety of forms of human leishmaniasis. Here, we describe the development of an adenovirus-based vaccine (Ad5-KH) comprising a synthetic haspb gene linked to a kmp11 gene via a viral 2A sequence. In nonvaccinated Leishmania donovani–infected BALB/c mice, HASPB- and KMP11-specific CD8+ T cell responses were undetectable, although IgG1 and IgG2a antibodies were evident. After therapeutic vaccination, antibody responses were boosted, and IFNγ+CD8+ T cell responses, particularly to HASPB, became apparent. A single vaccination with Ad5-KH inhibited splenic parasite growth by ∼66%, a level of efficacy comparable to that observed in early stage testing of clinically approved antileishmanial drugs in this model. These studies indicate the usefulness of adenoviral vectors to deliver leishmanial antigens in a potent and host protective manner to animals with existing L. donovani infection. PMID:22301630
Shimizu, K.; Fields, R. C.; Giedlin, M.; Mule, J. J.
We have reported previously that murine bone marrow-derived dendritic cells (DC) pulsed with whole tumor lysates can mediate potent antitumor immune responses both in vitro and in vivo. Because successful therapy was dependent on host immune T cells, we have now evaluated whether the systemic administration of the T cell stimulatory/growth promoting cytokine interleukin-2 (IL-2) could enhance tumor lysate-pulsed DC-based immunizations to further promote protective immunity toward, and therapeutic rejection of, syngeneic murine tumors. In three separate approaches using a weakly immunogenic sarcoma (MCA-207), the systemic administration of non-toxic doses of recombinant IL-2 (20,000 and 40,000 IU/dose) was capable of mediating significant increases in the potency of DC-based immunizations. IL-2 could augment the efficacy of tumor lysate-pulsed DC to induce protective immunity to lethal tumor challenge as well as enhance splenic cytotoxic T lymphocyte activity and interferon-γ production in these treated mice. Moreover, treatment with the combination of tumor lysate-pulsed DC and IL-2 could also mediate regressions of established pulmonary 3-day micrometastases and 7-day macrometastases as well as established 14- and 28-day s.c. tumors, leading to either significant cure rates or prolongation in overall survival. Collectively, these findings show that nontoxic doses of recombinant IL-2 can potentiate the antitumor effects of tumor lysate-pulsed DC in vivo and provide preclinical rationale for the use of IL-2 in DC-based vaccine strategies in patients with advanced cancer.
Dang, Chi V; Hamaker, Max; Sun, Peng; Le, Anne; Gao, Ping
In 1927, Otto Warburg and coworkers reported the increased uptake of glucose and production of lactate by tumors in vivo as compared with normal tissues. This phenomenon, now known as the Warburg effect, was recapitulated in vitro with cancer tissue slices exhibiting excessive lactate production even with adequate oxygen. Warburg's in vivo studies of tumors further suggest that the dependency of tumors in vivo on glucose could be exploited for therapy, because reduction of arterial glucose by half resulted in a four-fold reduction in tumor fermentation. Recent work in cancer metabolism indicates that the Warburg effect or aerobic glycolysis contributes to redox balance and lipid synthesis, but glycolysis is insufficient to sustain a growing and dividing cancer cell. In this regard, glutamine, which contributes its carbons to the tricarboxylic acid (TCA) cycle, has been re-discovered as an essential bioenergetic and anabolic substrate for many cancer cell types. Could alterations in cancer metabolism be exploited for therapy? Here, we address this question by reviewing current concepts of normal metabolism and altered metabolism in cancer cells with specific emphasis on molecular targets involved directly in glycolysis or glutamine metabolism.
A major problem with tuberculosis (TB) control is the long duration of drug therapy –both for latent and for active TB. Therapeutic vaccination has been postulated to improve this situation, and to this end there are several candidates already in clinical phases of development. These candidates follow two main designs, namely bacilli-directed therapy based on inactivated -whole or -fragmented bacillus (Mycobacterium w and RUTI) or fusion proteins that integrate non-replicating bacilli -relate...
Dillon, Lloye M.; Miller, Todd W.
Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is one of the most frequently disrupted tumor suppressors in cancer. The lipid phosphatase activity of PTEN antagonizes the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway to repress tumor cell growth and survival. In the nucleus, PTEN promotes chromosome stability and DNA repair. Consequently, loss of PTEN function increases genomic instability. PTEN deficiency is caused by inherited germline mutations, somatic mutations, epigenetic and transcriptional silencing, post-translational modifications, and protein-protein interactions. Given the high frequency of PTEN deficiency across cancer subtypes, therapeutic approaches that exploit PTEN loss-of-function could provide effective treatment strategies. Herein, we discuss therapeutic strategies aimed at cancers with loss of PTEN function, and the challenges involved in treating patients afflicted with such cancers. We review preclinical and clinical findings, and highlight novel strategies under development to target PTEN-deficient cancers. PMID:24387334
Tissot, Tazzio; Arnal, Audrey; Jacqueline, Camille; Poulin, Robert; Lefèvre, Thierry; Mery, Frédéric; Renaud, François; Roche, Benjamin; Massol, François; Salzet, Michel; Ewald, Paul; Tasiemski, Aurélie; Ujvari, Beata; Thomas, Frédéric
Similar to parasites, cancer cells depend on their hosts for sustenance, proliferation and reproduction, exploiting the hosts for energy and resources, and thereby impairing their health and fitness. Because of this lifestyle similarity, it is predicted that cancer cells could, like numerous parasitic organisms, evolve the capacity to manipulate the phenotype of their hosts to increase their own fitness. We claim that the extent of this phenomenon and its therapeutic implications are, however, underappreciated. Here, we review and discuss what can be regarded as cases of host manipulation in the context of cancer development and progression. We elaborate on how acknowledging the applicability of these principles can offer novel therapeutic and preventive strategies. The manipulation of host phenotype by cancer cells is one more reason to adopt a Darwinian approach in cancer research. © 2016 WILEY Periodicals, Inc.
Chandra, Dinesh; Quispe-Tintaya, Wilber; Jahangir, Arthee; Asafu-Adjei, Denise; Ramos, Ilyssa; Sintim, Herman O; Zhou, Jie; Hayakawa, Yoshihiro; Karaolis, David K R; Gravekamp, Claudia
Cancer vaccination may be our best and most benign option for preventing or treating metastatic cancer. However, breakthroughs are hampered by immune suppression in the tumor microenvironment. In this study, we analyzed whether cyclic diguanylate (c-di-GMP), a ligand for stimulator of interferon genes (STING), could overcome immune suppression and improve vaccination against metastatic breast cancer. Mice with metastatic breast cancer (4T1 model) were therapeutically immunized with an attenuated Listeria monocytogenes (LM)-based vaccine, expressing tumor-associated antigen Mage-b (LM-Mb), followed by multiple low doses of c-di-GMP (0.2 μmol/L). This treatment resulted in a striking and near elimination of all metastases. Experiments revealed that c-di-GMP targets myeloid-derived suppressor cells (MDSC) and tumor cells. Low doses of c-di-GMP significantly increased the production of IL12 by MDSCs, in correlation with improved T-cell responses to Mage-b, whereas a high dose of c-di-GMP (range, 0.3-3 mmol/L) activated caspase-3 in the 4T1 tumor cells and killed the tumor cells directly. On the basis of these results, we tested one administration of high-dose c-di-GMP (3 mmol/L) followed by repeated administrations of low-dose c-di-GMP (0.2 μmol/L) in the 4T1 model, and found equal efficacy compared with the combination of LM-Mb and c-di-GMP. This finding correlated with a mechanism of improved CD8 T-cell responses to tumor-associated antigens (TAA) Mage-b and Survivin, most likely through cross-presentation of these TAAs from c-di-GMP-killed 4T1 tumor cells, and through c-di-GMP-activated TAA-specific T cells. Our results demonstrate that activation of STING-dependent pathways by c-di-GMP is highly attractive for cancer immunotherapy. ©2014 American Association for Cancer Research.
Tan, Y S; Sansanaphongpricha, K; Prince, M E P; Sun, D; Wolf, G T; Lei, Y L
The recent Food and Drug Administration's approval of monoclonal antibodies targeting immune checkpoint receptors (ICRs) for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) offers exciting promise to improve patient outcome and reduce morbidities. A favorable response to ICR blockade relies on an extensive collection of preexisting tumor-specific T cells in the tumor microenvironment (TME). ICR blockade reinvigorates exhausted CD8 + T cells and enhances immune killing. However, resistance to ICR blockade is observed in about 85% of patients with HNSCC, therefore highlighting the importance of characterizing the mechanisms underlying HNSCC immune escape and exploring combinatorial strategies to sensitize hypoimmunogenic cold HNSCC to ICR inhibition. Cancer vaccines are designed to bypass the cold TME and directly deliver cancer antigens to antigen-presenting cells (APCs); these vaccines epitomize a priming strategy to synergize with ICR inhibitors. Cancer cells are ineffective antigen presenters, and poor APC infiltration as well as the M2-like polarization in the TME further dampens antigen uptake and processing, both of which render ineffective innate and adaptive immune detection. Cancer vaccines directly activate APC and expand the tumor-specific T-cell repertoire. In addition, cancer vaccines often contain an adjuvant, which further improves APC function, promotes epitope spreading, and augments host intrinsic antitumor immunity. Thus, the vaccine-induced immune priming generates a pool of effectors whose function can be enhanced by ICR inhibitors. In this review, we summarize the major HNSCC immune evasion strategies, the ongoing effort toward improving HNSCC vaccines, and the current challenges limiting the efficacy of cancer vaccines.
Goossen, Ginette M; Kremer, Leontien C M; van de Wetering, Marianne D
Influenza infection is a potential cause of severe morbidity in children with cancer; therefore vaccination against influenza is recommended. However, data are conflicting regarding the immune response to influenza vaccination in children with cancer, and the value of vaccination remains unclear. 1. To assess the efficacy of influenza vaccination in stimulating an immunological response in children with cancer during chemotherapy, compared with control groups.2. To assess the efficacy of influenza vaccination in preventing confirmed influenza and influenza-like illness and/or in stimulating immunological response in children with cancer treated with chemotherapy, compared with placebo, no intervention or different dosage schedules.3. To identify the adverse effects associated with influenza vaccines in children with cancer treated with chemotherapy, compared with other control groups. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1966 to 2012) and EMBASE (1980 to 2012) up to August 2012. We also searched reference lists of relevant articles and conference proceedings of the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), the Infectious Diseases Society of America (IDSA), the Multinational Association of Supportive Care in Cancer (MASCC) and the International Society of Paediatric Oncology (SIOP). We considered randomised controlled trials (RCTs) and controlled clinical trials (CCTs) in which the serological response to influenza vaccination of children with cancer was compared with that of control groups. We also considered RCTs and CCTs that compared the effects of influenza vaccination on clinical response and/or immunological response in children with cancer being treated with chemotherapy, compared with placebo, no intervention or different dosage schedules. Two independent review authors assessed the methodological quality of included studies and extracted the data. We included 1 RCT and 9 CCTs
In 1974, Jay A. Berzofsky, M.D., Ph.D., now Chief of CCR’s Vaccine Branch, came to NIH to study protein folding. His curious mind and collaborative spirit quickly led him into the intertwined fields of immunology and vaccine development. With close to 500 publications to his name, Berzofsky has pioneered the characterization of B- and T-cell epitopes and their modification to make vaccines directed against cancer and chronic infectious diseases. He has also characterized and taken advantage of the cellular and molecular regulators of immune responses in order to enhance tumor immunity and vaccine efficacy. In the last several years, he has translated many of these strategies into promising clinical trials. From the microcosm of his laboratory, he brings the same spirit of cross-fertilizing, bench-to-bedside research to leading the Vaccine Branch as a whole.
Yeung, Man Lung; Jeang, Kuan-Teh
MicroRNAs (miRNAs) are small physiological non-coding RNAs that regulate gene expression through an RNA interference (RNAi) mechanism. The expression of miRNAs is tightly controlled both spatially and temporally. Aberrant miRNA expression has been correlated with various cancers. Recent findings suggest that some miRNAs can function as tumor suppressors or oncogenes. In model experiments, the cancer phenotype of some cells can be reverted to normal when the cells are treated with miRNA mimics or inhibitors. Here, we discuss in brief the potential utility of miRNA-based cancer therapy as well as the current limitations thwarting their useful clinical application.
Krishnan, Harini; Rayes, Julie; Miyashita, Tomoyuki; Ishii, Genichiro; Retzbach, Edward P; Sheehan, Stephanie A; Takemoto, Ai; Chang, Yao-Wen; Yoneda, Kazue; Asai, Jun; Jensen, Lasse; Chalise, Lushun; Natsume, Atsushi; Goldberg, Gary S
Podoplanin (PDPN) is a transmembrane receptor glycoprotein that is upregulated on transformed cells, cancer associated fibroblasts (CAFs), and inflammatory macrophages that contribute to cancer progression. In particular, PDPN increases tumor cell clonal capacity, epithelial mesenchymal transition (EMT), migration, invasion, metastasis, and inflammation. Antibodies, CAR-T cells, biologics, and synthetic compounds that target PDPN can inhibit cancer progression and septic inflammation in preclinical models. This review describes recent advances in how PDPN may be used as a biomarker and therapeutic target for many types of cancer including glioma, squamous cell carcinoma, mesothelioma, and melanoma. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
Palucka, Karolina; Ueno, Hideki; Zurawski, Gerard; Fay, Joseph; Banchereau, Jacques
T cells can reject established tumors when adoptively transferred into patients, thereby demonstrating that the immune system can be harnessed for cancer therapy. However, such passive immunotherapy is unlikely to maintain memory T cells that might control tumor outgrowth on the long term. Active immunotherapy with vaccines has the potential to induce tumor-specific effector and memory T cells. Vaccines act through dendritic cells (DCs) which induce, regulate and maintain T cell immunity. Cli...
Pitisuttithum, Punnee; Velicer, Christine; Luxembourg, Alain
Human papillomavirus (HPV) is the causative agent of nearly all cervical cancer cases as well as a substantial proportion of anal, vulvar, vaginal, penile and oropharyngeal cancers, making it responsible for approximately 5% of the global cancer burden. The first-generation HPV vaccines that is, quadrivalent HPV type 6/11/16/18 vaccine and bivalent HPV type 16/18 vaccine were licensed in 2006 and 2007, respectively. A second-generation 9-valent HPV type 6/11/16/18/31/33/45/52/58 vaccine with broader cancer coverage was initiated even before the first vaccines were approved. By preventing HPV infection and disease due to HPV31/33/45/52/58, the 9vHPV vaccine has the potential to increase prevention of cervical cancer from 70 to 90%. In addition, the 9vHPV vaccine has the potential to prevent 85-95% of HPV-related vulvar, vaginal and anal cancers. Overall, the 9vHPV vaccine addresses a significant unmet medical need, although further health economics and implementation research is needed.
Bleeker, Willem Aldert
Colon cancer is one of the main health issues in the western world. In the Netherlands more than 7000 patients are diagnosed yearly with this disease and half of them will die from it. Prognosis largely depends on tumor stage, which is estimated by radiological, clinical and histological
The area of immunotherapeutics for the treatment of metastatic castrate-resistant prostate cancer has made significant progress since the autologous cell-based vaccine sipuleucel T became the first and to date only immunotherapy for its treatment. This review focuses on a broad patent landscaping exercise of this therapeutic area and considers if basing this landscaping on key mechanisms of action is appropriate to elicit the main patenting trends.
Klosky, James L; Hudson, Melissa M; Chen, Yanjun; Connelly, James A; Wasilewski-Masker, Karen; Sun, Can-Lan; Francisco, Liton; Gustafson, Laura; Russell, Kathryn M; Sabbatini, Gina; Flynn, Jessica S; York, Jocelyn M; Giuliano, Anna R; Robison, Leslie L; Wong, F Lennie; Bhatia, Smita; Landier, Wendy
Purpose Cancer survivors are at high risk for human papillomavirus (HPV)-related morbidities; we estimated the prevalence of HPV vaccine initiation in cancer survivors versus the US population and examined predictors of noninitiation. Methods Participants included 982 cancer survivors (9 to 26 years of age; 1 to 5 years postcompletion of therapy); we assessed HPV vaccine initiation, sociodemographic and clinical characteristics, and vaccine-specific health beliefs; age-, sex-, and year-matched US population comparisons were from the National Immunization Survey-Teen and the National Health Interview Survey (2012-2015). Results The mean age at the time of the study was 16.3 ± 4.7 years; the mean time off therapy was 2.7 ± 1.2 years; participants were 55% male and 66% non-Hispanic white; 59% had leukemia/lymphoma. Vaccine initiation rates were significantly lower in cancer survivors versus the general population (23.8%; 95% CI, 20.6% to 27.0% v 40.5%; 95% CI, 40.2% to 40.7%; P P P young adult survivors and peers (ages 18 to 26 years) was comparably low (25.3%; 95% CI, 20.9% to 29.7% v 24.2%; 95% CI, 23.6% to 24.9%). Predictors of noninitiation included lack of provider recommendation (OR, 10.8; 95% CI, 6.5 to 18.0; P P P P P < .001; comparison, 13 to 17 years). Conclusion HPV vaccine initiation rates in cancer survivors are low. Lack of provider recommendation and barriers to vaccine receipt should be targeted in vaccine promotion efforts.
Esquerré, Michaël; Momot, Marie; Goubier, Anne; Gonindard, Christophe; Leung-Theung-Long, Stéphane; Misseri, Yolande; Bissery, Marie-Christine
GTL001 is a bivalent therapeutic vaccine containing human papillomavirus (HPV) 16 and HPV18 E7 proteins inserted in the Bordetella pertussis adenylate cyclase (CyaA) vector intended to prevent cervical cancer in HPV-infected women with normal cervical cytology or mild abnormalities. To be effective, therapeutic cervical cancer vaccines should induce both a T cell-mediated effector response against HPV-infected cells and a robust CD8 + T-cell memory response to prevent potential later infection. We examined the ability of GTL001 and related bivalent CyaA-based vaccines to induce, in parallel, effector and memory CD8 + T-cell responses to both vaccine antigens. Intradermal vaccination of C57BL/6 mice with GTL001 adjuvanted with a TLR3 agonist (polyinosinic-polycytidylic acid) or a TLR7 agonist (topical 5% imiquimod cream) induced strong HPV16 E7-specific T-cell responses capable of eradicating HPV16 E7-expressing tumors. Tumor-free mice also had antigen-specific memory T-cell responses that protected them against a subsequent challenge with HPV18 E7-expressing tumor cells. In addition, vaccination with bivalent vaccines containing CyaA-HPV16 E7 and CyaA fused to a tumor-associated antigen (melanoma-specific antigen A3, MAGEA3) or to a non-viral, non-tumor antigen (ovalbumin) eradicated HPV16 E7-expressing tumors and protected against a later challenge with MAGEA3- and ovalbumin-expressing tumor cells, respectively. These results show that CyaA-based bivalent vaccines such as GTL001 can induce both therapeutic and prophylactic anti-tumor T-cell responses. The CyaA platform can be adapted to different antigens and adjuvants, and therefore may be useful for developing other therapeutic vaccines. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.
Full Text Available Recent breakthroughs in translational oncology are opening new perspectives for the treatment of cancer. The advent of targeted therapies has provided the proof-of-concept to selectively turn-off deregulated oncogenic proteins, while the identification and validation of predictive biomarkers of response has allowed to improve, at least in some cases, their performance. Moreover, a subpopulation of tumor-propagating cells has been identified from many solid and hematological tumors. These cells share functional properties of normal stem cells, and are commonly referred to as cancer stem cells (CSCs. It is emerging that CSCs are defended against broadly-used anticancer agents by means of different, partly interconnected, mechanisms. However, CSCs rely on specific pathways involved in self-renewal that can be pharmacologically antagonized by experimental molecular targeted agents, some of which have recently entered early phases of clinical development. Here, we discuss the spectrum of pharmacological strategies under clinical or preclinical development for CSCs targeting.
Diaz, Arlhee, E-mail: email@example.com; Leon, Kalet [Department of Systems Biology, Center of Molecular Immunology, 216 Street, PO Box 16040, Atabey, Havana 11600 (Cuba)
The clinical relevance of cancer stem cells (CSC) remains a major challenge for current cancer therapies, but preliminary findings indicate that specific targeting may be possible. Recent studies have shown that these tumor subpopulations promote tumor angiogenesis through the increased production of VEGF, whereas the VEGF neutralizing antibody bevacizumab specifically inhibits CSC growth. Moreover, nimotuzumab, a monoclonal antibody against the epidermal growth factor receptor (EGFR) with a potent antiangiogenic activity, has been shown by our group to reduce the frequency of CSC-like subpopulations in mouse models of brain tumors when combined with ionizing radiation. These studies and subsequent reports from other groups support the relevance of approaches based on molecular-targeted therapies to selectively attack CSC. This review discusses the relevance of targeting both the EGFR and angiogenic pathways as valid approaches to this aim. We discuss the relevance of identifying better molecular markers to develop drug screening strategies that selectively target CSC.
Diaz, Arlhee; Leon, Kalet
The clinical relevance of cancer stem cells (CSC) remains a major challenge for current cancer therapies, but preliminary findings indicate that specific targeting may be possible. Recent studies have shown that these tumor subpopulations promote tumor angiogenesis through the increased production of VEGF, whereas the VEGF neutralizing antibody bevacizumab specifically inhibits CSC growth. Moreover, nimotuzumab, a monoclonal antibody against the epidermal growth factor receptor (EGFR) with a potent antiangiogenic activity, has been shown by our group to reduce the frequency of CSC-like subpopulations in mouse models of brain tumors when combined with ionizing radiation. These studies and subsequent reports from other groups support the relevance of approaches based on molecular-targeted therapies to selectively attack CSC. This review discusses the relevance of targeting both the EGFR and angiogenic pathways as valid approaches to this aim. We discuss the relevance of identifying better molecular markers to develop drug screening strategies that selectively target CSC
Inhibitor of Apoptosis (IAP) proteins are overexpressed in a variety of human cancers. Therefore, they are considered as promising targets for the design of therapeutic strategies. Smac mimetics mimic the endogenous mitochondrial protein Smac that antagonizes IAP proteins upon its release into the cytosol. Multiple preclinical studies have documented the ability of Smac mimetics to either directly induce cell death of cancer cells or to prime them to agents that trigger cell death. At present, several Smac mimetics are being evaluated in early clinical trials. The current review provides an overview on the potential of Smac mimetics as cancer therapeutics to target IAP proteins for cancer therapy. © 2017 Elsevier Inc. All rights reserved.
Moses Muia Masika
Full Text Available Vaccines against human papillomavirus (HPV infection have the potential to reduce the burden of cervical cancer. School-based delivery of HPV vaccines is cost-effective and successful uptake depends on school teachers' knowledge and acceptability of the vaccine. The aim of this study is to assess primary school teachers' knowledge and acceptability of HPV vaccine and to explore facilitators and barriers of an ongoing Gavi Alliance-supported vaccination program in Kitui County, Kenya.This was a cross-sectional, mixed methods study in Central Division of Kitui County where the Ministry of Health is offering the quadrivalent HPV vaccine to grade four girls. Data on primary school teachers' awareness, knowledge and acceptability of HPV vaccine as well as facilitators and barriers to the project was collected through self-administered questionnaires and two focus group discussions.339 teachers (60% female completed the survey (62% response rate and 13 participated in 2 focus group discussions. Vaccine awareness among teachers was high (90%, the level of knowledge about HPV and cervical cancer among teachers was moderate (48%, SD = 10.9 and females scored higher than males (50% vs. 46%, p = 0.002. Most teachers (89% would recommend the vaccine to their daughter or close relatives. Those who would recommend the vaccine had more knowledge than those who would not (p = <0.001. The main barriers were insufficient information about the vaccine, poor accessibility of schools, absenteeism of girls on vaccine days, and fear of side effects.Despite low to moderate levels of knowledge about HPV vaccine among school teachers, vaccine acceptability is high. Teachers with little knowledge on HPV vaccine are less likely to accept the vaccine than those who know more; this may affect uptake if not addressed. Empowering teachers to be vaccine champions in their community may be a feasible way of disseminating information about HPV vaccine and cervical cancer.
C.; Senzer, N.; Netto, G.; Rich, D.; Mhashilkar, A.; Parker, K.; Coffee , K.; Ramesh, R.; Ekmekcioglu, S.; Grimm, E.A.; van Wart Hood, J.; Merritt, J...Vukelja, S.; Richards, D.; Hood, J.; Coffee , K.; Nemunaitis, J. Mol. Ther., 2005, 11, 149.  Degos, L. J. Cell Physiol., 1997, 173, 285.  Sachs, L...Cancer Immunol. Immunother., 1989, 30, 262.  Guarini, L.; Graham, G.M.; Jiang, H.; Ferrone, S.; Zucker, S.; Fisher, P.B. Pigment Cell Res., 1992
Lin, May Young
The growing number of tuberculosis (TB) casualties urges development of not only more effective drugs and preventive vaccines but also development of post-exposure/therapeutic TB vaccines. Post-exposure/therapeutic TB vaccines are needed since 2 billion people worldwide harbor a latent Mycobacterium
Jin, Liting; Han, Bingchen; Siegel, Emily; Cui, Yukun; Giuliano, Armando; Cui, Xiaojiang
Distant metastasis accounts for the vast majority of deaths in patients with cancer. Breast cancer exhibits a distinct metastatic pattern commonly involving bone, liver, lung, and brain. Breast cancer can be divided into different subtypes based on gene expression profiles, and different breast cancer subtypes show preference to distinct organ sites of metastasis. Luminal breast tumors tend to metastasize to bone while basal-like breast cancer (BLBC) displays a lung tropism of metastasis. However, the mechanisms underlying this organ-specific pattern of metastasis still remain to be elucidated. In this review, we will summarize the recent advances regarding the molecular signaling pathways as well as the therapeutic strategies for treating breast cancer lung metastasis.
Razungles, Julie; Cavaillès, Vincent; Jalaguier, Stéphan; Teyssier, Catherine
Cancer cell metabolism described by Otto Warburg in the thirties became a cancer specific hallmark, also called "Warburg effect". Cancer cells use essentially glucose as fuel, through glycolysis, in order to meet their energy and biomass needs to insure their cell proliferation. Recent advances describe Warburg effect regulation by oncogenes and tumor suppressor genes. Moreover, mutations in some glycolysis enzymes are found in various cancers, highlighting the role of cell metabolism in cancer. In this review, we describe the mechanisms responsible for the Warburg effect at the molecular and cellular level, the role of cell signalling along with the implication of different transcription factors. As a cause or a consequence of tumorigenesis, the Warburg effect is now considered as a promising therapeutic target in the fight against cancer. © 2013 médecine/sciences – Inserm.
Xu, Xin; Hegazy, Wael A H; Guo, Linjie; Gao, Xiuhua; Courtney, Amy N; Kurbanov, Suhrab; Liu, Daofeng; Tian, Gengwen; Manuel, Edwin R; Diamond, Don J; Hensel, Michael; Metelitsa, Leonid S
Vaccines explored for cancer therapy have been based generally on injectable vector systems used to control foreign infectious pathogens, to which the immune system evolved to respond naturally. However, these vectors may not be effective at presenting tumor-associated antigens (TAA) to the immune system in a manner that is sufficient to engender antitumor responses. We addressed this issue with a novel orally administered Salmonella-based vector that exploits a type III secretion system to deliver selected TAA in the cytosol of professional antigen-presenting cells in situ. A systematic comparison of candidate genes from the Salmonella Pathogenicity Island 2 (SPI2) locus was conducted in the vaccine design, using model antigens and a codon-optimized form of the human TAA survivin (coSVN), an oncoprotein that is overexpressed in most human cancers. In a screen of 20 SPI2 promoter:effector combinations, a PsifB::sseJ combination exhibited maximal potency for antigen translocation into the APC cytosol, presentation to CD8 T cells, and murine immunogenicity. In the CT26 mouse model of colon carcinoma, therapeutic vaccination with a lead PsifB::sseJ-coSVN construct (p8032) produced CXCR3-dependent infiltration of tumors by CD8 T cells, reversed the CD8:Treg ratio at the tumor site, and triggered potent antitumor activity. Vaccine immunogenicity and antitumor potency were enhanced by coadministration of the natural killer T-cell ligand 7DW8-5, which heightened the production of IL12 and IFNγ. Furthermore, combined treatment with p8032 and 7DW8-5 resulted in complete tumor regression in A20 lymphoma-bearing mice, where protective memory was demonstrated. Taken together, our results demonstrate how antigen delivery using an oral Salmonella vector can provide an effective platform for the development of cancer vaccines. ©2014 American Association for Cancer Research.
Karpf, Adam R
The discovery of epigenetic silencing as a key mechanism of tumor suppressor gene inactivation in human cancer has led to great interest in utilizing epigenetic modulatory drugs as cancer therapeutics. It is less appreciated that medically important tumor-associated antigens, particularly the Cancer Testis or Cancer/Germ-line family of antigens (CG antigens), which are being actively tested as cancer vaccine targets, are epigenetically activated in many human cancers. However, a major limitation to the therapeutic value of CG antigen-directed vaccines is the limited and heterogeneous expression of CG antigens in tumors. Recent work has begun to dissect the specific epigenetic mechanisms controlling differential expression of CG antigen genes in human cancers. From a clinical perspective, convincing data indicate that epigenetic modulatory agents, including DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors, robustly promote the expression of CG antigens, as well as class I major histocompatibility complex (MHC I) and other immune costimulatory molecules, in tumors. Importantly, the effects of these agents on CG antigen gene expression often show marked specificity for tumor cells as compared to normal cells. Taken together, these data encourage clinical evaluation of combination therapies involving epigenetic modulatory drugs and CG antigen-directed tumor vaccines for the treatment of human malignancies.
or acting in concert regulate different biological processes and under what cellular circumstances. The question of the activity of Pim iso - forms...Gibbons JJ, Abraham RT, Yu K (2009) Mammalian target of rapamycin: Discovery of rapamydn reveals a signaling pathway important for norma ! and cancer cell...Cells were harvested in lysis buffer A consisting of 50 mmol/L Tris, pH 7.4, ISO mmoi/L NaCI, I% NP-40, aad 5 mmoi/L EDTA. Protein concentrations
Full Text Available Epigenetic modifications and alterations in chromatin structure and function contribute to the cumulative changes observed as normal cells undergo malignant transformation. These modifications and enzymes (DNA methyltransferases, histone deacetylases, histone methyltransferases, and demethylases related to them have been deeply studied to develop new drugs, epigenome-targeted therapies and new diagnostic tools. Epigenetic modifiers aim to restore normal epigenetic modification patterns through the inhibition of epigenetic modifier enzymes. Four of them (azacitidine, decitabine, vorinostat and romidepsin are approved by the U.S. Food and Drug Administration. This article provides an overview about the known functional roles of epigenetic enzymes in cancer development.
Ferrigno, R.; Petitto, J.V.
Osseous metastases are the most frequent sites of dissemination in breast cancer and diminish the quality of patients life, being one of the most serious problems of the disease. The authors discuss the clinical, diagnosis and therapeutic aspects, based on their own experience and data from the literature. (author)
Wu, Miaowei; Wang, Guosheng; Tian, Wei; Deng, Yongchuan; Xu, Yibing
miRNA, a small non-coding RNA molecule containing about 22 nucleotides, functions in RNA silencing and post-transcriptional regulation of gene expression. With these qualities, miRNAs modulate multiple signaling pathways involved in cancer development, such as cellular proliferation, apoptosis, and migration. The goal of this review is to discuss possible miRNAs-based therapeutic strategies, through defining performance of miRNAs in carcinogenesis, in particular in lung cancer. miRNA, a non-coding RNA, is divided into two main types: tumor suppressor miRNAs and oncogenic miRNAs. In addition, special processed miRNAs can be an assistant therapeutic tool. In order to develope antitumor therapy, miRNAs-based therapeutic strategies are worth of deeper studies. In this process, the stability, effectiveness, and side effects should be considered. Copyright© Bentham Science Publishers; For any queries, please email at firstname.lastname@example.org.
Kumer Biswas, Amit; Reazul Islam, Md; Sadek Choudhury, Zahid; Mostafa, Asif; Fahim Kadir, Mohammad
The current decades are marked not by the development of new molecules for the cure of various diseases but rather the development of new delivery methods for optimum treatment outcome. Nanomedicine is perhaps playing the biggest role in this concern. Nanomedicine offers numerous advantages over conventional drug delivery approaches and is particularly the hot topic in anticancer research. Nanoparticles (NPs) have many unique criteria that enable them to be incorporated in anticancer therapy. This topical review aims to look at the properties and various forms of NPs and their use in anticancer treatment, recent development of the process of identifying new delivery approaches as well as progress in clinical trials with these newer approaches. Although the outcome of cancer therapy can be increased using nanomedicine there are still many disadvantages of using this approach. We aim to discuss all these issues in this review.
Biswas, Amit Kumer; Islam, Md Reazul; Choudhury, Zahid Sadek; Kadir, Mohammad Fahim; Mostafa, Asif
The current decades are marked not by the development of new molecules for the cure of various diseases but rather the development of new delivery methods for optimum treatment outcome. Nanomedicine is perhaps playing the biggest role in this concern. Nanomedicine offers numerous advantages over conventional drug delivery approaches and is particularly the hot topic in anticancer research. Nanoparticles (NPs) have many unique criteria that enable them to be incorporated in anticancer therapy. This topical review aims to look at the properties and various forms of NPs and their use in anticancer treatment, recent development of the process of identifying new delivery approaches as well as progress in clinical trials with these newer approaches. Although the outcome of cancer therapy can be increased using nanomedicine there are still many disadvantages of using this approach. We aim to discuss all these issues in this review. (review)
ABSTRACT: BACKGROUND: Immunological therapies enhance the ability of the immune system to recognise and destroy cancer cells via selective killing mechanisms. DNA vaccines have potential to activate the immune system against specific antigens, with accompanying potent immunological adjuvant effects from unmethylated CpG motifs as on prokaryotic DNA. We investigated an electroporation driven plasmid DNA vaccination strategy in animal models for treatment of prostate cancer. METHODS: Plasmid expressing human PSA gene (phPSA) was delivered in vivo by intra-muscular electroporation, to induce effective anti-tumour immune responses against prostate antigen expressing tumours. Groups of male C57 BL\\/6 mice received intra-muscular injections of phPSA plasmid. For phPSA delivery, quadriceps muscle was injected with 50 mug plasmid. After 80 seconds, square-wave pulses were administered in sequence using a custom designed pulse generator and acustom-designed applicator with 2 needles placed through the skin central to the muscle. To determine an optimum treatment regimen, three different vaccination schedules were investigated. In a separate experiment, the immune potential of the phPSA vaccine was further enhanced with co- administration of synthetic CpG rich oligonucleotides. One week after last vaccination, the mice were challenged subcutaneously with TRAMPC1\\/hPSA (prostate cancer cell line stably expressing human PSA) and tumour growth was monitored. Serum from animals was examined by ELISA for anti-hPSA antibodies and for IFNgamma. Histological assessment of the tumours was also carried out. In vivo and in vitro cytotoxicity assays were performed with splenocytes from treated mice. RESULTS: The phPSA vaccine therapy significantly delayed the appearance of tumours and resulted in prolonged survival of the animals. Four-dose vaccination regimen provided optimal immunological effects. Co - administration of the synthetic CpG with phPSA increased anti-tumour responses
Bitton, Roberto J; Guthmann, Marcel D; Gabri, Mariano R; Carnero, Ariel J L; Alonso, Daniel F; Fainboim, Leonardo; Gomez, Daniel E
Vaccine development is one of the most promising and exciting fields in cancer research; numerous approaches are being studied to developed effective cancer vaccines. The aim of this form of therapy is to teach the patient's immune system to recognize the antigens expressed in tumor cells, but not in normal tissue, to be able to destroy these abnormal cells leaving the normal cells intact. In other words, is an attempt to teach the immune system to recognize antigens that escaped the immunologic surveillance and are by it, therefore able to survive and, in time, disseminate. However each research group developing a cancer vaccine, uses a different technology, targeting different antigens, combining different carriers and adjuvants, and using different immunization schedules. Most of the vaccines are still experimental and not approved by the US or European Regulatory Agencies. In this work, we will offer an update in the knowledge in cancer immunology and all the anticancer vaccine approaches, with special emphasis in ganglioside based vaccines. It has been demonstrated that quantitative and qualitative changes occur in ganglioside expression during the oncogenic transformation. Malignant transformation appears to activate enzymes associated with ganglioside glycosylation, resulting in altered patterns of ganglioside expression in tumors. Direct evidence of the importance of gangliosides as potential targets for active immunotherapy has been suggested by the observation that human monoclonal antibodies against these glycolipids induce shrinkage of human cutaneous melanoma metastasis. Thus, the cellular over-expression and shedding of gangliosides into the interstitial space may play a central role in cell growth regulation, immune tolerance and tumor-angiogenesis, therefore representing a new target for anticancer therapy. Since 1993 researchers at the University of Buenos Aires and the University of Quilmes (Argentina), have taken part in a project carried out by
Inhibitor of Apoptosis (IAP) proteins block programmed cell death and are expressed at high levels in various human cancers, thus making them attractive targets for cancer drug development. Second mitochondrial activator of caspases (Smac) mimetics are small-molecule inhibitors that mimic Smac, an endogenous antagonist of IAP proteins. Preclinical studies have shown that Smac mimetics can directly trigger cancer cell death or, even more importantly, sensitize tumor cells for various cytotoxic therapies, including conventional chemotherapy, radiotherapy, or novel agents. Currently, several Smac mimetics are under evaluation in early clinical trials as monotherapy or in rational combinations (i.e., GDC-0917/CUDC-427, LCL161, AT-406/Debio1143, HGS1029, and TL32711/birinapant). This review discusses the promise as well as some challenges at the translational interface of exploiting Smac mimetics as cancer therapeutics. ©2015 American Association for Cancer Research.
Rosenberg, Steven A.; Yang, James C.; Schwartzentruber, Douglas J.; Hwu, Patrick; Marincola, Francesco M.; Topalian, Suzanne L.; Restifo, Nicholas P.; Dudley, Mark E.; Schwarz, Susan L.; Spiess, Paul J.; Wunderlich, John R.; Parkhurst, Maria R.; Kawakami, Yutaka; Seipp, Claudia A.; Einhorn, Jan H.; White, Donald E.
The cloning of the genes encoding cancer antigens has opened new possibilities for the treatment of patients with cancer. In this study, immunodominant peptides from the gp100 melanoma-associated antigen were identified, and a synthetic peptide, designed to increase binding to HLA-A2 molecules, was used as a cancer vaccine to treat patients with metastatic melanoma. On the basis of immunologic assays, 91% of patients could be successfully immunized with this synthetic peptide, and 13 of 31 patients (42%) receiving the peptide vaccine plus IL-2 had objective cancer responses, and four additional patients had mixed or minor responses. Synthetic peptide vaccines based on the genes encoding cancer antigens hold promise for the development of novel cancer immunotherapies. PMID:9500606
Anthony J. Berdis
Full Text Available Inhibiting DNA synthesis is an important therapeutic strategy that is widely used to treat a number of hyperproliferative diseases including viral infections, autoimmune disorders, and cancer. This chapter describes two major categories of therapeutic agents used to inhibit DNA synthesis. The first category includes purine and pyrmidine nucleoside analogs that directly inhibit DNA polymerase activity. The second category includes DNA damaging agents including cisplatin and chlorambucil that modify the composition and structure of the nucleic acid substrate to indirectly inhibit DNA synthesis. Special emphasis is placed on describing the molecular mechanisms of these inhibitory effects against chromosomal and mitochondrial DNA polymerases. Discussions are also provided on the mechanisms associated with resistance to these therapeutic agents. A primary focus is toward understanding the roles of specialized DNA polymerases that by-pass DNA lesions produced by DNA damaging agents. Finally, a section is provided that describes emerging areas in developing new therapeutic strategies targeting specialized DNA polymerases.
Obel, J; McKenzie, J; Buenconsejo-Lum, L E
guidelines and policies for HPV vaccination. CONCLUSION: Current practices to prevent cervical cancer in the Pacific Region do not match the high burden of disease from cervical cancer. A regional approach, including reducing vaccine prices by bulk purchase of vaccine, technical support for implementation...
Roč. 47, č. 5 (2001), s. 153-155 ISSN 0015-5500 R&D Projects: GA MZd NC5526 Keywords : dendritic cells * cancer vaccines Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 0.519, year: 2001
Jul 14, 2012 ... first sexual exposure, and secondarily through screening and treatment of identified precancerous lesions. Aim: To determine the awareness and acceptability of the HPV vaccine and screening for cervical cancer among female health-care workers in Enugu, southeastern Nigeria. Materials and Methods: ...
Aim: To determine the awareness and acceptability of the HPV vaccine and screening for cervical cancer among female health-care workers in Enugu, southeastern Nigeria. Materials and Methods: Questionnaires were administered to a cross-section of 177 female health-care workers selected systematically from the ...
Ononye, S N; Shi, W; Wali, V B; Aktas, B; Jiang, T; Hatzis, C; Pusztai, L
The functional redundancy of metabolic enzyme expression may present a new strategy for developing targeted therapies in cancer. To satisfy the increased metabolic demand required during neoplastic transformations and proliferation, cancer cells may rely on additional isoforms of a metabolic enzyme to satisfy the increased demand for metabolic precursors, which could subsequently render cancer cells more vulnerable to isoform-specific inhibitors. In this review, we provide a survey of common isoenzyme shifts that have been reported to be important in cancer metabolism and link those to metabolic pathways that currently have drugs in various stages of development. This phenomenon suggests a potentially new therapeutic strategy for the treatment of cancer by identifying shifts in the expression of metabolic isoenzymes between cancer and normal cells. We also delineate other putative metabolic isoenzymes that could be targets for novel targeted therapies for cancer. Changes in isoenzyme expression that occur during neoplastic transformations or in response to environmental pressure in cancer cells may result in isoenzyme diversity that may subsequently render cancer cells more vulnerable to isoform-specific inhibitors due to reliance on a single isoform to perform a vital enzymatic function.
Byeong Mo Kim
Full Text Available Ionizing radiation (IR, such as X-rays and gamma (γ-rays, mediates various forms of cancer cell death such as apoptosis, necrosis, autophagy, mitotic catastrophe, and senescence. Among them, apoptosis and mitotic catastrophe are the main mechanisms of IR action. DNA damage and genomic instability contribute to IR-induced cancer cell death. Although IR therapy may be curative in a number of cancer types, the resistance of cancer cells to radiation remains a major therapeutic problem. In this review, we describe the morphological and molecular aspects of various IR-induced types of cell death. We also discuss cytogenetic variations representative of IR-induced DNA damage and genomic instability. Most importantly, we focus on several pathways and their associated marker proteins responsible for cancer resistance and its therapeutic implications in terms of cancer cell death of various types and characteristics. Finally, we propose radiation-sensitization strategies, such as the modification of fractionation, inflammation, and hypoxia and the combined treatment, that can counteract the resistance of tumors to IR.
Kim, Byeong Mo; Hong, Yunkyung; Lee, Seunghoon; Liu, Pengda; Lim, Ji Hong; Lee, Yong Heon; Lee, Tae Ho; Chang, Kyu Tae; Hong, Yonggeun
Ionizing radiation (IR), such as X-rays and gamma (γ)-rays, mediates various forms of cancer cell death such as apoptosis, necrosis, autophagy, mitotic catastrophe, and senescence. Among them, apoptosis and mitotic catastrophe are the main mechanisms of IR action. DNA damage and genomic instability contribute to IR-induced cancer cell death. Although IR therapy may be curative in a number of cancer types, the resistance of cancer cells to radiation remains a major therapeutic problem. In this review, we describe the morphological and molecular aspects of various IR-induced types of cell death. We also discuss cytogenetic variations representative of IR-induced DNA damage and genomic instability. Most importantly, we focus on several pathways and their associated marker proteins responsible for cancer resistance and its therapeutic implications in terms of cancer cell death of various types and characteristics. Finally, we propose radiation-sensitization strategies, such as the modification of fractionation, inflammation, and hypoxia and the combined treatment, that can counteract the resistance of tumors to IR. PMID:26569225
Cross-sectional and longitudinal analysis of cancer vaccination trials registered on the US Clinical Trials Database demonstrates paucity of immunological trial endpoints and decline in registration since 2008
Janowitz, Tobias; Lu,Liangjian; Yan,Haixi; Shyam-Sundar,Vijay
Liangjian Lu,1 Haixi Yan,1 Vijay Shyam-Sundar,1 Tobias Janowitz2 1School of Clinical Medicine, 2Cancer Research UK, Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK Introduction: Cancer vaccination has been researched as a means of treating and preventing cancer, but successful translational efforts yielding clinical therapeutics have been limited. Numerous reasons have been offered in explanation, pertaining both to the vaccine formulation, and the clinical tri...
Kotiyal, Srishti; Bhattacharya, Susinjan, E-mail: email@example.com
Highlights: • Therapeutic targeting or inhibition of the key molecules of signaling pathways can control growth of breast cancer stem cells (BCSCs). • Development of BCSCs also involves miRNA interactions. • Therapeutic achievement can be done by targeting identified targets in the BCSC pathways. - Abstract: A small heterogeneous population of breast cancer cells acts as seeds to induce new tumor growth. These seeds or breast cancer stem cells (BCSCs) exhibit great phenotypical plasticity which allows them to undergo “epithelial to mesenchymal transition” (EMT) at the site of primary tumor and a future reverse transition. Apart from metastasis they are also responsible for maintaining the tumor and conferring it with drug and radiation resistance and a tendency for post-treatment relapse. Many of the signaling pathways involved in induction of EMT are involved in CSC generation and regulation. Here we are briefly reviewing the mechanism of TGF-β, Wnt, Notch, TNF-α, NF-κB, RTK signalling pathways which are involved in EMT as well as BCSCs maintenance. Therapeutic targeting or inhibition of the key/accessory players of these pathways could control growth of BCSCs and hence malignant cancer. Additionally several miRNAs are dysregulated in cancer stem cells indicating their roles as oncogenes or tumor suppressors. This review also lists the miRNA interactions identified in BCSCs and discusses on some newly identified targets in the BCSC regulatory pathways like SHIP2, nicastrin, Pin 1, IGF-1R, pro-inflammatory cytokines and syndecan which can be targeted for therapeutic achievements.
Kotiyal, Srishti; Bhattacharya, Susinjan
Highlights: • Therapeutic targeting or inhibition of the key molecules of signaling pathways can control growth of breast cancer stem cells (BCSCs). • Development of BCSCs also involves miRNA interactions. • Therapeutic achievement can be done by targeting identified targets in the BCSC pathways. - Abstract: A small heterogeneous population of breast cancer cells acts as seeds to induce new tumor growth. These seeds or breast cancer stem cells (BCSCs) exhibit great phenotypical plasticity which allows them to undergo “epithelial to mesenchymal transition” (EMT) at the site of primary tumor and a future reverse transition. Apart from metastasis they are also responsible for maintaining the tumor and conferring it with drug and radiation resistance and a tendency for post-treatment relapse. Many of the signaling pathways involved in induction of EMT are involved in CSC generation and regulation. Here we are briefly reviewing the mechanism of TGF-β, Wnt, Notch, TNF-α, NF-κB, RTK signalling pathways which are involved in EMT as well as BCSCs maintenance. Therapeutic targeting or inhibition of the key/accessory players of these pathways could control growth of BCSCs and hence malignant cancer. Additionally several miRNAs are dysregulated in cancer stem cells indicating their roles as oncogenes or tumor suppressors. This review also lists the miRNA interactions identified in BCSCs and discusses on some newly identified targets in the BCSC regulatory pathways like SHIP2, nicastrin, Pin 1, IGF-1R, pro-inflammatory cytokines and syndecan which can be targeted for therapeutic achievements
S C Mohapatra; V K Srivastava; P Mohapatra; J NP Gupta; J Tandon
The natural history of a diseases is greatly influenced by the course of therapeutic management. Just after the tissue stage of the disease is aver. The cure rate of diseases, particularly those of cancers, could probably be modified to a greater extent, if the natural history of the therapeutic management is understood properly, so that the community education programme be organised in the proper direction, to trigger early diagnosis. Home remedy urn the first preference of 76.8% of oral ca...
Lam, Samuel Siu Kit; Chen, Wei R.
Cancer immunotherapy is the concept of harnessing our own immune system to fight against cancer cells. The most attractive features of immunotherapy include relatively low toxicities compared to traditional therapies (surgery, chemotherapy and radiation), the possibility of eliminating distant metastases and the potential of preventing relapses. After decades of research, its therapeutic efficacy has finally been recognized and a number of approaches has been approved by the FDA over the past 10 years. Dendritic cell vaccine and checkpoint blockade strategies were among the first to enter the clinic, with many other strategies such as peptide vaccine, whole cell tumor vaccine, and adoptive T cell transfer (with Chimeric Antigen Receptors) etc. closely following in clinical trials. Immunophotonics is developing a novel in situ autologous cancer vaccine (InCVAX) by combining thermal laser phototherapy with immunotherapy. InCVAX is a two-step procedure: (1) Delivery of low-power thermal laser to any accessible tumor to cause partial cell death, increase tumor immunogenicity by releasing tumor antigens and Damage Associated Molecular Patterns (DAMPs). This is followed immediately by (2) injection of our proprietary immunostimulant, N-dihydro-acetylglucosamine (GC), into the laser-treated region to stimulate antigen presenting cells. These two steps work synergistically to enhance the systemic anti-tumor T cell response which is capable of eliminating both primary and metastatic cancers in some patients with advanced, stage III/IV, breast cancer with minimal toxicity. Our approach has the unique benefits of stimulating an immune response against a wide array of tumor antigens, and thus the potential to induce a strong, comprehensive and long-term anti-tumor protection in patients with minimal costs. Following early data showing efficacy in breast cancer patients, a multi-center, randomized clinical trial is currently underway in South America to consolidate the findings
Wei, Wei-Zen; Jones, Richard F; Juhasz, Csaba; Gibson, Heather; Veenstra, Jesse
Advances in cancer vaccine development are facilitated by animal models reflecting key features of human cancer and its interface with host immunity. Several series of transplantable preneoplastic and neoplastic mouse mammary lesions have been used to delineate mechanisms of anti-tumor immunity. Mimicking immune tolerance to tumor-associated antigens (TAA) such as HER2/neu, transgenic mice developing spontaneous mammary tumors are strong model systems for pre-clinical vaccine testing. In these models, HER2 DNA vaccines are easily administered, well-tolerated, and induce both humoral and cellular immunity. Although engineered mouse strains have advanced cancer immunotherapy, basic shortcomings remain. For example, multiple mouse strains have to be tested to recapitulate genetic regulation of immune tolerance in humans. Outbred domestic felines more closely parallel humans in the natural development of HER2 positive breast cancer and their varying genetic background. Electrovaccination with heterologous HER2 DNA induces robust adaptive immune responses in cats. Importantly, homologous feline HER2 DNA with a single amino acid substitution elicits unique antibodies to feline mammary tumor cells, unlocking a new vaccine principle. As an alternative approach to targeted vaccination, non-surgical tumor ablation such as cryoablation induces anti-tumor immunity via in situ immunization, particularly when combined with toll-like receptor (TLR) agonist. As strategies for vaccination advance, non-invasive monitoring of host response becomes imperative. As an example, magnetic resonance imaging (MRI) and positron emission tomography (PET) scanning following administration of tryptophan metabolism tracer [11C]-alpha-methyl-tryptophan (AMT) provides non-invasive imaging of both tumor growth and metabolic activities. Because AMT is a substrate of indoleamine-pyrrole 2,3-dioxygenase (IDO), an enzyme that produces the immune regulatory molecule kynurenine, AMT imaging can provide
Fleury, Herve; Tumiotto, Camille; Bellecave, Pantxika; Recordon-Pinson, Patricia
The scientific and medical community is seeking to cure HIV. Several pathways have been or are being explored including therapeutic vaccination. Viroimmunological studies on primary infection as well as on elite controllers have demonstrated the importance of the cytotoxic CD8 response and have mainly oriented research on vaccine constructs toward this type of response. The results of these trials are clearly not commensurate with the hope placed in them. Might there be one or more uncontrolled variables? The genetics of patients need to be taken into consideration, especially their human lymphocyte antigen (HLA) alleles. There is a need to find a balance between the conservation of cytotoxic T lymphocyte (CTL) epitopes and presentation by HLA alleles. The pathway is a narrow one between adaptation of the virus to HLA I restriction and the definition of conserved proviral CTL epitopes presentable by HLA I alleles. It is likely that the genetics of patients will need to be considered for HIV-1 vaccine studies and that multidisciplinary collaboration will be essential in this field of infectious diseases.
Meena K. Sakharkar
Full Text Available PPARs are ligand activated transcription factors. PPARγ agonists have been reported as a new and potentially efficacious treatment of inflammation, diabetes, obesity, cancer, AD, and schizophrenia. Since cancer cells show dysregulation of glycolysis they are potentially manageable through changes in metabolic environment. Interestingly, several of the genes involved in maintaining the metabolic environment and the central energy generation pathway are regulated or predicted to be regulated by PPARγ. The use of synthetic PPARγ ligands as drugs and their recent withdrawal/restricted usage highlight the lack of understanding of the molecular basis of these drugs, their off-target effects, and their network. These data further underscores the complexity of nuclear receptor signalling mechanisms. This paper will discuss the function and role of PPARγ in energy metabolism and cancer biology in general and its emergence as a promising therapeutic target in breast cancer.
Ferroni, Letizia; Gardin, Chiara; Della Puppa, Alessandro; Sivolella, Stefano; Brunello, Giulia; Scienza, Renato; Bressan, Eriberto; D'Avella, Domenico; Zavan, Barbara
Despite progress in surgery, radiotherapy, and in chemotherapy, an effective curative treatment of brain cancer, specifically malignant gliomas, does not yet exist. The efficacy of current anti-cancer strategies in brain tumors is limited by the lack of specific therapies against malignant cells. Besides, the delivery of the drugs to brain tumors is limited by the presence of the blood-brain barrier. Nanotechnology today offers a unique opportunity to develop more effective brain cancer imaging and therapeutics. In particular, the development of nanocarriers that can be conjugated with several functional molecules including tumor-specific ligands, anticancer drugs, and imaging probes, can provide new devices which are able to overcome the difficulties of the classical strategies. Nanotechnology-based approaches hold great promise for revolutionizing brain cancer medical treatments, imaging, and diagnosis.
Perez Machin, Maikel; Torre Santos, Ana V de la; Perez Ramirez, Kirenia; Marinello, Patricia; Suarez Martinez, Giselle
Among the best-studied antigenic systems, which have their expression increased in the membrane of tumor cells, are the gangliosides. Several clinical trials with therapeutic vaccines containing N-glycolylated gangliosides have been made in Cuba by the Center Molecular Immunology. One of these studies, it is the trial: 'Specific active immunotherapy with the vaccine preparation NGcGM3 / VSSP / Montanide ISA 51 in the treatment of patients with breast cancer metastatic. Phase II'. In order to assess the major events events related to this product, were reviewed the medical records of total patients in the clinical trial performed in the service Oncology Hospital Universitario 'Celestino Hernandez Robau' Villa Clara. (Author)
Asif, Arun; Manzoor, Sobia; Tuz-Zahra, Fatima; Saalim, Muhammad; Ashraf, Maliha; Ishtiyaq, Javeria; Khalid, Madiha
The sudden emergence of infectious pathogens such as Zika virus (ZIKV) holds global health concerns. Recent dissemination of ZIKV from Pacific to Americas with an upsurge of congenital anomalies and Guillain Barre Syndrome (GBS) in adults has created an alarming situation. High-throughput studies are in progress to understand ZIKV's mode of pathogenesis and mechanism of immune escape, yet the pathogenesis remains obscure. Mainly ZIKV's envelope (E) protein and nonstructural proteins (mainly NS1 and NS5) manipulate host cell to support viral immune escape by modulation of the interferon pathway and complement antagonism. The development of direct therapeutics for ZIKV infection is required to overcome the rapidly evolving viral threat. Currently, the existing strategies for ZIKV treatment are only supportive. Although, there is no prophylactic or therapeutic vaccine presently available, however, recent efforts have brought up ZIKV vaccines into clinical trial phase 1. This review presents the highlights of recent advances in understanding immune evasion strategies adapted by ZIKV and existing therapies against the virus.
Many cell types were known to have migratory properties towards tumors and different research groups have shown reliable results regarding cells as delivery vehicles of therapeutics for targeted cancer treatment. Present report discusses proof of concept for 1. Cell mediated delivery of Magnetic nanoparticles (MNPs) and targeted Magnetic hyperthermia (MHT) as a cancer treatment by using in vivo mouse cancer models, 2. Cells surface engineering with chimeric proteins for targeted cancer treatment by using in vitro models. 1. Tumor homing cells can carry MNPs specifically to the tumor site and tumor burden will decrease after alternating magnetic field (AMF) exposure. To test this hypothesis, first we loaded Fe/Fe3O4 bi-magnetic NPs into neural progenitor cells (NPCs), which were previously shown to migrate towards melanoma tumors. We observed that NPCs loaded with MNPs travel to subcutaneous melanoma tumors. After alternating magnetic field (AMF) exposure, the targeted delivery of MNPs by the NPCs resulted in a mild decrease in tumor size (Chapter-2). Monocytes/macrophages (Mo/Ma) are known to infiltrate tumor sites, and also have phagocytic activity which can increase their uptake of MNPs. To test Mo/Ma-mediated MHT we transplanted Mo/Ma loaded with MNPs into a mouse model of pancreatic peritoneal carcinomatosis. We observed that MNP-loaded Mo/Ma infiltrated pancreatic tumors and, after AMF treatment, significantly prolonged the lives of mice bearing disseminated intraperitoneal pancreatic tumors (Chapter-3). 2. Targeted cancer treatment could be achieved by engineering tumor homing cell surfaces with tumor proteases cleavable, cancer cell specific recombinant therapeutic proteins. To test this, Urokinase and Calpain (tumor specific proteases) cleavable; prostate cancer cell (CaP) specific (CaP1 targeting peptide); apoptosis inducible (Caspase3 V266ED3)- rCasp3V266ED3 chimeric protein was designed in silico. Hypothesized membrane anchored chimeric protein (rCasp3V
Halim, S S; Collins, D N; Ramsingh, A I
The ultimate goal in the treatment of HIV-infected persons is to prevent disease progression. A strategy to accomplish this goal is to use chemotherapy to reduce viral load followed by immunotherapy to stimulate HIV-specific immune responses that are observed in long-term asymptomatic individuals. An effective, live, recombinant virus, expressing HIV sequences, would be capable of inducing both CTL and CD4(+) helper T cell responses. To accomplish these goals, the viral vector must be immunogenic yet retain its avirulent phenotype in a T cell-deficient host. We have identified a coxsackievirus variant, CB4-P, that can induce protective immunity against a virulent variant. In addition, the CB4-P variant remains avirulent in mice lacking CD4(+) helper T cells, suggesting that CB4-P may be uniquely suited as a viral vector for a therapeutic HIV vaccine. Two strategies designed to elicit CTL and CD4(+) helper T cell responses were used to construct CB4-P/HIV recombinants. Recombinant viruses were viable, genetically stable, and retained the avirulent phenotype of the parental virus. In designing a viral vector for vaccine development, an issue that must be addressed is whether preexisting immunity to the vector would affect subsequent administration of the recombinant virus. Using a test recombinant, we showed that prior exposure to the parental CB4-P virus did not affect the ability of the recombinant to induce a CD4(+) T cell response against the foreign sequence. The results suggest that a "cocktail" of coxsackie/HIV recombinants may be useful as a therapeutic HIV vaccine.
José Manuel Calderón-Montaño
Full Text Available Cardiac glycosides, also known as cardiotonic steroids, are a group of natural products that share a steroid-like structure with an unsaturated lactone ring and the ability to induce cardiotonic effects mediated by a selective inhibition of the Na+/K+-ATPase. Cardiac glycosides have been used for many years in the treatment of cardiac congestion and some types of cardiac arrhythmias. Recent data suggest that cardiac glycosides may also be useful in the treatment of cancer. These compounds typically inhibit cancer cell proliferation at nanomolar concentrations, and recent high-throughput screenings of drug libraries have therefore identified cardiac glycosides as potent inhibitors of cancer cell growth. Cardiac glycosides can also block tumor growth in rodent models, which further supports the idea that they have potential for cancer therapy. Evidence also suggests, however, that cardiac glycosides may not inhibit cancer cell proliferation selectively and the potent inhibition of tumor growth induced by cardiac glycosides in mice xenografted with human cancer cells is probably an experimental artifact caused by their ability to selectively kill human cells versus rodent cells. This paper reviews such evidence and discusses experimental approaches that could be used to reveal the cancer therapeutic potential of cardiac glycosides in preclinical studies.
Sheikh Tasnim Jahan
Full Text Available In nanomedicine, targeted therapeutic nanoparticle (NP is a virtual outcome of nanotechnology taking the advantage of cancer propagation pattern. Tying up all elements such as therapeutic or imaging agent, targeting ligand, and cross-linking agent with the NPs is the key concept to deliver the payload selectively where it intends to reach. The microenvironment of tumor tissues in lymphatic vessels can also help targeted NPs to achieve their anticipated accumulation depending on the formulation objectives. This review accumulates the application of poly(lactic-co-glycolic acid (PLGA and polyethylene glycol (PEG based NP systems, with a specific perspective in cancer. Nowadays, PLGA, PEG, or their combinations are the mostly used polymers to serve the purpose of targeted therapeutic NPs. Their unique physicochemical properties along with their biological activities are also discussed. Depending on the biological effects from parameters associated with existing NPs, several advantages and limitations have been explored in teaming up all the essential facts to give birth to targeted therapeutic NPs. Therefore, the current article will provide a comprehensive review of various approaches to fabricate a targeted system to achieve appropriate physicochemical properties. Based on such findings, researchers can realize the benefits and challenges for the next generation of delivery systems.
Sabrina Daniela Silva
Full Text Available Oral cancer cavity (OCC is associated with high incidence of loco-regional recurrences, which account for the majority of treatment failures post-surgery and radiotherapy. The time-course of relapse manifestation and metastasis are unpredictable. Relapsed OCC represents a major clinical challenge in part due to their aggressive and invasive behaviors. Chemotherapy remains the only option for advanced OCC whenever salvage surgery or re-irradiation is not feasible, but its efficacy is limited as a result of the drug resistance development. Alternatives to use of different permutations of standard cytotoxic drugs or combinations with modulators of drug resistance have led to incremental therapeutic benefits. The introduction of targeted agents and biologics against selective targets that drive cancer progression has opened-up optimism to achieve superior therapeutic activity and overcome drug resistance because, unlike the non-selective cytotoxic, the target can be monitored at molecular levels to identify patients who can benefit from the drug. This review discusses the multifactorial aspects of clinical drug resistance and emerging therapeutic approaches in recurrent OCC, emphasizing recent advances in targeted therapies, immunotherapy, and potential relevance of new concepts such as epithelial-mesenchymal transition and cancer stem cell hypothesis to drug resistance.
Vinay, Dass S; Ryan, Elizabeth P; Pawelec, Graham; Talib, Wamidh H; Stagg, John; Elkord, Eyad; Lichtor, Terry; Decker, William K; Whelan, Richard L; Kumara, H M C Shantha; Signori, Emanuela; Honoki, Kanya; Georgakilas, Alexandros G; Amin, Amr; Helferich, William G; Boosani, Chandra S; Guha, Gunjan; Ciriolo, Maria Rosa; Chen, Sophie; Mohammed, Sulma I; Azmi, Asfar S; Keith, W Nicol; Bilsland, Alan; Bhakta, Dipita; Halicka, Dorota; Fujii, Hiromasa; Aquilano, Katia; Ashraf, S Salman; Nowsheen, Somaira; Yang, Xujuan; Choi, Beom K; Kwon, Byoung S
Cancer immune evasion is a major stumbling block in designing effective anticancer therapeutic strategies. Although considerable progress has been made in understanding how cancers evade destructive immunity, measures to counteract tumor escape have not kept pace. There are a number of factors that contribute to tumor persistence despite having a normal host immune system. Immune editing is one of the key aspects why tumors evade surveillance causing the tumors to lie dormant in patients for years through "equilibrium" and "senescence" before re-emerging. In addition, tumors exploit several immunological processes such as targeting the regulatory T cell function or their secretions, antigen presentation, modifying the production of immune suppressive mediators, tolerance and immune deviation. Besides these, tumor heterogeneity and metastasis also play a critical role in tumor growth. A number of potential targets like promoting Th1, NK cell, γδ T cell responses, inhibiting Treg functionality, induction of IL-12, use of drugs including phytochemicals have been designed to counter tumor progression with much success. Some natural agents and phytochemicals merit further study. For example, use of certain key polysaccharide components from mushrooms and plants have shown to possess therapeutic impact on tumor-imposed genetic instability, anti-growth signaling, replicative immortality, dysregulated metabolism etc. In this review, we will discuss the advances made toward understanding the basis of cancer immune evasion and summarize the efficacy of various therapeutic measures and targets that have been developed or are being investigated to enhance tumor rejection. Copyright © 2015 Elsevier Ltd. All rights reserved.
Full Text Available Prophylactic vaccines are available for women and girls not yet infected with HPV, but women already infected with HPV need a treatment to prevent progression to high-grade cervical lesions and cancer. GTL001 is a bivalent therapeutic vaccine for eradicating HPV-infected cells that contains HPV16 E7 and HPV18 E7 both fused to detoxified adenylate cyclase from Bordetella pertussis, which binds specifically to CD11b+ antigen-presenting cells. This study examined the ability of therapeutic vaccination with GTL001 adjuvanted with topical imiquimod cream to induce functional HPV16 E7- and HPV18 E7-specific CD8+ T cell responses.Binding of GTL001 to human CD11b was assessed by a cell-based competition binding assay. Cellular immunogenicity of intradermal vaccination with GTL001 was assessed in C57BL/6 mice by enzyme-linked immunospot assay and in vivo killing assays. In vivo efficacy of GTL001 vaccination was investigated in the TC-1 murine HPV16 E7-expressing tumor model.GTL001 bound specifically to the human CD11b/CD18 receptor. GTL001 adjuvanted with topical 5% imiquimod cream induced HPV16 E7 and HPV18 E7-specific CD8+ T cell responses. This CD8+ T-cell response mediated in vivo killing of HPV E7-expressing cells. In the HPV16 E7-expressing tumor model, GTL001 adjuvanted with imiquimod but not imiquimod alone or a combination of unconjugated HPV16 E7 and HPV18 E7 caused complete tumor regression.GTL001 adjuvanted with topical 5% imiquimod is immunogenic and induces HPV16 E7 and HPV18 E7-specific CD8+ T cell responses that can kill HPV E7-expressing cells and eliminate HPV E7-expressing tumors.
Tung, Frank Y; Tung, Jack K; Pallikkuth, Suresh; Pahwa, Savita; Fischl, Margaret A
HIV-1 specific cellular immunity plays an important role in controlling viral replication. In this first-in-human therapeutic vaccination study, a replication-defective HIV-1 vaccine (HIVAX) was tested in HIV-1 infected participants undergoing highly active antiretroviral therapy (HAART) to enhance anti-HIV immunity (Clinicaltrials.gov, identifier NCT01428596). A010 was a randomized, placebo-controlled trial to evaluate the safety and the immunogenicity of a replication defective HIV-1 vaccine (HIVAX) given as a subcutaneous injection to HIV-1 infected participants who were receiving HAART with HIV-1 viral load 500 cells/mm(3). HIV-1 specific immune responses were monitored by INF-γ enzyme linked immunospot (Elispot) and intracellular cytokine staining (ICS) assay after vaccination. Following the randomized placebo-controlled vaccination phase, subjects who received HIVAX vaccine and who met eligibility underwent a 12-week analytical antiretroviral treatment interruption (ATI). Viral load was monitored throughout the study. HIVAX was well tolerated in trial participants. Transient grade 1 to 2 (mild to moderate) injection site reactions occurred in 8 of 10 vaccinated participants. HIVAX was immunogenic in all vaccinated participants. The functionality of T cells was significantly enhanced after vaccination. Median viral load (3.45 log10 copies/ml, range of 96-12,830 copies/ml) at the end of the 12-week treatment interruption in HIVAX vaccinated group was significantly lower than the pre-treatment levels. Three vaccinated participants extended ATI for up to 2 years with stable CD4 cells and low viral loads. HIVAX vaccine is generally safe, elicits strong anti-HIV-1 immune responses, and may play an important role in controlling viral load during treatment interruption in HIV-1 infected participants. Copyright © 2016 Elsevier Ltd. All rights reserved.
Choi, Dae-Han; Woo, Jong Kyu; Choi, Yun; Seo, Hye-Sook; Kim, Chul-Woo
Intensive efforts to improve vaccines against cancer are currently outgoing. Mucin 1 (Muc1) is a tumor-specific antigen that is overexpressed and heavily glycosylated in a variety of adenocarcinomas. In the present study, the efficacy of an anticancer DNA vaccination strategy was demonstrated using Muc1 fusion vaccines. To enhance antigen presentation and tumor-suppressive efficacy, a chimeric Muc1 vaccine was designed, encoding the transmembrane- and C-terminal domain-deleted Muc1 gene (∆TM) fused to the human HSP70 gene. To confirm the expression and secretion of fusion protein, cell culture supernatants were subjected to Western blotting. We found secreted Muc1 ΔTM-HSP0 fusion protein in the supernatants. These results demonstrate that the Muc1 ΔTM-HSP0 construct can be efficiently expressed and secreted from transfected cells. When the chimeric Muc1 vaccine was administered to mice, antigen-specific cellular immune responses were observed. Notably, we observed that antigen-specific lymphocyte proliferation and cytotoxic responses were effectively induced only in the group of mice that had been vaccinated with the chimeric Muc1 vaccine. Concurrent with the Muc1-specific tumor-suppressive effect, the growth of established Muc1-expressing B16 mouse melanoma cells was also significantly inhibited by vaccination with the chimeric Muc1 vaccine. The growth of B16 mouse melanoma cells expressing human Muc1 in C57BL/6 mice was effectively suppressed by the Muc1-HSP70 chimeric DNA vaccine. Our results reveal that the antitumor efficacy of the chimeric DNA vaccine was improved by the presence of HSP/70.
Graziani, Gina M; Angel, Jonathan B
Although current antiretroviral therapy (ART) has transformed HIV infection into a chronic, manageable disease, ART does not cure HIV infection. Furthermore, the majority of the world's infected individuals live in resource-limited countries in which access to ART is limited. Thus, the development of an effective therapeutic HIV vaccine would be an invaluable treatment alternative. Developed by the late Dr. Jonas Salk, HIV-1 Immunogen (Remune®) is a candidate therapeutic vaccine that has been studied in thousands of HIV-infected individuals in more than a dozen clinical trials during almost three decades. This Drug Evaluation, which summarizes the results of these trials that have shown the vaccine to be safe and immunogenic, also discusses the contradictory and controversial conclusions drawn from the phases 2, 2/3 and 3 trials that assessed the clinical efficacy of this vaccine. Given the lack of unequivocal clinical benefits of HIV-1 Immunogen despite almost 30 years of extensive testing, it does not appear, in our view, that this vaccine is a clinically effective immunotherapy. However, inclusion of this vaccine in the newly proposed 'Kick/Shock and Kill' strategy for HIV eradication, or use as a prophylactic vaccine, could be considered for future trials.
Full Text Available The review pinpoints operational concepts related to the redox biology network applied to the pathophysiology and therapeutics of solid tumors. A sophisticated network of intrinsic and extrinsic cues, integrated in the tumor niche, drives tumorigenesis and tumor progression. Critical mutations and distorted redox signaling pathways orchestrate pathologic events inside cancer cells, resulting in resistance to stress and death signals, aberrant proliferation and efficient repair mechanisms. Additionally, the complex inter-cellular crosstalk within the tumor niche, mediated by cytokines, redox-sensitive danger signals (HMGB1 and exosomes, under the pressure of multiple stresses (oxidative, inflammatory, metabolic, greatly contributes to the malignant phenotype. The tumor-associated inflammatory stress and its suppressive action on the anti-tumor immune response are highlighted. We further emphasize that ROS may act either as supporter or enemy of cancer cells, depending on the context. Oxidative stress-based therapies, such as radiotherapy and photodynamic therapy, take advantage of the cytotoxic face of ROS for killing tumor cells by a non-physiologically sudden, localized and intense oxidative burst. The type of tumor cell death elicited by these therapies is discussed. Therapy outcome depends on the differential sensitivity to oxidative stress of particular tumor cells, such as cancer stem cells, and therefore co-therapies that transiently down-regulate their intrinsic antioxidant system hold great promise. We draw attention on the consequences of the damage signals delivered by oxidative stress-injured cells to neighboring and distant cells, and emphasize the benefits of therapeutically triggered immunologic cell death in metastatic cancer. An integrative approach should be applied when designing therapeutic strategies in cancer, taking into consideration the mutational, metabolic, inflammatory and oxidative status of tumor cells, cellular
Ribassin-Majed, Laureen; Hill, Catherine; Lounes, Rachid
International audience; Human papillomavirus (HPV) types 16 and 18 cause 70% of cervical cancers, and currently two vaccines protecting against these types are available. In a previous paper, we estimated the long-term effect of HPV vaccination on the risk of cervical cancer in the French population using mathematical modeling. Several vaccination scenarios were tested, including different vaccination coverage rates of females alone or in conjunction with males. In the first scenario, which i...
Despite of growing oncology pipeline, cancer vaccines contribute only to a minor share of total oncology-attributed revenues. This is mainly because of a limited number of approved products and limited sales from products approved under compassionate or via early access entry in smaller and less developed markets. However revenue contribution from these products is extremely limited and it remains to be established whether developers are breaking even or achieving profitability with existing sales. Cancer vaccine field is well recognized for high development costs and risks, low historical rates of investment return and high probability of failures arising in ventures, partnerships and alliances. The cost of reimbursement for new oncology agents is not universally acceptable to payers limiting the potential for a global expansion, market access and reducing probability of commercial success. In addition, the innovation in cancer immunotherapy is currently focused in small and mid-size biotech companies and academic institutions struggling for investment. Existing R&D innovation models are deemed unsustainable in current "value-for-money" oriented healthcare environment. New business models should be much more open to collaborative, networked and federated styles, which could help to outreach global, markets and increase cost-efficiencies across an entire value chain. Lessons learned from some developing countries and especially from South Korea illustrate that further growth of cancer vaccine industry will depends not only on new business models but also will heavily rely on regional support and initiatives from different bodies, such as governments, payers and regulatory bodies.
Messerschmidt, G.L.; Hoover, R.; Young, R.C.
Therapeutic intervention in a course of illness, while producing the desired result, also may have some adverse long-term effects on the patient. Second malignancies are one of the known complications of therapy. The treatments of gynecologic cancers by surgery, irradiation and chemotherapy have been associated with subsequent neoplasms. Care must be exercised in associating previous therapy and a subsequent malignancy. Naturally occurring second cancers must be separated from those which are iatrogenic. Associations in the literature have been made involving malignancies as a sequelae of prior gynecologic therapy. The use of normal skin from the thigh to fabricate an artificial vagina has resulted in more squamous cell carcinomas than expected. Alkylating agents used in the treatment of ovarian cancer and other diseases have been shown to lead to an increased risk of leukemia. Irradiation therapy, however, has not yet been shown to be related to leukemia in cervical cancer patients. The incidence of lymphoma and uterine, urinary bladder and colon carcinomas has been associated with prior irradiation for gynecologic disease. The literature regarding the therapeutically induced risk factors in gynecologic therapy is reviewed and areas of our knowledge that require more investigation are identified
Rafiq A. Rather
Full Text Available Cancer is a genetic disease characterized by unregulated growth and dissemination of malignantly transformed neoplastic cells. The process of cancer development goes through several stages of biochemical and genetic alterations in a target cell. Several dietary alkaloids have been found to inhibit the molecular events and signaling pathways associated with various stages of cancer development and therefore are useful in cancer chemoprevention. Cancer chemoprevention has long been recognized as an important prophylactic strategy to reduce the burden of cancer on health care system. Cancer chemoprevention assumes the use of one or more pharmacologically active agents to block, suppress, prevent, or reverse the development of invasive cancer. Piperine is an active alkaloid with an excellent spectrum of therapeutic activities such as anti-oxidant, anti-inflammatory, immunomodulatory, anti-asthmatic, anti-convulsant, anti-mutagenic, antimycobacterial, anti-amoebic, and anti-cancer activities. In this article, we made an attempt to sum up the current knowledge on piperine that supports the chemopreventive potential of this dietary phytochemical. Many mechanisms have been purported to understand the chemopreventive action of piperine. Piperine has been reported to inhibit the proliferation and survival of many types of cancer cells through its influence on activation of apoptotic signaling and inhibition of cell cycle progression. Piperine is known to affect cancer cells in variety of other ways such as influencing the redox homeostasis, inhibiting cancer stem cell (CSC self-renewal and modulation of ER stress and autophagy. Piperine can modify activity of many enzymes and transcription factors to inhibit invasion, metastasis, and angiogenesis. Piperine is a potent inhibitor of p-glycoprotein (P-gp and has a significant effect on the drug metabolizing enzyme (DME system. Because of its inhibitory influence on P-gp activity, piperine can reverse
It has been shown that autologous D Cs pulsed with peptides specific for prostate specific Ag (PSA) or prostate-specific membrane Ag are capable of stimulating potent CT L in vitro. However there is evidence to believe that multiple tumour derived antigens would be more potent to elicit anti-tumour responses. Based on these observations a Phase I/II clinical trial in has been initiated. Autologous monocyte-derived dendritic cells (DC s) were transfected with mRNA from three prostate cancer cell lines (DU145, LNCaP and P C-3) and used for vaccination. Twenty patients have been enrolled and 19 have finished vaccination. Each patient received at least four weekly injections. Of them, 10 patients were vaccinated intranodally under ultrasonic guidance and 9 others received the vaccine intradermally. Safety and feasibility were evaluated. No evidence of toxicity and adverse events was observed. Immune response was measured as DTH and by vitro immunoassays including ELISPOT, T cell proliferation test and cytotoxicity test in pre- and post-vaccination peripheral blood samples. Twelve patients developed a specific immune response to tumour cells. Ten patients showed a significant decrease in log slope PSA. Patients with lower PSA tend to give a better response. The early clinical outcome was significantly related to immune responses (p<0.05). We conclude that the strategy of vaccinating with mRNA transfected D Cs functions to elicit cellular immune responses specific for antigens associated with prostate cancer cells and such responses may result in a clinical benefit for the patients
Laubreton, Daphné; Bay, Sylvie; Sedlik, Christine; Artaud, Cécile; Ganneau, Christelle; Dériaud, Edith; Viel, Sophie; Puaux, Anne-Laure; Amigorena, Sebastian; Gérard, Catherine; Lo-Man, Richard; Leclerc, Claude
Malignant transformations are often associated with aberrant glycosylation processes that lead to the expression of new carbohydrate antigens at the surface of tumor cells. Of these carbohydrate antigens, the Tn antigen is particularly highly expressed in many carcinomas, especially in breast carcinoma. We designed MAG-Tn3, a fully synthetic vaccine based on three consecutive Tn moieties that are O-linked to a CD4+ T cell epitope, to induce anti-Tn antibody responses that could be helpful for therapeutic vaccination against cancer. To ensure broad coverage within the human population, the tetanus toxoid-derived peptide TT830-844 was selected as a T-helper epitope because it can bind to various HLA-DRB molecules. We showed that the MAG-Tn3 vaccine, which was formulated with the GSK proprietary immunostimulant AS15 and designed for human cancer therapy, is able to induce an anti-Tn antibody response in mice of various H-2 haplotypes, and this response correlates with the ability to induce a specific T cell response against the TT830-844 peptide. The universality of the TT830-844 peptide was extended to new H-2 and HLA-DRB molecules that were capable of binding this T cell epitope. Finally, the MAG-Tn3 vaccine was able to induce anti-Tn antibody responses in cynomolgus monkeys, which targeted Tn-expressing tumor cells and mediated tumor cell death both in vitro and in vivo. Thus, MAG-Tn3 is a highly promising anticancer vaccine that is currently under evaluation in a phase I clinical trial.
Cui, Qingbin; Wen, Shijun; Huang, Peng
Mitochondria play a key role in ATP generation, redox homeostasis and regulation of apoptosis. Due to the essential role of mitochondria in metabolism and cell survival, targeting mitochondria in cancer cells is considered as an attractive therapeutic strategy. However, metabolic flexibility in cancer cells may enable the upregulation of compensatory pathways, such as glycolysis to support cancer cell survival when mitochondrial metabolism is inhibited. Thus, compounds capable of both targeting mitochondria and inhibiting glycolysis may be particularly useful to overcome such drug-resistant mechanism. This review provides an update on recent development in the field of targeting mitochondria and novel compounds that impact mitochondria, glycolysis or both. Key challenges in this research area and potential solutions are also discussed.
Full Text Available Lung cancer is a heterogeneous disease responsible for the most cases of cancer-related deaths. The majority of patients are clinically diagnosed at advanced stages, with a poor survival rate. For this reason, the identification of oncodrivers and novel biomarkers is decisive for the future clinical management of this pathology. The rise of high throughput technologies popularly referred to as “omics” has accelerated the discovery of new biomarkers and drivers for this pathology. Within them, tyrosine kinase receptors (TKRs have proven to be of importance as diagnostic, prognostic, and predictive tools and, due to their molecular nature, as therapeutic targets. Along this review, the role of TKRs in the different lung cancer histologies, research on improvement of anti-TKR therapy, and the current approaches to manage anti-TKR resistance will be discussed.
Toosi, M.; Moaddabshoar, L.; Malek-Hosseini, S.A.; Sasani, M.R.; Maral Mokhtari, M.; Mohammad Mohammadianpanah, M.
Introduction: The occurrence of colorectal cancer during pregnancy is rare and is associated with diagnostic and therapeutic challenges. Herein, we report such a case of rectal cancer in pregnancy and review the literature. Case report: A 31-year-old multiparous, pregnant woman, in the 20th week of gestation, presented with rectal bleeding progressing to spasmodic abdominal pain and right flank vague pain. A flexible recto sigmoidoscopy showed a large ulcerative mass located in the recto sigmoid junction, 15 cm away from anal verge. Imaging studies and biopsy proved it to be rectal adenocarcinoma with single liver metastasis. The patient’s pregnancy was terminated and neoadjuvant therapy followed by curative surgery was performed. She is currently receiving adjuvant systemic therapy to eradicate potential micro metastatic disease. Conclusion: This case suggests that colorectal cancer can mimic the signs and the symptoms of pregnancy and tends to present at an advanced stage in pregnant women.
Hodge, James W; Poole, Diane J; Aarts, Wilhelmina M; Gómez Yafal, Alicia; Gritz, Linda; Schlom, Jeffrey
Cancer vaccine regimens use various strategies to enhance immune responses to specific tumor-associated antigens (TAAs), including the increasing use of recombinant poxviruses [vaccinia (rV) and fowlpox (rF)] for delivery of the TAA to the immune system. However, the use of replication competent vectors with the potential of adverse reactions have made attenuation a priority for next-generation vaccine strategies. Modified vaccinia Ankara (MVA) is a replication defective form of vaccinia virus. Here, we investigated the use of MVA encoding a tumor antigen gene, carcinoembryonic antigen (CEA), in addition to multiple costimulatory molecules (B7-1, intercellular adhesion molecule-1, and lymphocyte function-associated antigen-3 designated TRICOM). Vaccination of mice with MVA-CEA/TRICOM induced potent CD4+ and CD8+ T-cell responses specific for CEA. MVA-CEA/TRICOM could be administered twice in vaccinia naïve mice and only a single time in vaccinia-immune mice before being inhibited by antivector-immune responses. The use of MVA-CEA/TRICOM in a diversified prime and boost vaccine regimen with rF-CEA/TRICOM, however, induced significantly greater levels of both CD4+ and CD8+ T-cell responses specific for CEA than that seen with rV-CEA/TRICOM prime and rF-CEA/TRICOM boost. In a self-antigen tumor model, the diversified MVA-CEA/TRICOM/rF-CEA/ TRICOM vaccination regimen resulted in a significant therapeutic antitumor response as measured by increased survival, when compared with the diversified prime and boost regimen, rV-CEA/TRICOM/rF-CEA/TRICOM. The studies reported here demonstrate that MVA, when used as a prime in a diversified vaccination, is clearly comparable with the regimen using the recombinant vaccinia in both the induction of cellular immune responses specific for the "self"-TAA transgene and in antitumor activity.
Lee, Hee Yun; Kwon, Melissa; Vang, Suzanne; DeWolfe, Jessica; Kim, Nam Keol; Lee, Do Kyung; Yeung, Miriam
Purpose: Low rates of human papillomavirus (HPV) vaccination among young Asian American and Pacific Islander (AAPI) women need to be addressed, particularly given the high incidence of cervical cancer in this population. The current study aims to investigate predictors of HPV vaccination in young AAPI and non-Latina white (NLW) women. Methods: A…
Full Text Available Hatem Soliman,1 Melanie Mediavilla-Varela,2 Scott J Antonia,3 1Department of Women's Oncology and Experimental Therapeutics, 2Department of Immunology, 3Department of Thoracic Oncology, Moffitt Cancer Center, Tampa, FL, USA Background: There is increasing interest in using cancer vaccines to treat breast cancer patients in the adjuvant setting to prevent recurrence in high risk situations or in combination with other immunomodulators in the advanced setting. Current peptide vaccines are limited by immunologic compatibility issues, and engineered autologous cellular vaccines are difficult to produce on a large scale. Using standardized bystander cell lines modified to secrete immune stimulating adjuvant substances can greatly enhance the ability to produce immunogenic cellular vaccines using unmodified autologous cells or allogeneic medical grade tumor cell lines as targets. We investigated the efficacy of a cellular vaccine using B78H1 bystander cell lines engineered to secrete granulocyte macrophage-colony stimulating factor and CD40 ligand (BCG in a murine model of breast cancer. Methods: Five-week-old female BALB/c mice were injected orthotopically in the mammary fat pad with 4T1 tumor cells. Treatment consisted of irradiated 4T1 ± BCG cells given subcutaneously every 4 days and was repeated three times per mouse when tumors became palpable. Tumors were measured two to three times per week for 25 days. The vaccine's activity was confirmed in a second experiment using Lewis lung carcinoma (LLC cells in C57BL/6 mice to exclude a model specific effect. Interferon-γ (IFN-γ and interleukin-2 (IL-2 enzyme-linked immunospots (ELISPOTS were performed on splenic lymphocytes incubated with 4T1 lysates along with immunohistochemistry for CD3 on tumor sections. Results: Tumor growth was significantly inhibited in the 4T1-BCG and LLC-BCG treatment groups when compared to 4T1 and LLC treatment groups. There were higher levels of IL-2 and IFN
Temkin, Sarah M; Seibel, Nita L
Survivors of pediatric and young adult cancers remain at risk for subsequent diseases, including those related to human papillomavirus (HPV) infection. Prevention of HPV acquisition through vaccination has become possible over the last decade. HPV vaccines have been shown to be safe and effective, yet rates of vaccination among childhood cancer survivors have remained low. Multiple factors, including stronger advocacy for this intervention from providers, could potentially increase vaccination and lead to lower HPV disease burdens for childhood cancer survivors. Health care providers for survivors of pediatric and adolescent cancers should prioritize counseling for HPV vaccination at follow-up visits. Cancer 2015;121:3435-43. © 2015 American Cancer Society. © 2015 American Cancer Society.
Jan B W J Cornelissen
Full Text Available High numbers of Toxoplasma gondii oocysts in the environment are a risk factor to humans. The environmental contamination might be reduced by vaccinating the definitive host, cats. An experimental challenge model is necessary to quantitatively assess the efficacy of a vaccine or drug treatment. Previous studies have indicated that bradyzoites are highly infectious for cats. To infect cats, tissue cysts were isolated from the brains of mice infected with oocysts of T. gondii M4 strain, and bradyzoites were released by pepsin digestion. Free bradyzoites were counted and graded doses (1000, 100, 50, 10, and 250 intact tissue cysts were inoculated orally into three cats each. Oocysts shed by these five groups of cats were collected from faeces by flotation techniques, counted microscopically and estimated by real time PCR. Additionally, the number of T. gondii in heart, tongue and brains were estimated, and serology for anti T. gondii antibodies was performed. A Beta-Poisson dose-response model was used to estimate the infectivity of single bradyzoites and linear regression was used to determine the relation between inoculated dose and numbers of oocyst shed. We found that real time PCR was more sensitive than microscopic detection of oocysts, and oocysts were detected by PCR in faeces of cats fed 10 bradyzoites but by microscopic examination. Real time PCR may only detect fragments of T. gondii DNA without the presence of oocysts in low doses. Prevalence of tissue cysts of T. gondii in tongue, heart and brains, and anti T. gondii antibody concentrations were all found to depend on the inoculated bradyzoite dose. The combination of the experimental challenge model and the dose response analysis provides a suitable reference for quantifying the potential reduction in human health risk due to a treatment of domestic cats by vaccination or by therapeutic drug application.
investigational) product, whether or not related to the medicinal (investigational) product. This will also include intercurrent diseases and accidents ...definitive radiotherapy in patients with localized prostate cancer. Clin Cancer Res, 11:3353-3362, 2005 50. Small, EJ, Fratesi, P, Reese, DM, at al...diseases and accidents observed during the research intervention period as well as corresponding events during drug-free, pre- and post- intervention
Dinis, Márcia; Tavares, Delfina; Veiga-Malta, Isabel; Fonseca, António J M M; Andrade, Elva Bonifácio; Trigo, Gabriela; Ribeiro, Adília; Videira, Arnaldo; Cabrita, António M Silvério; Ferreira, Paula
Dental caries is among the more prevalent chronic human infections for which an effective human vaccine has not yet been achieved. Enolase from Streptococcus sobrinus has been identified as an immunomodulatory protein. In the present study, we used S. sobrinus recombinant enolase (rEnolase) as a target antigen and assessed its therapeutic effect in a rat model of dental caries. Wistar rats that were fed a cariogenic solid diet on day 18 after birth were orally infected with S. sobrinus on day 19 after birth and for 5 consecutive days thereafter. Five days after infection and, again, 3 weeks later, rEnolase plus alum adjuvant was delivered into the oral cavity of the rats. A sham-immunized group of rats was contemporarily treated with adjuvant alone. In the rEnolase-immunized rats, increased levels of salivary IgA and IgG antibodies specific for this recombinant protein were detected. A significant decrease in sulcal, proximal enamel, and dentin caries scores was observed in these animals, compared with sham-immunized control animals. No detectable histopathologic alterations were observed in all immunized animals. Furthermore, the antibodies produced against bacterial enolase did not react with human enolase. Overall, these results indicate that rEnolase could be a promising and safe candidate for testing in trials of vaccines against dental caries in humans.
Svane, Inge Marie; Soot, Mette Line; Buus, Søren
During the last decade use of dendritic cells (DC) has moved from murine and in vitro studies to clinical trials as adjuvant in cancer immunotherapy. Here they function as delivery vehicles for exogenous tumor antigens, promoting an efficient antigen presentation. The development of protocols...... for large-scale generation of dendritic cells for clinical applications has made possible phase I/II studies designed to analyze the toxicity, feasibility and efficacy of this approach. In clinical trials, DC-based vaccination of patients with advanced cancer has in many cases led to immunity...
Gjerstorff, Morten Frier; Burns, Jorge; Ditzel, Henrik Jorn
can be achieved using epigenetic modifiers. AREAS COVERED IN THIS REVIEW: We provide an overview of the potential of CG antigens as targets for cancer immunotherapy, including advantages and disadvantages. We also discuss the current state of development of CG antigen vaccines, and the potential...... synergistic effect of combining CG antigen immunotherapeutic strategies with epigenetic modifiers. WHAT THE READER WILL GAIN: The reader will gain an overview of the past, present and future role of CG antigens in cancer immunotherapy. TAKE HOME MESSAGE: Chemoimmunotherapy using epigenetic drugs and CG...
Wang, Chao; Cheng, Liang; Liu, Zhuang
Photodynamic therapy (PDT) is a non-invasive treatment modality for a variety of diseases including cancer. PDT based on upconversion nanoparticles (UCNPs) has received much attention in recent years. Under near-infrared (NIR) light excitation, UCNPs are able to emit high-energy visible light, which can activate surrounding photosensitizer (PS) molecules to produce singlet oxygen and kill cancer cells. Owing to the high tissue penetration ability of NIR light, NIR-excited UCNPs can be used to activate PS molecules in much deeper tissues compared to traditional PDT induced by visible or ultraviolet (UV) light. In addition to the application of UCNPs as an energy donor in PDT, via similar mechanisms, they could also be used for the NIR light-triggered drug release or activation of 'caged' imaging or therapeutic molecules. In this review, we will summarize the latest progresses regarding the applications of UCNPs for photodynamic therapy, NIR triggered drug and gene delivery, as well as several other UCNP-based cancer therapeutic approaches. The future prospects and challenges in this emerging field will be also discussed.
Bai, Longchuan; Smith, David C; Wang, Shaomeng
Apoptosis is a tightly regulated cellular process and faulty regulation of apoptosis is a hallmark of human cancers. Targeting key apoptosis regulators with the goal to restore apoptosis in tumor cells has been pursued as a new cancer therapeutic strategy. XIAP, cIAP1, and cIAP2, members of inhibitor of apoptosis (IAP) proteins, are critical regulators of cell death and survival and are attractive targets for new cancer therapy. The SMAC/DIABLO protein is an endogenous antagonist of XIAP, cIAP1, and cIAP2. In the last decade, intense research efforts have resulted in the design and development of several small-molecule SMAC mimetics now in clinical trials for cancer treatment. In this review, we will discuss the roles of XIAP, cIAP1, and cIAP2 in regulation of cell death and survival, and the design and development of small-molecule SMAC mimetics as novel cancer treatments. Copyright © 2014 Elsevier Inc. All rights reserved.
Bruketa, Tomislav; Majerovic, Matea; Augustin, Goran
Fournier's gangrene (FG) is a rapid progressive bacterial infection that involves the subcutaneous fascia and part of the deep fascia but spares the muscle in the scrotal, perianal and perineal region. The incidence has increased dramatically, while the reported incidence of rectal cancer-induced FG is unknown but is extremely low. Pathophysiology and clinical presentation of rectal cancer-induced FG per se does not differ from the other causes. Only rectal cancer-specific symptoms before presentation can lead to the diagnosis. The diagnosis of rectal cancer-induced FG should be excluded in every patient with blood on digital rectal examination, when urogenital and dermatological causes are excluded and when fever or sepsis of unknown origin is present with perianal symptomatology. Therapeutic options are more complex than for other forms of FG. First, the causative rectal tumor should be removed. The survival of patients with rectal cancer resection is reported as 100%, while with colostomy it is 80%. The preferred method of rectal resection has not been defined. Second, oncological treatment should be administered but the timing should be adjusted to the resolution of the FG and sometimes for the healing of plastic reconstructive procedures that are commonly needed for the reconstruction of large perineal, scrotal and lower abdominal wall defects.
Román, Victor Raúl Gómez; Jensen, Kristoffer Jarlov; Jensen, Sanne Skov
We have designed a therapeutic HIV-1 vaccine concept based on peptides together with the adjuvant CAF01. Peptides represented 15 HLA-supertype-restricted subdominant and conserved CD8 T cell epitopes and three CD4 T-helper cell epitopes. In this phase I clinical trial, safety and immunogenicity...... were assessed in untreated HIV-1-infected individuals in Guinea-Bissau, West Africa. Twenty-three HIV-1-infected individuals were randomized to receive placebo (n=5) or vaccine (n=18). Safety was appraised by clinical follow-up combined with monitoring of biochemistry, hematology, CD4 T cell counts......, and HIV-1 viral loads. T cell immunogenicity was monitored longitudinally by interferon (IFN)-γ ELISpot. New vaccine-specific T cell responses were induced in 6/14 vaccinees for whom ELISpot data were valid. CD4 T cell counts and viral loads were stable. The study shows that therapeutic immunization...
Mermelstein, H T; Holland, J C
Medically ill patients who cannot come to the psychotherapist's office on a regular basis frequently are encountered in consultation-liaison settings. For these individuals the telephone becomes the only link to psychological counseling. The two cases presented in this article of successful telephone therapy with cancer patients exemplify and highlight the effect of this mode of interaction on the therapeutic process and relationship. Telephone communication also differs from face-to-face interaction in areas of therapist-patient accessibility, control, formality, and anonymity, which make it an especially effective psychotherapeutic tool for the medically ill patient.
Full Text Available Abstract Background Dendritic cells (DCs have the potential for cancer immunotherapy due to their ability to process and present antigens to T-cells and also in stimulating immune responses. However, DC-based vaccines have only exhibited minimal effectiveness against established tumours in mice and humans. The use of appropriate adjuvant enhances the efficacy of DC based cancer vaccines in treating tumours. Methods In this study we have used tocotrienol-rich fraction (TRF, a non-toxic natural compound, as an adjuvant to enhance the effectiveness of DC vaccines in treating mouse mammary cancers. In the mouse model, six-week-old female BALB/c mice were injected subcutaneously with DC and supplemented with oral TRF daily (DC+TRF and DC pulsed with tumour lysate from 4T1 cells (DC+TL. Experimental mice were also injected with DC pulsed with tumour lysate and supplemented daily with oral TRF (DC+TL+TRF while two groups of animal which were supplemented daily with carrier oil (control and with TRF (TRF. After three times vaccination, mice were inoculated with 4T1 cells in the mammary breast pad to induce tumour. Results Our study showed that TRF in combination with DC pulsed with tumour lysate (DC+TL+TRF injected subcutaneously significantly inhibited the growth of 4T1 mammary tumour cells as compared to control group. Analysis of cytokines production from murine splenocytes showed significant increased productions of IFN-γ and IL-12 in experimental mice (DC+TL+TRF compared to control, mice injected with DC without TRF, mice injected with DC pulsed with tumour lysate and mice supplemented with TRF alone. Higher numbers of cytotoxic T cells (CD8 and natural killer cells (NK were observed in the peripheral blood of TRF adjuvanted DC pulsed tumour lysate mice. Conclusion Our study show that TRF has the potential to be an adjuvant to augment DC based immunotherapy.
Uveal melanoma is a rare eye cancer that affects about 1,600 people in the United States. A study by scientists in the Center for Cancer Research and Aura Biosciences, Cambridge, Mass., published December 14, 2017, in Molecular Cancer Therapeutics, provides new hope for the early treatment of uveal melanoma. Read more…
Full Text Available The immune system has a substantial effect on colorectal cancer (CRC progression. Additionally, the response to immunotherapeutics and conventional treatment options (e.g., chemotherapy, radiotherapy and targeted therapies is influenced by the immune system. The molecular characterization of colorectal cancer (CRC has led to the identification of favorable and unfavorable immunological attributes linked to clinical outcome. With the definition of consensus molecular subtypes (CMSs based on transcriptomic profiles, multiple characteristics have been proposed to be responsible for the development of the tumor immune microenvironment and corresponding mechanisms of immune escape. In this review, a detailed description of proposed immune phenotypes as well as their interaction with different therapeutic modalities will be provided. Finally, possible strategies to shift the CRC immune phenotype towards a reactive, anti-tumor orientation are proposed per CMS.
Bibeau, Frédéric; Bazille, Céline; Svrcek, Magali; Pierson, Rémi; Lagorce-Pagès, Christine; Cohen, Romain; André, Thierry
The aim of this article is to emphasize the impact of the immune response in digestive cancers, especially from colorectal (CRC) origin. In this setting, an adaptive lymphocytic infiltrate underlines the prognostic impact of the immune response, because it is associated to a favorable outcome. The next challenge will be to validate, in a prospective therapeutic trial, the integration of the immune response as decisional parameter for adjuvant therapy. The immune response is also a predictive parameter in microsatellite instable metastatic CRC, characterized by an adaptive lymphocytic infiltrate, leading to a very high response rate to immune therapies. However, prognostic and predictive biomarkers still need to be optimized in order to better select patients. These data are also valuable for digestive non-colorectal cancers, which are briefly analyzed. The methodology for the assessment of these prognostic and predictive biomarkers, which represents an important issue in precision medicine, is also discussed. Copyright © 2016. Published by Elsevier Masson SAS.
Warmoes, Marc O; Locasale, Jason W
Upregulated glycolysis, both in normoxic and hypoxic environments, is a nearly universal trait of cancer cells. The enormous difference in glucose metabolism offers a target for therapeutic intervention with a potentially low toxicity profile. The past decade has seen a steep rise in the development and clinical assessment of small molecules that target glycolysis. The enzymes in glycolysis have a highly heterogeneous nature that allows for the different bioenergetic, biosynthetic, and signaling demands needed for various tissue functions. In cancers, these properties enable them to respond to the variable requirements of cell survival, proliferation and adaptation to nutrient availability. Heterogeneity in glycolysis occurs through the expression of different isoforms, posttranslational modifications that affect the kinetic and regulatory properties of the enzyme. In this review, we will explore this vast heterogeneity of glycolysis and discuss how this information might be exploited to better target glucose metabolism and offer possibilities for biomarker development. Published by Elsevier Inc.
Lao, Yeh-Hsing; Phua, Kyle K L; Leong, Kam W
Aptamer nanomedicine, including therapeutic aptamers and aptamer nanocomplexes, is beginning to fulfill its potential in both clinical trials and preclinical studies. Especially in oncology, aptamer nanomedicine may perform better than conventional or antibody-based chemotherapeutics due to specificity compared to the former and stability compared to the latter. Many proof-of-concept studies on applying aptamers to drug delivery, gene therapy, and cancer imaging have shown promising efficacy and impressive safety in vivo toward translation. Yet, there remains ample room for improvement and critical barriers to be addressed. In this review, we will first introduce the recent progress in clinical trials of aptamer nanomedicine, followed by a discussion of the barriers at the design and in vivo application stages. We will then highlight recent advances and engineering strategies proposed to tackle these barriers. Aptamer cancer nanomedicine has the potential to address one of the most important healthcare issues of the society.
Gritzapis, Angelos D; Voutsas, Ioannis F; Baxevanis, Constantin N
Disrupting tumor-mediated mechanisms suppressing host immunity represents a novel approach to tumor immunotherapy. Depletion of regulatory T cells (Tregs) increases endogenous anti-tumor immunity and the efficacy of active immunotherapy in experimental tumor models. HLA-A2.1/HLA-DR1 (A2.1/DR1) × BALB- neuT+ (neuT+) triple transgenic mice represent an improvement over neuT+ mice for evaluating vaccination regimens to overcome tolerance against HER-2/neu. We questioned whether depletion of Tregs with Denileukin diftitox (Ontak) enhances the efficacy of a therapeutic vaccine consisting of HER-2(85-94) (p85) CTL and HER-2(776-790) (p776) Th peptides against the growth of TUBO.A2 transplantable tumor in male A2.1/DR1 × neuT+ Tg mice. While the therapeutic vaccine primed the tumor-reactive CD8+ CTLs and CD4+ effector T lymphocytes (Teffs) compartment, inducing activation, tumor infiltration, and tumor rejection or delay in tumor growth, treatment with Ontak 1 day prior to vaccination resulted in enhanced CD4+ and CD8+ T-cell-mediated vaccine-specific immune responses in the periphery. This was closely associated with greater infiltration and a striking change in the intratumor balance of Tregs and vaccine-specific CTLs/Teffs that directly correlated with markedly enhanced antitumor activity. The data suggest that Tregs control both CD4+ and CD8+ T-cell activity within the tumor, emphasize the importance of the intratumor ratio of vaccine-specific lymphocytes to Tregs, and demonstrate significant inversion of this ratio and correlation with tumor rejection during Ontak/vaccine immunotherapy.
Murad, Yanal M; Clay, Timothy M
Toll-like receptors (TLRs) are part of the innate immune system, and they belong to the pattern recognition receptors (PRR) family. The PRR family is designed to recognize and bind conserved pathogen-associated molecular patterns, which are not generated by the host and are restricted and essential to micro-organisms. TLR9, which recognizes unmethylated CpG (cytosine guanosine dinucleotide), is a very promising target for therapeutic activation. Stimulation of TLR9 activates human plasmacytoid dendritic cells and B cells, and results in potent T helper-1 (T(h)1)-type immune responses and antitumor responses in mouse tumor models and in patients. Several pharmaceutical companies, such as Pfizer, Idera, and Dynavax, are developing CpG oligodeoxynucleotides (ODNs) for the treatment of cancer, along with other conditions, such as infections and allergy. CpG ODNs have shown promising results as vaccine adjuvants and in combination with cancer immunotherapy. Several TLR9 agonists are being developed and have entered clinical trials to evaluate their safety and efficacy for the treatment of several hematopoietic and solid tumors. In this review, we discuss the use of CpG ODNs in several phase I and II clinical trials for the treatment of NHL, renal cell carcinoma, melanoma, and non-small cell lung cancer, either alone or in combination with other agents.
Grigg, Patricia; Titong, Allison; Jones, Leslie A; Yilma, Tilahun D; Verardi, Paulo H
Replication-competent viruses, such as Vaccinia virus (VACV), are powerful tools for the development of oncolytic viral therapies and elicit superior immune responses when used as vaccine and immunotherapeutic vectors. However, severe complications from uncontrolled viral replication can occur, particularly in immunocompromised individuals or in those with other predisposing conditions. VACVs constitutively expressing interferon-γ (IFN-γ) replicate in cell culture indistinguishably from control viruses; however, they replicate in vivo to low or undetectable levels, and are rapidly cleared even in immunodeficient animals. In an effort to develop safe and highly effective replication-competent VACV vectors, we established a system to inducibly express IFN-γ. Our SMART (safety mechanism assisted by the repressor of tetracycline) vectors are designed to express the tetracycline repressor under a constitutive VACV promoter and IFN-γ under engineered tetracycline-inducible promoters. Immunodeficient SCID mice inoculated with VACVs not expressing IFN-γ demonstrated severe weight loss, whereas those given VACVs expressing IFN-γ under constitutive VACV promoters showed no signs of infection. Most importantly, mice inoculated with a VACV expressing the IFN-γ gene under an inducible promoter remained healthy in the presence of doxycycline, but exhibited severe weight loss in the absence of doxycycline. In this study, we developed a safety mechanism for VACV based on the conditional expression of IFN-γ under a tightly controlled tetracycline-inducible VACV promoter for use in vaccines and oncolytic cancer therapies.
Ali, Ahlam A; McCrudden, Cian M; McCaffrey, Joanne; McBride, John W; Cole, Grace; Dunne, Nicholas J; Robson, Tracy; Kissenpfennig, Adrien; Donnelly, Ryan F; McCarthy, Helen O
HPV subtypes (16, 18) are associated with the development of cervical cancer, with oncoproteins E6 and E7 responsible for pathogenesis. The goal of this study was to evaluate our 'smart system' technology platform for DNA vaccination against cervical cancer. The vaccination platform brings together two main components; a peptide RALA which condenses DNA into cationic nanoparticles (NPs), and a polymeric polyvinylpyrrolidone (PVP) microneedle (MN) patch for cutaneous delivery of the loaded NPs. RALA condensed E6/E7 DNA into NPs not exceeding 100nm in diameter, and afforded the DNA protection from degradation in PVP. Sera from mice vaccinated with MN/RALA-E6/E7 were richer in E6/E7-specific IgGs, displayed a greater T-cell-mediated TC-1 cytotoxicity and contained more IFN-γ than sera from mice that received NPs intramuscularly. More importantly, MN/RALA-E6/E7 delayed TC-1 tumor initiation in a prophylactic model, and slowed tumor growth in a therapeutic model of vaccination, and was more potent than intramuscular vaccination. Copyright © 2016 Elsevier Inc. All rights reserved.
L. Stewart Massad
Conclusion: Substantial gaps in understanding of HPV and cervical cancer prevention exist despite years of health education. While more effective educational interventions may help, optimal cancer prevention may require opt-out vaccination programs that do not require nuanced understanding.
Skoberne, Mojca; Cardin, Rhonda; Lee, Alexander; Kazimirova, Ana; Zielinski, Veronica; Garvie, Danielle; Lundberg, Amy; Larson, Shane; Bravo, Fernando J; Bernstein, David I; Flechtner, Jessica B; Long, Deborah
Immunotherapeutic herpes simplex virus 2 (HSV-2) vaccine efficacy depends upon the promotion of antigen-specific immune responses that inhibit reactivation or reactivated virus, thus controlling both recurrent lesions and viral shedding. In the present study, a candidate subunit vaccine, GEN-003/MM-2, was evaluated for its ability to induce a broad-spectrum immune response in mice and therapeutic efficacy in HSV-2-infected guinea pigs. GEN-003 is comprised of HSV-2 glycoprotein D2 (gD2ΔTMR340-363) and a truncated form of infected cell polypeptide 4 (ICP4383-766), formulated with Matrix M-2 (MM-2) adjuvant (GEN-003/MM-2). In addition to eliciting humoral immune responses, CD4(+) and CD8(+) T cells characterized by the secretion of multiple cytokines and cytolytic antigen-specific T cell responses that were able to be recalled at least 44 days after the last immunization were induced in immunized mice. Furthermore, vaccination with either GEN-003 or GEN-003/MM-2 led to significant reductions in both the prevalence and severity of lesions in HSV-2-infected guinea pigs compared to those of phosphate-buffered saline (PBS) control-vaccinated animals. While vaccination with MM-2 adjuvant alone decreased recurrent disease symptoms compared to the PBS control group, the difference was not statistically significant. Importantly, the frequency of recurrent viral shedding was considerably reduced in GEN-003/MM-2-vaccinated animals but not in GEN-003- or MM-2-vaccinated animals. These findings suggest a possible role for immunotherapeutic GEN-003/MM-2 vaccination as a viable alternative to chronic antiviral drugs in the treatment and control of genital herpes disease.
Qazi, Asif Khurshid; Siddiqui, Jawed A; Jahan, Rahat; Chaudhary, Sanjib; Walker, Larry A; Sayed, Zafar; Jones, Dwight T; Batra, Surinder K; Macha, Muzafar A
Cancer remains a leading cause of death in the USA and around the world. Although the current synthetic inhibitors used in targeted therapies have improved patient prognosis, toxicity and development of resistance to these agents remain a challenge. Plant-derived natural products and their derivatives have historically been used to treat various diseases, including cancer. Several leading chemotherapeutic agents are directly or indirectly based on botanical natural products. Beyond these important drugs, however, a number of crude herbal or botanical preparations have also shown promising utility for cancer and other disorders. One such natural resource is derived from certain plants of the family Annonaceae, which are widely distributed in tropical and subtropical regions. Among the best known of these is Annona muricata, also known as soursop, graviola or guanabana. Extracts from the fruit, bark, seeds, roots and leaves of graviola, along with several other Annonaceous species, have been extensively investigated for anticancer, anti-inflammatory and antioxidant properties. Phytochemical studies have identified the acetogenins, a class of bioactive polyketide-derived constituents, from the extracts of Annonaceous species, and dozens of these compounds are present in different parts of graviola. This review summarizes current literature on the therapeutic potential and molecular mechanism of these constituents from A.muricata against cancer and many non-malignant diseases. Based on available data, there is good evidence that these long-used plants could have both chemopreventive and therapeutic potential. Appropriate attention to safety studies will be important to assess their effectiveness on various diseases caused or promoted by inflammation.
Juan, Long; Xiao, Zhao; Song, Yun; Zhijian, Zhang; Jing, Jin; Kun, Yu; Yuna, Hao; Dongfa, Dai; Lili, Ding; Liuxin, Tan; Fei, Liang; Nan, Liu; Fang, Yuan; Yuying, Sun; Yongzhi, Xi
Current clinically available treatments for rheumatoid arthritis (RA) fail to cure the disease or unsatisfactorily halt disease progression. To overcome these limitations, the development of therapeutic DNA vaccines and boosters may offer new promising strategies. Because type II collagen (CII) as a critical autoantigen in RA and native chicken type II collagen (nCCII) has been used to effectively treat RA, we previously developed a novel therapeutic DNA vaccine encoding CCII (pcDNA-CCOL2A1) with efficacy comparable to that of the current "gold standard", methotrexate(MTX). Here, we systemically evaluated the safety and immunogenicity of the pcDNA-CCOL2A1 vaccine in normal Wistar rats. Group 1 received only a single intramuscular injection into the hind leg with pcDNA-CCOL2A1 at the maximum dosage of 3 mg/kg on day 0; Group 2 was injected with normal saline (NS) as a negative control. All rats were monitored daily for any systemic adverse events, reactions at the injection site, and changes in body weights. Plasma and tissues from all experimental rats were collected on day 14 for routine examinations of hematology and biochemistry parameters, anti-CII IgG antibody reactivity, and histopathology. Our results indicated clearly that at the maximum dosage of 3 mg/kg, the pcDNA-CCOL2A1 vaccine was safe and well-tolerated. No abnormal clinical signs or deaths occurred in the pcDNA-CCOL2A1 group compared with the NS group. Furthermore, no major alterations were observed in hematology, biochemistry, and histopathology, even at the maximum dose. In particularly, no anti-CII IgG antibodies were detected in vaccinated normal rats at 14 d after vaccination; this was relevant because we previously demonstrated that the pcDNA-CCOL2A1 vaccine, when administered at the therapeutic dosage of 300 μg/kg alone, did not induce anti-CII IgG antibody production and significantly reduced levels of anti-CII IgG antibodies in the plasma of rats with established collagen-induced arthritis
Lech, Gustaw; Słotwiński, Robert; Słodkowski, Maciej; Krasnodębski, Ireneusz Wojciech
Colorectal cancer (CRC) is the second most commonly diagnosed cancer among females and third among males worldwide. It also contributes significantly to cancer-related deaths, despite the continuous progress in diagnostic and therapeutic methods. Biomarkers currently play an important role in the detection and treatment of patients with colorectal cancer. Risk stratification for screening might be augmented by finding new biomarkers which alone or as a complement of existing tests might recognize either the predisposition or early stage of the disease. Biomarkers have also the potential to change diagnostic and treatment algorithms by selecting the proper chemotherapeutic drugs across a broad spectrum of patients. There are attempts to personalise chemotherapy based on presence or absence of specific biomarkers. In this review, we update review published last year and describe our understanding of tumour markers and biomarkers role in CRC screening, diagnosis, treatment and follow-up. Goal of future research is to identify those biomarkers that could allow a non-invasive and cost-effective diagnosis, as well as to recognise the best prognostic panel and define the predictive biomarkers for available treatments.
Lech, Gustaw; Słotwiński, Robert; Słodkowski, Maciej; Krasnodębski, Ireneusz Wojciech
Colorectal cancer (CRC) is the second most commonly diagnosed cancer among females and third among males worldwide. It also contributes significantly to cancer-related deaths, despite the continuous progress in diagnostic and therapeutic methods. Biomarkers currently play an important role in the detection and treatment of patients with colorectal cancer. Risk stratification for screening might be augmented by finding new biomarkers which alone or as a complement of existing tests might recognize either the predisposition or early stage of the disease. Biomarkers have also the potential to change diagnostic and treatment algorithms by selecting the proper chemotherapeutic drugs across a broad spectrum of patients. There are attempts to personalise chemotherapy based on presence or absence of specific biomarkers. In this review, we update review published last year and describe our understanding of tumour markers and biomarkers role in CRC screening, diagnosis, treatment and follow-up. Goal of future research is to identify those biomarkers that could allow a non-invasive and cost-effective diagnosis, as well as to recognise the best prognostic panel and define the predictive biomarkers for available treatments. PMID:26855534
Scarpa, Emanuele-Salvatore; Ninfali, Paolino
The theory that several carcinogenetic processes are initiated and sustained by cancer stem cells (CSCs) has been validated, and specific methods to identify the CSCs in the entire population of cancer cells have also proven to be effective. This review aims to provide an overview of recently acquired scientific knowledge regarding phytochemicals and herbal extracts, which have been shown to be able to target and kill CSCs. Many genes and proteins that sustain the CSCs' self-renewal capacity and drug resistance have been described and applications of phytochemicals able to interfere with these signaling systems have been shown to be operatively efficient both in vitro and in vivo. Identification of specific surface antigens, mammosphere formation assays, serial colony-forming unit assays, xenograft transplantation and label-retention assays coupled with Aldehyde dehydrogenase 1 (ALDH1) activity evaluation are the most frequently used techniques for measuring phytochemical efficiency in killing CSCs. Moreover, it has been demonstrated that EGCG, curcumin, piperine, sulforaphane, β-carotene, genistein and the whole extract of some plants are able to kill CSCs. Most of these phytochemicals act by interfering with the canonical Wnt (β-catenin/T cell factor-lymphoid enhancer factor (TCF-LEF)) pathway implicated in the pathogenesis of several cancers. Therefore, the use of phytochemicals may be a true therapeutic strategy for eradicating cancer through the elimination of CSCs.
Full Text Available Tissue invasion, metastasis and therapeutic resistance to anti-cancer treatments are common and main causes of death in cancer patients. Tumor cells mount complex and still poorly understood molecular defense mechanisms to counteract and evade oxygen deprivation, nutritional restrictions as well as radio- and chemotherapeutic treatment regimens aimed at destabilizing their genomes and important cellular processes. In thyroid cancer, as in other tumors, such defense strategies include the reactivation in cancer cells of early developmental programs normally active exclusively in stem cells, the stimulation of cancer stem-like cells resident within the tumor tissue and the recruitment of bone marrow-derived progenitors into the tumor (Thomas et al., 2008;Klonisch et al., 2009;Derwahl, 2011. Metastasis and therapeutic resistance in cancer (stem cells involves the epithelial-to-mesenchymal transition- (EMT- mediated enhancement in cellular plasticity, which includes coordinated dynamic biochemical and nuclear changes (Ahmed et al., 2010. The purpose of the present review is to provide an overview of the role of DNA repair mechanisms contributing to therapeutic resistance in thyroid cancer and highlight the emerging roles of autophagy and damage associated molecular pattern (DAMP responses in EMT and chemoresistance in tumor cells. Finally, we use the stem cell factor and nucleoprotein High Mobility Group A2 (HMGA2 as an example to demonstrate how factors intended to protect stem cells are wielded by cancer (stem cells to gain increased transformative cell plasticity which enhances metastasis, therapeutic resistance and cell survival. Wherever possible, we have included information on these cellular processes and associated factors as they relate to thyroid cancer cells.
Alamodi, Abdulhadi A; Eshaq, Abdulaziz M; Hassan, Sofie-Yasmin; Al Hmada, Youssef; El Jamal, Siraj M; Fothan, Ahmed M; Arain, Omair M; Hassan, Sarah-Lilly; Haikel, Youssef; Megahed, Mosaad; Hassan, Mohamed
Human malignant melanoma is a highly aggressive skin tumor that is characterized by its extraordinary heterogeneity, propensity for dissemination to distant organs and resistance to cytotoxic agents. Although chemo- and immune-based therapies have been evaluated in clinical trials, most of these therapeutics do not show significant benefit for patients with advanced disease. Treatment failure in melanoma patients is attributed mainly to the development of tumor heterogeneity resulting from the formation of genetically divergent subpopulations. These subpopulations are composed of cancer stem-like cells (CSCs) as a small fraction and non-cancer stem cells that form the majority of the tumor mass. In recent years, CSCs gained more attention and suggested as valuable experimental model system for tumor study. In melanoma, intratumoral heterogeneity, progression and drug resistance result from the unique characteristics of melanoma stem cells (MSCs). These MSCs are characterized by their distinct protein signature and tumor growth-driving pathways, whose activation is mediated by driver mutation-dependent signal. The molecular features of MSCs are either in a causal or consequential relationship to melanoma progression, drug resistance and relapse. Here, we review the current scientific evidence that supports CSC hypothesis and the validity of MSCs-dependent pathways and their key molecules as potential therapeutic target for melanoma treatment.
intratumoral injection of the fol- lowing experimental products: oncolytic viruses ,24 suicide genes,25;26 tumor-suppressor,27;28 and cy- tokine genes... pathogenetic factor in Hashimoto’s thyroiditis. Endocrine Pathol 1998;3:201–8. 40. Martin BK, Chin KC, Olsen JC, et al. Induction of MHC class I expression by...of murine prostate tumor growth and activation of immunoregulatory cells with recombinant canary- pox viruses . J. Natl. Cancer Inst. 93, 998–1007
Luongo, Monica; Critelli, Rosina; Grottola, Antonella; Gitto, Stefano; Bernabucci, Veronica; Bevini, Mirco; Vecchi, Chiara; Montagnani, Giuliano; Villa, Erica
HBV vaccine contains the 'a' determinant region, the major immune-target of antibodies (anti-HBs). Failure of immunization may be caused by vaccine-induced or spontaneous 'a' determinant surface gene mutants. Here, we evaluate the possible lack of protection by HBV vaccine, describing the case of an acute hepatitis B diagnosed in a 55-year-old Caucasian male unpaid blood donor, vaccinated against HBV. Sequencing data for preS-S region revealed multiple point mutations. Of all the substitutions found, Q129H, located in the "a" determinant region of HBsAg, can alter antigenicity, leading to mutants. This mutant may cause vaccine failure especially when associated with high viremia of infecting source. Copyright © 2014 Elsevier B.V. All rights reserved.
Full Text Available Although hepatocellular cancers (HCC frequently arise in the setting of fibrosis and a hepatic regenerative response requiring new cell growth, therapeutic strategies for these cancers have not targeted protein synthesis. Silvestrol, a rocaglate isolated from Aglaiafoveolata, can inhibit protein synthesis by modulating the initiation of translation through the eukaryotic initiation factor 4A. In this study, we evaluated the therapeutic efficacy of silvestrol for HCC.The efficacy of silvestrol was examined using human HCC cells in vitro using an orthotopic tumor cell xenograft model in a fibrotic liver. The impact of silvestrol on the liver was assessed in vivo in wild-type mice.Silvestrol inhibited cell growth with an IC50 of 12.5-86 nM in four different HCC cell lines. In vitro, silvestrol increased apoptosis and caspase 3/7 activity accompanied by loss of mitochondrial membrane potential and decreased expression of Mcl-1 and Bcl-xL. A synergistic effect was observed when silvestrol was combined with other therapeutic agents, with a dose-reduction index of 3.42-fold with sorafenib and 1.75-fold with rapamycin at a fractional effect of 0.5. In vivo, an antitumor effect was observed with 0.4 mg/kg silvestrol compared to controls after one week, and survival of tumor-bearing mice was improved with a median survival time of 42 and 28 days in the silvestrol and control groups, respectively. The effect on survival was not observed in orthotopic xenografts in non-fibrotic livers. Silvestrol treatment in vivo did not alter liver structure.These data identify silvestrol as a novel, structurally unique drug with potent anticancer activity for HCC and support the potential value of targeting initiation of translation in the treatment of HCC.
Park, Ji Ho
The unique electromagnetic and biologic properties of nanomaterials are being harnessed to build powerful new medical technologies. Particularly, there have been recently increasing interests in cancer nanotechnology, wherein nanomaterials play an important role in ultrasensitive imaging, targeting, and therapy of cancer. However, these nanomaterials typically function as individual units and are designed to independently perform their tasks. In this dissertation, new cooperative nanosystems consisting of two distinct nanomaterials that work together to target, identify, or treat tumors in vivo were studied. In the first two chapters, the synthesis of worm-shaped dextran-coated iron oxide nanoparticles (nanoworms, NW) exhibiting substantial in vivo circulation times and significant tumor targeting when coated with tumor-homing peptides were studied. NWs are also found to display a greater magnetic resonance (MR) response than the spherical nanoparticles. Next, two types of multifunctional nanoparticles were fabricated for simultaneous detection and treatment of cancer. Micellar hybrid nanoparticles (MHN) that contain magnetic nanoparticles, quantum dots, and an anti-cancer drug doxorubicin (DOX) within a single PEG-modified phospholipid micelle were first prepared. Simultaneous multimodal imaging (MR and fluorescence) and targeted drug delivery in vitro and in vivo was performed using DOX-incorporated targeted MHN. Secondly, luminescent porous silicon nanoparticles (LPSINP) that were drug-loadable, biodegradable and relatively non-toxic were prepared. In contrast to most inorganic nanomaterials, LPSINP were degraded in vivo in a relatively short time with no noticeable toxicity. The clearance and degradation of intravenously injected LPSINP in the bladder, liver, and spleen were established by whole-body fluorescence imaging. Finally, two types of cooperative nanomaterials systems to amplify targeting and deliver drugs efficiently to regions of tumor invasion were
Full Text Available Objective To evaluate the safety and immunogenicity of the therapeutic dual-plasmid HBV DNA vaccine mediated by electroporation (EP in vivo against the hepatitis B virus in healthy adult volunteers. Methods The enrolled 30 healthy volunteers were randomly divided into three dosage groups (10 volunteers in each group, namely: high-dose (4mg, middle-dose (2mg and low-dose (1mg groups. Volunteers received four intramuscular injections of HBV DNA vaccine mediated by in vivo EP at the 0, 4th, 12th and 24th week. Each dose group was further divided into 2 sub-groups (5 persons/per group with different EP frequencies, i.e. 36 and 60 volt. The changes in response was determined by physical diagnosis (ECG, chest X-ray, type-B ultrasound, lab findings (blood and urine routine, blood biochemistry, prothrombin time, thyroid function, tumor biomarkers, immunological variables (IFN-γ, ANA, anti-dsDNA Ab, serological variables pertaining to HBV (HBsAg, HBcAb, HBeAg, HBeAb, HBV DNA and serum anti-HBs status in volunteers before and after receiving EP mediated HBV DNA vaccination. Results The dual-plasmid HBV DNA vaccination mediated by in vivo EP was well tolerated in all healthy volunteers with a stable life signs. It was found that EP-mediated immunization of the therapeutic DNA vaccine against hepatitis B virus had a specific and obvious anti-HBs humoral immune response in one volunteer (17.22mU/ml. Four repeated intramuscular injections of the vaccine did not show any significant adverse effects in the receptors. Although mild elevation of serum ALT and enlarged spleen were found in one individual, the abnormalities disappeared spontaneously at the end of the trial. Conclusions EP-mediated dual-plasmid HBV DNA vaccine is safe and well tolerated with certain degree of humoral immunogenicity.
De Vlieghere, Elly; Verset, Laurine; Demetter, Pieter; Bracke, Marc; De Wever, Olivier
Cancer-associated fibroblasts (CAFs) are drivers of tumour progression and are considered as a target and a tool in cancer diagnostic and therapeutic applications. An increased abundance of CAFs or CAF signatures are recognized as a bad prognostic marker in several cancer types. Tumour-environment biomimetics strongly improve our understanding of the communication between CAFs, cancer cells and other host cells. Several experimental drugs targeting CAFs are in clinical trials for multiple tumour entities; alternatively, CAFs can be exploited as a tool to characterize the functionality of circulating tumour cells or to capture them as a tool to prevent metastasis. The continuous interaction between tissue engineers, biomaterial experts and cancer researchers creates the possibility to biomimic the tumour-environment and provides new opportunities in cancer diagnostics and management.
Isabela Resende Pereira
Full Text Available Chagas disease (CD, caused by the protozoan Trypanosoma cruzi, is a prototypical neglected tropical disease. Specific immunity promotes acute phase survival. Nevertheless, one-third of CD patients develop chronic chagasic cardiomyopathy (CCC associated with parasite persistence and immunological unbalance. Currently, the therapeutic management of patients only mitigates CCC symptoms. Therefore, a vaccine arises as an alternative to stimulate protective immunity and thereby prevent, delay progression and even reverse CCC. We examined this hypothesis by vaccinating mice with replication-defective human Type 5 recombinant adenoviruses (rAd carrying sequences of amastigote surface protein-2 (rAdASP2 and trans-sialidase (rAdTS T. cruzi antigens. For prophylactic vaccination, naïve C57BL/6 mice were immunized with rAdASP2+rAdTS (rAdVax using a homologous prime/boost protocol before challenge with the Colombian strain. For therapeutic vaccination, rAdVax administration was initiated at 120 days post-infection (dpi, when mice were afflicted by CCC. Mice were analyzed for electrical abnormalities, immune response and cardiac parasitism and tissue damage. Prophylactic immunization with rAdVax induced antibodies and H-2Kb-restricted cytotoxic and interferon (IFNγ-producing CD8+ T-cells, reduced acute heart parasitism and electrical abnormalities in the chronic phase. Therapeutic vaccination increased survival and reduced electrical abnormalities after the prime (analysis at 160 dpi and the boost (analysis at 180 and 230 dpi. Post-therapy mice exhibited less heart injury and electrical abnormalities compared with pre-therapy mice. rAdVax therapeutic vaccination preserved specific IFNγ-mediated immunity but reduced the response to polyclonal stimuli (anti-CD3 plus anti-CD28, CD107a+ CD8+ T-cell frequency and plasma nitric oxide (NO levels. Moreover, therapeutic rAdVax reshaped immunity in the heart tissue as reduced the number of perforin+ cells
Cancer vaccine targeting cancer stem cells is proposed to serve as a potent immunotherapy. Thus, it would be useful to examine the main trends in stem cell patenting activity as a guide for those seeking to develop such cancer vaccines. We found that a substantial number of stem cell patents were granted up to the end of 2010, including ~2000 issued in the US. Many of these have been filed since 2001, including 7,551 applications in the US. Stem cell development, as evidenced by the numbers of PubMed articles, has matured steadily in recent years. However, the other metrics, such as the number of patent applications, the technology-science linkage and the number of patent assignees, have been stagnant. Moreover, the ownership of stem cell patents is still quiet fragmented across multiple organizations, and the number of stem cell patent assignees from the business sector has not increased significantly. Academic and nonprofit institutions not only account for a large share of stem cell patents but also apply for patents continually. Based on this analysis, the strength of stem cell resources seems to remain stagnant in recent years due to the ban on government funding of embryonic stem cell research. Furthermore, the patent prosecution or technical barriers in the field of stem cells would be another main reason that the number of US-issued stem cell patents for each application have been in gradual decline since 2000. Therefore, we consider stem cell technology to still be under development.
Schuler-Thurner, B; Bartz-Schmidt, K-U; Bornfeld, N; Cursiefen, C; Fuisting, B; Grisanti, S; Heindl, L M; Holbach, L; Keserü, M; Knorr, H; Koch, K; Kruse, F; Meiller, R; Metz, C; Meyer-ter-Vehn, T; Much, M; Reinsberg, M; Schliep, S; Seitz, B; Schuler, G; Süsskind, D; Viestenz, A; Wagenfeld, L; Zeschnigk, M
Uveal melanomas are the most common malignant tumors of the eye. With modern molecular biological diagnostic methods, such as chromosome 3 typing and gene expression analysis, these tumors can be categorized into highly aggressive (monosomy 3, class II) and less aggressive forms. This molecular biological stratification is primarily important for determining the risk of these tumors as no therapy is currently available that is able to prevent or delay metastases. A randomized study of patients with a poor prognosis (monosomy 3) is currently being carried out in order to determine whether a cancer vaccine prepared from autologous (patient's own) dendritic cells and uveal melanoma RNA can prevent or delay progression and further metastases of this extremely aggressive form of cancer. Inclusion in the uveal melanoma study, which hopes to provide a potential therapeutic option for patients, is only possible if patients are referred to an institution that is able to manufacture and provide this vaccination before the patient is operated on or treated with radiation. Untreated tumor material is necessary for producing the vaccine on an individualized patient basis.
Bogani, Giorgio; Leone Roberti Maggiore, Umberto; Signorelli, Mauro; Martinelli, Fabio; Ditto, Antonino; Sabatucci, Ilaria; Mosca, Lavinia; Lorusso, Domenica; Raspagliesi, Francesco
Human papillomavirus (HPV) is the most common sexually transmitted disease, worldwide. Primary prevention thorough vaccination si able to reduce the burden of HPV-related lesions. Ten years ago the Food and drug Administration (FDA) approved the first vaccine against HPV. In the last decades, growing data on safety and effectiveness have been collected. In the present review we report the current knowledge on vaccine against HPV, highlighting the current value and prospective regarding the widespread diffusion of HPV vaccines. The role of emerging therapeutic vaccines is reviewed. Copyright © 2017 Elsevier B.V. All rights reserved.
...) . A number of promising therapeutic targets for androgen-independent and metastatic prostate cancers are contained within the signaling cascades downstream of the ECM-binding Integrin molecules...
Wong, Li Ping
It has been a little more than a year ago since the prophylactic vaccine against human papillomavirus (HPV) was released in Malaysia. Little is known about parental knowledge and acceptability of the vaccine. The objective of this study is to assess the mother's knowledge and attitudes toward HPV vaccination. The results are aimed to provide insights into the provision of appropriate educational and promotional program for effective immunization uptake. Purposive sampling method was adopted for recruitment of participants. A total of 47 mothers participated across 8 focus group discussions carried out between October and November 2007. The transcribed group discussions were analyzed using open-, axial-, and selective-coding procedures. Respondents have low awareness about the newly released vaccine and the link between HPV and cervical cancer. When provided with information about HPV and cervical cancer, most mothers were in favor of protecting their daughters from cervical cancer using the vaccine. As with any new vaccine, efficacy and safety were the major concern, particularly when the vaccine is recommended to preadolescent. Many expressed concern about the high cost of the vaccine and hope that the inoculation could be at least partially subsidized by the government. A minority were concerned that the sexually transmitted disease-related vaccine would promote sexual activities, and some opposed making vaccination mandatory. For Muslim respondents, the kosher issue of HPV vaccine was an important factor for acceptance. Developing public health messages that focus on the susceptibility of HPV infection and its link to cervical cancer to educate parents may have the greatest impact on improving the uptake of the vaccine. Apart from the major concern about safety and efficacy, affordability, and acceptability of vaccinating young children, religious and ethnic backgrounds were important considerations when recommending the HPV vaccine. To foster broad acceptance
Glycosylation changes are universal hallmarks of malignant transformation and tumour progression in human cancer, which take place on the whole cells or some specific molecules. Accordingly, those changes make them prominent candidates for cancer biomarkers in the meantime. This review mainly focuses on the ...
Full Text Available Emiliano Calvo1, Victoria Bolós2, Enrique Grande21Centro Integral Oncológico Clara Campal (CiOCC, Madrid. Spain; 2Pfizer Oncology, Alcobendas-Madrid, SpainAbstract: The prominence of the PI3K-Akt signaling pathway in several tumors indicates a relationship with tumor grade and proliferation. Critical cellular processes are driven through this pathway. More detailed knowledge of the pathogenesis of tumors would enable us to design targeted drugs to block both membrane tyrosine kinase receptors and the intracellular kinases involved in the transmission of the signal. The newly approved molecular inhibitors sunitinib (an inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and other tyrosine kinase receptors, sorafenib (a serine–threonine kinase inhibitor that acts against B-Raf and temsirolimus (an mTOR inhibitor shown clinical activity in advanced kidney cancer. Chronic myeloid leukemia has changed its natural history thanks to imatinib and dasatinib, both of which inhibit the intracellular bcr/abl protein derived from the alteration in the Philadelphia chromosome. Intracellular pathways are still important in cancer development and their blockade directly affects outcome. Cross-talk has been observed but is not well understood. Vertical and horizontal pathway blockade are promising anticancer strategies. Indeed, preclinical and early clinical data suggest that combining superficial and intracellular blocking agents can synergize and leverage single-agent activity. The implication of the Akt signaling pathway in cancer is well established and has led to the development of new anticancer agents that block its activation.Keywords: Akt, cancer, therapeutic target, Akt inhibitors
Nicco, Carole; Batteux, Frédéric
Reactive Oxygen Species (ROS) are chemically reactive chemical species containing oxygen. The redox status of a cell is function of the relative concentrations of oxidized and reduced forms of proteins, enzymes, ROS, molecules containing thiol and other factors. In the organism, the redox balance is based on the generation and elimination of ROS produced by endogenous and exogenous sources. All living organisms must maintain their redox equilibrium to survive and proliferate. Enzymatic and molecular pathways control ROS levels tightly but differentially depending on the type of cell. This review is an overview of various molecules that modulate ROS production/detoxification and have a synergistic action with the chemotherapies to kill cancer cells while preserving normal cells to avoid anticancer drugs side effects, allowing a better therapeutic index of the anticancer treatments.
Full Text Available BACKGROUND: Warts are common cutaneous viral infection. Various therapeutic modalities have been using in treatment of wart, but none of them are standardised. Immunotherapy is new current approach in the treatment of wart. AIMS: To know the efficacy and safety profile of Measles Mumps Rubella (MMR Vaccine in the treatment of wart. METHODS: MMR vaccine was injected into a largest single wart intralesionally and subsequent injections given every 2 weeks apart for about 3 to 5 times. Every month followup of patients was done to know the clearance of wart. RESULTS: Complete remission of warts seen in 70.4% of patients, partial remission seen in 22.2% and no response was seen in 7.4% of patients. No serious adverse side effects were seen in the current study. CONCLUSION: MMR vaccine can be considered as a safe, effective, inexpensive intralesional immunotherapeutic modality in the treatment of wart.
Lyerly, H Kim
While the future of immunotherapy in the treatment of cancer is promising, it is difficult to compare the various approaches because monitoring assays have not been standardized in approach or technique. Common assays for measuring the immune response need to be established so that these assays can one day serve as surrogate markers for clinical response. Assays that accurately detect and quantitate T-cell-mediated, antigen-specific immune responses are particularly desired. However, to date, increases in the number of cytotoxic T cells through immunization have not been correlated with clinical tumor regression. Ideally, then, a T-cell assay not only needs to be sensitive, specific, reliable, reproducible, simple, and quick to perform, it must also demonstrate close correlation with clinical outcome. Assays currently used to measure T-cell response are delayed-type hypersensitivity testing, flow cytometry using peptide major histocompatibility complex tetramers, lymphoproliferation assay, enzyme-linked immunosorbant assay, enzyme-linked immunospot assay, cytokine flow cytometry, direct cytotoxicity assay, measurement of cytokine mRNA by quantitative reverse transcriptase polymerase chain reaction, and limiting dilution analysis. The purpose of this review is to describe the attributes of each test and compare their advantages and disadvantages.
Full Text Available Some bovine antibodies across all classes are unique, such as the CDR3 of the variable heavy-domain (VH CDR3, which is exceptionally long (up to 66 amino acids, unlike most conventional antibodies where the VH CDR3 loops range from 10 to 25 amino acids. The exceptionally long VH CDR3 is encoded by unusually long germline IGHD genes together with insertion of novel “a” nucleotide rich conserved short nucleotide sequence (CSNS specifically at the IGH V-D junction. Such an exceptionally long VH CDR3 confers unique “knob and stalk” structural architecture where the knob, formed by intra-VH CDR3 disulfide bridges, is separated by 20 Å solvent exposed stalk composed of anti-parallel beta strands. The substitution of the knob with cytokines, such as, erythropoietin and granulocyte colony stimulating factor 3 (granulocyte colony stimulating factor, results in expression of functional fusion proteins with enhanced pharmacokinetics. The beta stranded stalk can be substituted with other rigid structures, for example, repeat alpha helices to form coiled-coil that mimics the beta-stranded stalk and, thus, opens opportunities for insertion of this structure in the CDRs of antibodies across species. Given the versatility of such a structural platform in bovine antibody VH CDR3, it provides the opportunity for the development of new generation of diagnostics, therapeutics, vaccines and immunomodulating drugs.
Bernstein, David I; Wald, Anna; Warren, Terri; Fife, Kenneth; Tyring, Stephen; Lee, Patricia; Van Wagoner, Nick; Magaret, Amalia; Flechtner, Jessica B; Tasker, Sybil; Chan, Jason; Morris, Amy; Hetherington, Seth
Genital herpes simplex virus type 2 (HSV-2) infection causes recurrent lesions and frequent viral shedding. GEN-003 is a candidate therapeutic vaccine containing HSV-2 gD2∆TMR and ICP4.2, and Matrix-M2 adjuvant. Persons with genital herpes were randomized into 3 dose cohorts to receive 3 intramuscular doses 21 days apart of 10 µg, 30 µg, or 100 µg of GEN-003, antigens without adjuvant, or placebo. Participants obtained genital swab specimens twice daily for HSV-2 detection and monitored genital lesions for 28-day periods at baseline and at intervals after the last dose. One hundred and thirty-four persons received all 3 doses. Reactogenicity was associated with adjuvant but not with antigen dose or dose number. No serious adverse events were attributed to GEN-003. Compared with baseline, genital HSV-2 shedding rates immediately after dosing were reduced with GEN-003 (from 13.4% to 6.4% for 30 μg [P genital HSV shedding and lesion rates. NCT01667341 (funded by Genocea). © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail firstname.lastname@example.org.
Shi, Xiangxiang; Zheng, Jun; Yan, Tingting
Human respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in infants and young children. Here, the RSV fusion (F) glycoprotein epitope FFL was redesigned based on its complex crystal structure with motavizumab, an mAb drug in development for the prevention of RSV infections, aiming to obtain therapeutic peptide vaccines with high affinity to induce RSV-specific neutralizing antibodies. Computational modeling and analysis found that only a small region covering the helix-turn-helix (HTH) motif of FFL can directly interact with motavizumab and confer stability and specificity to the complex system, while the rest of the epitope primarily serves as a structural scaffold that stabilizes the HTH conformation of motavizumab-binding site. Molecular dynamics simulations revealed a large flexibility and intrinsic disorder for the isolated linear HTH peptide, which would incur a considerable entropy penalty upon binding to motavizumab. In this respect, the FFL epitope was redesigned by truncation, mutation, and cyclization to derive a number of small cyclic peptide immunogens. We also employed in vitro fluorescence-based assays to demonstrate that the linear epitope peptide has no observable affinity to motavizumab, whereas redesigned versions of the peptide can bind with a moderate or high potency. Graphical abstract Computationally modeled complex structure of RSV F glycoprotein with motavizumab and zoom up of the complex binding site.
Chen, Min; Li, Yong-Guo; Zhang, Da-Zhi; Wang, Zhi-Yi; Zeng, Wei-Qun; Shi, Xiao-Feng; Guo, Yuan; Guo, Shu-Hua; Ren, Hong
To investigate the therapeutic effect of autologous HBsAg-loaded dendritic cells (DCs) on patients with chronic hepatitis B. Monocytes were isolated from fresh peripheral blood of 19 chronic HBV-infected patients by Ficoll-Hypaque density gradient centrifugation and cultured by plastic-adherence methods. DCs were induced and proliferated in the culture medium with recombinant human granulocyte-macrophage-colony-stimulating factor (rhGM-CSF) and human interleukin-4 (rhIL-4). DCs pulsed with HBsAg for twelve hours were injected into patients subcutaneously twice at intervals of two weeks. Two patients received 100 mg oral lamivudine daily for 12 mo at the same time. HBV-DNA and viral markers in sera of patients were tested every two months. By the end of 2003, 11 of 19 (57.9%) patients had a clinical response to DC-treatment. HBeAg of 10 (52.6%) patients became negative, and the copies of HBV-DNA decreased 10(1.77+/-2.39) on average (t = 3.13, Pvaccine induced in vitro can effectively suppress HBV replication, reduce the virus load in sera, eliminate HBeAg and promote HBeAg/anti-HBe transformation. Not only the patients with high serum ALT levels but also those with normal ALT levels can respond to DC vaccine treatment, and the treatment combining DCs with lamivudine can eliminate viruses more effectively.
about Human Papilloma Virus (HPV) vaccination and cervical cancer screening among women in rural Uganda NKONWA INNOCENT H 1,2,3* , MICHAEL J...cancer and HPV in Uganda has been limited even among health workers. Objectives: To establish the level of knowledge in regard to HPV vaccination among...parents/guardians of the vaccinated girls and to assess the attitudes to HPV vaccination among parents/guardians of the vaccinated girls. Methods: A
, Snijders and Mao described that and “when the selection pressure is removed, amplifications are not maintained and eventually disappear. Thus, amplifications focus on those genes that are important for tumor development,” they said. Their analysis showed that, as tumorous cells progress toward malignancy, the DNA copy number plays a major role in the mechanism of increased expression levels for the 18-gene signature on chromosome 20q. “Strong associations between the DNA copy number and gene expression were observed in the majority of tumor types,” the researchers said. “For example, the RAE1 expression was found to be significantly associated with DNA copy number in 20 tumor types,” the study reported. “Elevated DNA copy numbers of MMP9 and SULF2 were associated with increased gene expressions in only two and seven tumor types, respectively,” it added. With their integrated multi-omics analysis of genes on chromosome 20q, Snijders and Mao believed that the 18-gene signature could become new molecular targets for cancer therapy. “Gene ontology analysis revealed significant enrichment of cell cycle and mitosis-related biological processes in our 18-gene, suggesting that a cluster of functionally related genes localize to chromosome 20q,” they said. The identification of good targets such as theirs is a critical step for the development of targeted therapies for cancer treatment, according to the researchers. Microarray and next generation sequencing technologies have become invaluable tools in cataloging genomic abnormalities in human cancers and identifying new potential therapeutic targets, in addition to the availability of large cancer genomic data sets which allows for unbiased approaches to identify genes that are important in tumor progression, the research study noted. “Here, we aggregated available cancer databases to identify cancer driver genes across tumor types by combining gene transcript and DNA copy number across chromosome 20q to
Fowler, Brynn; Bodson, Julia; Warner, Echo L; Dyer, Jane; Kepka, Deanna
Individuals overdue for recommended cancer screenings may not be receiving adequate cancer prevention education. Since Latinas have the highest incidence of cervical cancer among all racial/ethnic groups, human papillomavirus (HPV) vaccination education is especially important for this population. The correlates of HPV vaccine-related awareness and knowledge were assessed among Latinas who were overdue for recommended cancer screenings. N = 206 Latinas who were overdue for recommended cancer screenings were recruited by health educators from local community groups. Bivariate analyses and multivariable regression models were used to investigate factors associated with HPV vaccine-related awareness and knowledge among participants as well as to assess correlates of HPV vaccine receipt for eligible children of participants. In multivariable regression analyses, years living in the U.S. (p = 0.05) and health insurance status (p = 0.03) were significantly related to HPV vaccine-related knowledge measures. Age (p cancer screening status (p = 0.03), and HPV vaccine-related knowledge measures (p HPV vaccination outcomes for eligible daughters of participants. Cervical cancer screening status (p = 0.02) and HPV vaccine-related knowledge measures (p = 0.01) were significantly associated with HPV vaccination outcomes for eligible sons of participants. Results indicate poor HPV vaccine-related awareness and knowledge among Latinas. Interventions to improve HPV vaccine-related awareness and knowledge in Utah's growing Latino population should target vulnerable individuals (e.g., not employed outside the home, less educated, less acculturated, poor, uninsured, overdue for cervical cancer screening) by using materials that are culturally sensitive, linguistically appropriate, and easily accessible.
Nath, Amiya Kumar; Thappa, Devinder Mohan
This article takes a critical look at the pros and cons of human papillomavirus (HPV) vaccines. There is enough evidence to suggest that the prophylactic vaccines are efficacious in preventing various benign and malignant conditions (including cervical cancers) caused by HPV. Even though the vaccine is costly, hypothetical analysis has shown that HPV vaccination will be cost effective in the long run. Therapeutic HPV vaccines used to treat established disease are still undergoing evaluation in clinical studies, and results seem to be encouraging. Although several countries have started mandatory vaccination programs with the prophylactic HPV vaccines, conservatives have voiced concerns regarding the moral impact of such vaccination programs.
Full Text Available Plants are known to have many secondary metabolites and phytochemical compounds which are highly explored at biochemical and molecular genetics level and exploited enormously in the human health care sector. However, there are other less explored small molecular weight proteins, which inhibit proteases/proteinases. Plants are good sources of protease inhibitors (PIs which protect them against diseases, insects, pests, and herbivores. In the past, proteinaceous PIs were considered primarily as protein-degrading enzymes. Nevertheless, this view has significantly changed and PIs are now treated as very important signaling molecules in many biological activities such as inflammation, apoptosis, blood clotting and hormone processing. In recent years, PIs have been examined extensively as therapeutic agents, primarily to deal with various human cancers. Interestingly, many plant-based PIs are also found to be effective against cardiovascular diseases, osteoporosis, inflammatory diseases and neurological disorders. Several plant PIs are under further evaluation in in vitro clinical trials. Among all types of PIs, Bowman-Birk inhibitors (BBI has been studied extensively in the treatment of many diseases, especially in the field of cancer prevention. So far, crops such as beans, potatoes, barley, squash, millet, wheat, buckwheat, groundnut, chickpea, pigeonpea, corn and pineapple have been identified as good sources of PIs. The PI content of such foods has a significant influence on human health disorders, particularly in the regions where people mostly depend on these kind of foods. These natural PIs vary in concentration, protease specificity, heat stability, and sometimes several PIs may be present in the same species or tissue. However, it is important to carry out individual studies to identify the potential effects of each PI on human health. PIs in plants make them incredible sources to determine novel PIs with specific pharmacological and
as an oral contraceptive [6, 7]. Recently, its anti- cancer activity has been reported against advanced breast cancer  and head and neck squamous...Award Number: W81XWH-141-0154 TITLE: “A Novel Therapeutic Modality for Advanced-Stage Prostate Cancer Treatment” PRINCIPAL INVESTIGATOR...Novel Therapeutic Modality for Advanced-Stage Prostate Cancer Treatment” 5a. CONTRACT NUMBER: 5b. GRANT NUMBER: W81XWH-14-1-0154 5c. PROGRAM ELEMENT
Nanoparticles (NPs) are becoming increasingly common in consumer goods and are under investigation for a variety of industrial and biomedical applications. However, challenges in determining NP toxicity may prevent them from reaching their full potential. NPs cannot be treated as single class for toxicity evaluations. Even among particles made from the same material, particle-specific physical properties, including size, shape, surface charge, agglomeration state, and surface modifications have a strong effect on the toxicity. Even so, the obstacles to conclusively and reproducibly evaluating toxicity span all NP classes. NP literature is riddled with confusing and often contradictory reports regarding the biocompatibility of both engineered NPs, designed with biocompatibility as a priority, and NPs from occupational or environmental exposures. Incomplete NP characterization and sample inhomogeneity represent major confounding factors in disparate results from seemingly comparable study setups. Additionally, NPs can interfere with many conventional toxicity screening methods. Inappropriate doses, exposure routes, and toxicity endpoints further diminish the utility of many published studies. Given the burgeoning interest in NP-based therapeutic agents, consistent, reliable standards are needed to ensure the biocompatibility of new formulations. To those ends, the synthesis, characterization, and in vitro toxicity of a multi-functional NP therapeutic were investigated (Chapter 2). Specifically, superparamagnetic iron oxide nanoparticles (SPIONs) were coated with amphiphilic polymer and functionalized with antisense oligonucleotides targeting survivin, an anti-apoptotic protein that is highly overexpressed in cancer. SPION physical properties, including particle size and composition, were characterized at each step of synthesis. Our results showed that the SPION platform is biocompatible and capable of delivering functional antisense oligonucleotides to regulate
Tourdot, S; Airouche, S; Berjont, N; Da Silveira, A; Mascarell, L; Jacquet, A; Caplier, L; Langelot, M; Baron-Bodo, V; Moingeon, P
Second generation therapeutic vaccines based upon recombinant allergens or natural extracts, potentially formulated in vector systems or adjuvants, are being developed. To this aim, preclinical studies in relevant animal models are needed to select proper allergens, formulations and administration schemes. To develop a chronic house dust mite (HDM) allergy model to evaluate sublingual therapeutic vaccine candidates. The BABL/c mice that were used were sensitized with Dermatophagoides pteronyssinus (Dpte) and Dermatophagoides farinae (Dfar) mite extracts by intraperitoneal injections followed by aerosol exposures. Animals subsequently underwent sublingual immunotherapy (SLIT) with either Dpte, Dfar or Dpte/Dfar extracts, twice a week for 8 weeks. SLIT efficacy was assessed by whole body plethysmography, lung histology and broncho-alveolar lavages cell counts. Specific T cell and antibody responses to major and minor HDM allergens were monitored in tissues and serum/saliva, respectively. Mice sensitized to Dpte and Dfar allergens exhibited strong airway hyperresponsiveness (AHR) and lung inflammatory infiltrates including eosinophils. Sensitized animals mounted Th2-biased cellular and humoral responses specific for group 1 and 2 major allergens, as well as group 5, 7 and 10 minor allergens. This phenotype was sustained for at least 2 months, allowing the evaluation of immunotherapeutic protocols with HDM extracts-based vaccines. In this model, SLIT decreased AHR and Th2 responses and induced HDM-specific IgAs in saliva. The Dpte/Dfar mix proved the most efficacious when compared to Dpte or Dfar extracts alone. The efficacy of a sublingual vaccine based on a Dpte/Dfar allergen extract mix was demonstrated in a well standardized murine model of chronic allergic airway inflammation based on clinically relevant mite allergens. The latter will be used as a benchmark for evaluation of future vaccines, including recombinant allergens. This HDM allergic airway inflammation
Full Text Available One of the challenging issues in vaccine development is peptide and adjuvant delivery into target cells. In this study, we developed a vaccine and therapeutic delivery system to increase cytotoxic T lymphocyte (CTL response against a breast cancer model overexpressing HER2/neu. Gp2, a HER2/neu-derived peptide, was conjugated to Maleimide-mPEG2000-DSPE micelles and post inserted into liposomes composed of DMPC, DMPG phospholipids, and fusogenic lipid dioleoylphosphatidylethanolamine (DOPE containing monophosphoryl lipid A (MPL adjuvant (DMPC-DMPG-DOPE-MPL-Gp2. BALB/c mice were immunized with different formulations and the immune response was evaluated in vitro and in vivo. ELISpot and intracellular cytokine analysis by flow cytometry showed that the mice vaccinated with Lip-DOPE-MPL-GP2 incited the highest number of IFN-γ+ in CD8+ cells and CTL response. The immunization led to lower tumor sizes and longer survival time compared to the other groups of mice immunized and treated with the Lip-DOPE-MPL-GP2 formulation in both prophylactic and therapeutic experiments. These results showed that co-formulation of DOPE and MPL conjugated with GP2 peptide not only induces high antitumor immunity but also enhances therapeutic efficacy in TUBO mice model. Lip-DOPE-MPL-GP2 formulation could be a promising vaccine and a therapeutic delivery system against HER2 positive cancers and merits further investigation.
1- Knowledge and attitudes about Human Papilloma Virus (HPV) vaccination and cervical cancer screening among women in rural Uganda Authors... vaccination among parents/guardians of the vaccinated girls and to assess the attitudes to HPV vaccination among parents/guardians of the vaccinated girls...Methods: A cross-sectional study where 384 mothers/ female guardians of vaccinated girls were recruited into the study. One hundred and sixty four
Herberman, Ronald B; Pearce, Homer L; Lippman, Scott M; Pyenson, Bruce S; Alberts, David S
The emerging field of cancer prevention through chemoprevention agents and cancer vaccines offers significant promise for reducing suffering and death from cancer. However, that promise may not be kept unless major barriers to progress are lowered or eliminated. Among the most significant barriers are the relatively small investment from government and industry in research and development of cancer preventive agents; a predominant emphasis of translational cancer research on therapeutic interventions for metastatic or advanced cancer; complexities of prevention trial design; a relatively uncharted Food and Drug Administration (FDA) approval process for preventive agents; insufficient public and patient understanding of the importance and potential for cancer preventive measures, with consequent unpredictable public and patient willingness to take preventive agents; an uncertain reimbursement from payors; and limitations in patent law, liability protection, and data package exclusivity that undermine the opportunity for recouping investment. Viewed individually or collectively, each of these barriers serves as a substantial deterrent to intellectual and financial investment by all sectors of the cancer community. In an effort to ultimately overcome these barriers, a Cancer Prevention Research Summit was assembled June 12-13, 2006 in Bethesda, Maryland, organized by C-Change with support from the AACR. The Summit brought together some 120 leaders from private, public, and not-for-profit entities, including cancer researchers and clinicians; federal health officials; regulatory agency representatives; pharmaceutical, biotech, and food industry leaders; patent attorneys; economists; public and private provider group executives; and advocates. Participants engaged in a detailed process to more carefully define the major barriers, identify potential solutions, and formulate initial priorities and recommendations for action. At the conclusion of this dialogue among
Li, F; Kang, H; Li, J; Zhang, D; Zhang, Y; Dannenberg, A M; Liu, X; Niu, H; Ma, L; Tang, R; Han, X; Gan, C; Ma, X; Tan, J; Zhu, B
To screen effective antigens as therapeutic subunit vaccines against Mycobacterium latent infection, we did bioinformatics analysis and literature review to identify effective antigens and evaluated the immunogenicity of five antigens highly expressed in dormant bacteria, which included Rv2031c (HspX), Rv2626c (Hrp1), Rv2007c (FdxA), Rv1738 and Rv3130c. Then, several fusion proteins such as Rv2007c-Rv2626c (F6), Rv2031c-Rv1738-Rv1733c (H83), ESAT6-Rv1738-Rv2626c (LT40), ESAT6-Ag85B-MPT64 -Mtb8.4 (EAMM), and EAMM-Rv2626c (LT70) were constructed and their therapeutic effects were evaluated in pulmonary Mycobacterium bovis Bacilli Calmette-Guérin (BCG) - latently infected rabbit or mouse models. The results showed that EAMM and F6 plus H83 had therapeutic effect against BCG latent infection in the rabbit model, respectively, and that the combination of EAMM with F6 plus H83 significantly reduced the bacterial load. In addition, the fusion proteins LT40 and LT70 consisting of multistage antigens showed promising therapeutic effects in the mouse model. We conclude that subunit vaccines consisting of both latency and replicating-associated antigens show promising therapeutic effects in BCG latent infection animal models. © 2017 The Foundation for the Scandinavian Journal of Immunology.
Salazar-Onfray, Flavio; Pereda, Cristián; Reyes, Diego; López, Mercedes N
Here we summarize 10 years of effort in the development of a biomedical innovation with global projections. This innovation consists of a novel method for the production of therapeutic dendritic-like cells called Tumor Antigen Presenting Cells (TAPCells®). TAPCells-based immunotherapy was tested in more than 120 stage III and IV melanoma patients and 20 castration-resistant prostate cancer patients in a series of phase I and I/II clinical trials. TAPCells vaccines induced T cell-mediated memory immune responses that correlated with increased survival in melanoma patients and prolonged prostate-specific antigen doubling time in prostate cancer patients. Importantly, more than 60% of tested patients showed a Delayed Type Hypersensitivity (DTH) reaction against the lysates, indicating the development of anti-tumor immunological memory that correlates with clinical benefits. The in vitro analysis of the lysate mix showed that it contains damage-associated molecular patterns such as HMBG-1 protein which are capable to improve, through Toll-like receptor-4, maturation and antigen cross-presentation of the dendritic cells (DC). In fact, a Toll-like receptor-4 polymorphism correlates with patient clinical outcomes. Moreover, Concholepas concholepas hemocyanin (CCH) used as adjuvant proved to be safe and capable of enhancing the immunological response. Furthermore, we observed that DC vaccination resulted in a three-fold increase of T helper-1 lymphocytes releasing IFN-γ and a two-fold increase of T helper-17 lymphocytes capable of producing IL-17 in DTH+ with respect to DTH- patients. Important steps have been accomplished for TAPCells technology transfer, including patenting, packaging and technology assessment. Altogether, our results indicate that TAPCells vaccines constitute an exceptional Chilean national innovation of international value.
Full Text Available Here we summarize 10 years of effort in the development of a biomedical innovation with global projections. This innovation consists of a novel method for the production of therapeutic dendritic-like cells called Tumor Antigen Presenting Cells (TAPCells®. TAPCells-based immunotherapy was tested in more than 120 stage III and IV melanoma patients and 20 castration-resistant prostate cancer patients in a series of phase I and I/II clinical trials. TAPCells vaccines induced T cell-mediated memory immune responses that correlated with increased survival in melanoma patients and prolonged prostate-specific antigen doubling time in prostate cancer patients. Importantly, more than 60% of tested patients showed a Delayed Type Hypersensitivity (DTH reaction against the lysates, indicating the development of anti-tumor immunological memory that correlates with clinical benefits. The in vitro analysis of the lysate mix showed that it contains damage-associated molecular patterns such as HMBG-1 protein which are capable to improve, through Toll-like receptor-4, maturation and antigen cross-presentation of the dendritic cells (DC. In fact, a Toll-like receptor-4 polymorphism correlates with patient clinical outcomes. Moreover, Concholepas concholepas hemocyanin (CCH used as adjuvant proved to be safe and capable of enhancing the immunological response. Furthermore, we observed that DC vaccination resulted in a three-fold increase of T helper-1 lymphocytes releasing IFN-γ and a two-fold increase of T helper-17 lymphocytes capable of producing IL-17 in DTH+ with respect to DTH- patients. Important steps have been accomplished for TAPCells technology transfer, including patenting, packaging and technology assessment. Altogether, our results indicate that TAPCells vaccines constitute an exceptional Chilean national innovation of international value.
Toh, Uhi; Saku, Shuko; Okabe, Mina; Iwakuma, Nobutaka; Kimitsuki, Yuko; Akashi, Momoko; Ogo, Etsuyo; Yamada, Akira; Shichijo, Shigeki; Itoh, Kyogo; Akagi, Yoshito
Our previous phase II clinical trial showed that therapeutically selected personalized peptide vaccines(PPVs)were effective at boosting anticancer immunity; the immune response after PPV was associated with a clinical outcome as a prognostic factor for metastatic breast cancer(mBC). We conducted an early phase II study to evaluate the safety and efficacy of a new regimen using multiple peptide vaccines(KRM-19)for patients with metastatictriple -negative breast cancer. KRM-19 consisted of 19 mixed peptides chosen from the previously reported 31 PPVs according to their anti-tumor immunologiceffec ts and safety profiles for patients with mBC. All patients had histologically confirmed measurable ER-PgR-HER2- mBC and their human leukocyte antigen(HLA) / -A molecules were A2, A3, A11, A24, A26, A31, or A33. KRM-19(19mg/mL)was administrated subcutaneously every week for a total of 6 doses. Concurrent conventional chemo- and/or endocrine therapy were not permitted during treatment. This was an open-label, early phase II study. The primary endpoint was safety and anti-tumor immunologic effect, while the secondary endpoints were clinical responses and progression-free survival(PFS). The estimated enrollment was 10-15 and 8 patients were enrolled(Clinical trial registry number: UMIN000014616). Measurement of peptide-specific cytotoxic T lymphocyte and IgG responses were conducted before and after vaccination. The correlation between PFS and the increased IgG response and/or CTL levels were investigated.
Full Text Available Accumulating evidence has indicated that oxidative stress (OS is associated with the development of hepatocellular carcinoma (HCC. However, the mechanisms remain largely unknown. Normally, OS occurs when the body receives any danger signal—from either an internal or external source—and further induces DNA oxidative damage and abnormal protein expression, placing the body into a state of vulnerability to the development of various diseases such as cancer. There are many factors involved in liver carcinogenesis, including hepatitis B virus (HBV and hepatitis C virus (HCV infection, alcohol abuse, and nonalcoholic fatty liver disease (NAFLD. The relationship between OS and HCC has recently been attracting increasing attention. Therefore, elucidation of the impact of OS on the development of liver carcinogenesis is very important for the prevention and treatment of liver cancer. This review focuses mainly on the relationship between OS and the development of HCC from the perspective of cellular and molecular mechanisms and the etiology and therapeutic targets of HCC.
Diaz, M; Kim, J J; Albero, G; de Sanjosé, S; Clifford, G; Bosch, F X; Goldie, S J
Cervical cancer is a leading cause of cancer death among women in low-income countries, with approximately 25% of cases worldwide occurring in India. We estimated the potential health and economic impact of different cervical cancer prevention strategies. After empirically calibrating a cervical cancer model to country-specific epidemiologic data, we projected cancer incidence, life expectancy, and lifetime costs (I$2005), and calculated incremental cost-effectiveness ratios (I$/YLS) for the following strategies: pre-adolescent vaccination of girls before age 12, screening of women over age 30, and combined vaccination and screening. Screening differed by test (cytology, visual inspection, HPV DNA testing), number of clinical visits (1, 2 or 3), frequency (1 x , 2 x , 3 x per lifetime), and age range (35-45). Vaccine efficacy, coverage, and costs were varied in sensitivity analyses. Assuming 70% coverage, mean reduction in lifetime cancer risk was 44% (range, 28-57%) with HPV 16,18 vaccination alone, and 21-33% with screening three times per lifetime. Combining vaccination and screening three times per lifetime provided a mean reduction of 56% (vaccination plus 3-visit conventional cytology) to 63% (vaccination plus 2-visit HPV DNA testing). At a cost per vaccinated girl of I$10 (per dose cost of $2), pre-adolescent vaccination followed by screening three times per lifetime using either VIA or HPV DNA testing, would be considered cost-effective using the country's per capita gross domestic product (I$3452) as a threshold. In India, if high coverage of pre-adolescent girls with a low-cost HPV vaccine that provides long-term protection is achievable, vaccination followed by screening three times per lifetime is expected to reduce cancer deaths by half, and be cost-effective.
Mouallif, Mustapha; Bowyer, Harriet L; Festali, Soukaina; Albert, Adelin; Filali-Zegzouti, Younes; Guenin, Samuel; Delvenne, Philippe; Waller, Jo; Ennaji, Moulay Mustapha
Cervical cancer is a major public health concern in Morocco where it represents the second most common and lethal cancer in women. Human papillomavirus (HPV) vaccines have been licensed in Morocco since 2008 but there are no available data on their acceptability. This study aimed to assess awareness of HPV and the vaccine, and to identify factors associated with acceptability of the vaccine among parents in Morocco. We carried out a questionnaire-based survey using face-to-face interviews in a sample of 852 parents (670 mothers and 182 fathers) with at least one unmarried daughter ≤26 years. We collected data within public and private health centres and clinics in four regions in Morocco between July and August 2012. The main outcome measure was parental acceptability of the HPV vaccine for their daughter(s). Responses revealed very low awareness of HPV infection (4.7%) and the HPV vaccine (14.3%). None of the participants had vaccinated their daughter(s) against HPV and vaccine acceptability was low among mothers (32%) and fathers (45%). Higher education and income, previous awareness of the HPV vaccine and endorsement of the belief that a recommendation from the Ministry of Health or a doctor to have the vaccine would be encouraging, were associated with mothers' HPV vaccine acceptability. Non-acceptability among mothers was associated with having more than two daughters, believing the vaccine was expensive, lack of information and believing that whatever happens to an individual's health is God's will. The only factor associated with the fathers' acceptability of the vaccine was the cost of the vaccine. Increasing HPV and HPV vaccine awareness through educational campaigns, along with active recommendation by physicians and a publically funded vaccination programme could increase parental acceptability of the HPV vaccine in Morocco. Copyright © 2013 Elsevier Ltd. All rights reserved.
Ivan Y. C. Lin
Full Text Available Genetically attenuated microorganisms, including pathogenic and commensal bacteria, can be engineered to carry and deliver heterologous antigens to elicit host immunity against both the vector as well as the pathogen from which the donor gene is derived. These live attenuated bacterial vectors have been given much attention due to their capacity to induce a broad range of immune responses including localized mucosal, as well as systemic humoral and/or cell-mediated immunity. In addition, the unique tumor-homing characteristics of these bacterial vectors has also been exploited for alternative anti-tumor vaccines and therapies. In such approach, tumor-associated antigen, immunostimulatory molecules, anti-tumor drugs, or nucleotides (DNA or RNA are delivered. Different potential vectors are appropriate for specific applications, depending on their pathogenic routes. In this review, we survey and summarize the main features of the different types of live bacterial vectors and discussed the clinical applications in the field of vaccinology. In addition, different approaches for using live attenuated bacterial vectors for anti-cancer therapy is discussed, and some promising pre-clinical and clinical studies in this field are outlined.
Full Text Available The prophylactic capacity of the RUTI® vaccine, based on fragmented cells of Mycobacterium tuberculosis, has been evaluated in respect to aerosol challenge with virulent bacilli. Subcutaneous vaccination significantly reduced viable bacterial counts in both lungs and spleens of C57Bl mice, when challenged 4 weeks after vaccination. RUTI® protected the spleen less than BCG. Following a 9 month vaccination-challenge interval, protection was observed for the lungs, but not for the spleen. Survival of infected guinea pigs was prolonged by vaccination given 5 weeks before challenge. Inoculations of RUTI® shortly after infection significantly reduced the viable bacterial counts in the lungs, when compared with infected control mice. Thus, vaccination by RUTI® has potential for both the prophylaxis and immunotherapy of tuberculosis.
Draghiciu, Oana; Walczak, Mateusz; Hoogeboom, Baukje Nynke; Franken, Kees L M C; Melief, Kees J M; Nijman, Hans W; Daemen, Toos
Therapeutic cancer vaccines show promise in preclinical studies, yet their clinical efficacy is limited. Increased recruitment of immune cells into tumors and suppression of the immune suppressive tumor environment are critical components toward effective cancer immunotherapies. Here, we report how
Cooper, Dexter L; Hernandez, Natalie D; Rollins, Latrice; Akintobi, Tabia Henry; McAllister, Calvin
Black and Hispanic men are diagnosed with more HPV-related cancers and at later stages compared to other racial/ethnic groups. Physician communication with men about HPV vaccination may be beneficial to increasing HPV vaccinations and decreasing HPV transmission. The purpose of this study was to examine HPV and HPV vaccine awareness among men by race, and the association between trust in cancer information from physicians and ever hearing about HPV and the HPV vaccine. U.S. adult males (age 18+) were identified from the 2014 Health Information National Trends Survey (HINTS) (n=1203). Binomial logistic regression models assessed the influences of race/ethnicity and trust of cancer information from physicians on men having heard of HPV and the HPV vaccination. Approximately 50% of the sample had never heard of HPV and 53% had never heard of the vaccine. Black men were less likely to know that HPV is sexually transmitted compared to White and Hispanic men (pHPV vaccine when compared to White men (pcancer information compared to White and Black men (pHPV among men. Furthermore, statistically significant racial/ethnic differences were found in HPV vaccine knowledge and trust in receiving cancer information from physicians. Future interventions should include community-based approaches and improved physicians' HPV-related communication to increase knowledge and uptake of the HPV vaccine. Copyright © 2017 Elsevier Ltd. All rights reserved.
García-Pérez, Javier; García, Felipe; Blanco, Julia; Escribà-García, Laura; Gatell, Jose Maria; Alcamí, Jose; Plana, Montserrat; Sánchez-Palomino, Sonsoles
Background The generation of new immunogens able to elicit strong specific immune responses remains a major challenge in the attempts to obtain a prophylactic or therapeutic vaccine against HIV/AIDS. We designed and constructed a defective recombinant virus based on the HIV-1 genome generating infective but non-replicative virions able to elicit broad and strong cellular immune responses in HIV-1 seropositive individuals. Results Viral particles were generated through transient transfection in producer cells (293-T) of a full length HIV-1 DNA carrying a deletion of 892 base pairs (bp) in the pol gene encompassing the sequence that codes for the reverse transcriptase (NL4-3/ΔRT clone). The viral particles generated were able to enter target cells, but due to the absence of reverse transcriptase no replication was detected. The immunogenic capacity of these particles was assessed by ELISPOT to determine γ-interferon production in a cohort of 69 chronic asymptomatic HIV-1 seropositive individuals. Surprisingly, defective particles produced from NL4-3/ΔRT triggered stronger cellular responses than wild-type HIV-1 viruses inactivated with Aldrithiol-2 (AT-2) and in a larger proportion of individuals (55% versus 23% seropositive individuals tested). Electron microscopy showed that NL4-3/ΔRT virions display immature morphology. Interestingly, wild-type viruses treated with Amprenavir (APV) to induce defective core maturation also induced stronger responses than the same viral particles generated in the absence of protease inhibitors. Conclusions We propose that immature HIV-1 virions generated from NL4-3/ΔRT viral clones may represent new prototypes of immunogens with a safer profile and stronger capacity to induce cellular immune responses than wild-type inactivated viral particles. PMID:23144996
Oscarsson, Marie G; Dahlberg, Annica; Tydén, Tanja
To explore youth clinic midwives role in cervical cancer prevention and their attitude to HPV vaccination. Individual interviews with 13 midwives working at youth clinics in Sweden. The interviews were recorded, transcribed, and analysed by qualitative content analysis. Three themes were identified in the qualitative content analysis: "Cervical cancer prevention not a prioritised area", "Ambivalence to the HPV vaccine", and "Gender and socioeconomic controversies". Few midwives talked spontaneously about cervical cancer prevention. The responsibility for providing information about HPV vaccination was considered as primarily that of school health nurses and parents. Midwives were positive about the HPV vaccination, but recognised certain risks, such as its potential negative impact on cervical cancer screening and increased sexual risk taking. The midwives expressed concerns with medical risks, such as side effects and unknown long-term effects of the HPV vaccine. The midwives in the study had ethical concerns that boys were not included in the program and not all families had the financial resources to vaccinate their children. Thus, weak socioeconomic groups might be excluded. The midwives considered cervical cancer prevention as important, but did not integrate information on the HPV vaccine into their routine work, mainly because young people visiting youth clinics had had their sexual debut and they were concerned about the medical risks and that the vaccine was too expensive. Copyright Â© 2011 Elsevier B.V. All rights reserved.
Soriano, J.L.; Batista, N.; Lima, M.; Gonzalez, J.; Garcia, R.; Zarza, Y.; Lopez, M.V.; Rodriguez, M.; Loys, J.L.; Montejo, N.; Santiesteban, E.; Aguirre, F.; Macias, A.; Vazquez, A.M.
The use of low doses of cytotoxic agents continuously for prolonged periods is an alternative for the treatment of patients with metastatic breast cancer who have developed resistance to conventional chemotherapy. The combination of metronomic chemotherapy with therapeutic vaccines might increase the efficacy of the treatment. Twenty one patients with metastatic breast cancer in progression and a Karnosky index =60%, were treated with metronomic chemotherapy (50?mg of cyclophosphamide orally daily and 2.5 mg of methotrexate orally bi-daily), in combination with five bi-weekly subcutaneous injections of 1 mg of aluminum hydroxide-precipitated 1E10 anti-idiotype MAb (1E10-Alum), followed by re immunizations every 28 days. Five patients achieved objective response, eight showed stable disease and eight had disease progression. Median time to progression was 9,8 months, while median overall survival time was 12,93 months. The median duration of the response (CR+PR+SD) was 18,43 months (12,20-24,10 months), being higher than 12 months in 76,9% of the patients. Overall toxicity was generally mild. Metronomic chemotherapy combined with 1E10-Alum vaccine immunotherapy might be a useful therapeutic option for the treatment of metastatic breast cancer due to its potential impact on survival and patient quality of live, low toxicity and advantages of the administration.
Jorge L. Soriano
Full Text Available The use of low doses of cytotoxic agents continuously for prolonged periods is an alternative for the treatment of patients with metastatic breast cancer who have developed resistance to conventional chemotherapy. The combination of metronomic chemotherapy with therapeutic vaccines might increase the efficacy of the treatment. Twenty one patients with metastatic breast cancer in progression and a Karnosky index ≥60%, were treated with metronomic chemotherapy (50 mg of cyclophospamide orally daily and 2.5 mg of methotrexate orally bi-daily, in combination with five bi-weekly subcutaneous injections of 1 mg of aluminum hydroxide-precipitated 1E10 anti-idiotype MAb (1E10-Alum, followed by reimmunizations every 28 days. Five patients achieved objective response, eight showed stable disease and eight had disease progression. Median time to progression was 9,8 months, while median overall survival time was 12,93 months. The median duration of the response (CR+PR+SD was 18,43 months (12,20–24,10 months, being higher than 12 months in 76,9% of the patients. Overall toxicity was generally mild. Metronomic chemotherapy combined with 1E10-Alum vaccine immunotherapy might be a useful therapeutic option for the treatment of metastatic breast cancer due to its potential impact on survival and patient quality of live, low toxicity and advantages of the administration.
Full Text Available Abstract Background Liver cancer is one of most commonly diagnosed cancers among Koreans. Chronic hepatitis B virus (HBV infection is a major risk factor for liver cancer. HBV infection can be prevented by effective screening and vaccination programs. The purpose of this study is to examine the status of HBV infection and the predictors associated with HBV vaccination. Methods The study population was derived from the 2005 Korea National Cancer Screening Survey (KNCSS. The KNCSS is an annual cross-sectional survey that uses a nationally-representative random sampling to investigate cancer screening rates. A total of 1,786 Koreans over 40 years of age participated in this study. Results Of all the participants, 5.9% reported HBV positive (HBsAg+, HBsAb-, 41.8% were HBV negative but protected (HBsAg-, HBsAb+, and 52.3% were unprotected (HBsAg-, HBsAb-. Among unprotected individuals (n = 934, 23.1% reported to have received the vaccination. About half of those who had vaccinations completed the 3-shot vaccine series. In multiple analyses, education, having private cancer insurance, alcohol use, having regular check-up, and doing regular exercise were associated with completed HBV vaccination. Conclusion This study result suggests that we need a liver cancer education program to increase HBV awareness and to increase the liver cancer prevention message among low educated populations.
Senkomago, Virginia; Duran, Denise; Loharikar, Anagha; Hyde, Terri B; Markowitz, Lauri E; Unger, Elizabeth R; Saraiya, Mona
Cervical cancer incidence and mortality rates are high, particularly in developing countries. Most cervical cancers can be prevented by human papillomavirus (HPV) vaccination, screening, and timely treatment. The US Centers for Disease Control and Prevention (CDC) provides global technical assistance for implementation and evaluation of HPV vaccination pilot projects and programs and laboratory-related HPV activities to assess HPV vaccines. CDC collaborates with global partners to develop global cervical cancer screening recommendations and manuals, implement screening, create standardized evaluation tools, and provide expertise to monitor outcomes. CDC also trains epidemiologists in cancer prevention through its Field Epidemiology Training Program and is working to improve cancer surveillance by supporting efforts of the World Health Organization in developing cancer registry hubs and assisting countries in estimating costs for developing population-based cancer registries. These activities contribute to the Global Health Security Agenda action packages to improve immunization, surveillance, and the public health workforce globally.
Mamo, Laura; Epstein, Steven
Vaccine development is a core component of pharmaceutical industry activity and a key site for studying pharmaceuticalization processes. In recent decades, two so-called cancer vaccines have entered the U.S. medical marketplace: a vaccine targeting hepatitis B virus (HBV) to prevent liver cancers and a vaccine targeting human papillomavirus (HPV) to prevent cervical and other cancers. These viruses are two of six sexually transmissible infectious agents (STIs) that are causally linked to the development of cancers; collectively they reference an expanding approach to apprehending cancer that focuses attention simultaneously "inward" toward biomolecular processes and "outward" toward risk behaviors, sexual practices, and lifestyles. This paper juxtaposes the cases of HBV and HPV and their vaccine trajectories to analyze how vaccines, like pharmaceuticals more generally, are emblematic of contemporary pharmaceuticalization processes. We argue that individualized risk, in this case sexual risk, is produced and treated by scientific claims of links between STIs and cancers and through pharmaceutical company and biomedical practices. Simultaneous processes of sexualization and pharmaceuticalization mark these cases. Our comparison demonstrates that these processes are not uniform, and that the production of risks, subjects, and bodies depends not only on the specificities of vaccine development but also on the broader political and cultural frames within which sexuality is understood. Copyright © 2013 Elsevier Ltd. All rights reserved.
Sakamoto, Shinjiro; Matsueda, Satoko; Takamori, Shinzo; Toh, Uhi; Noguchi, Masanori; Yutani, Shigeru; Yamada, Akira; Shichijo, Shigeki; Yamada, Teppei; Suekane, Shigetaka; Kawano, Kouichiro; Sasada, Tetsuro; Hattori, Noboru; Kohno, Nobuoki; Itoh, Kyogo
To develop a peptide vaccine for cancer patients with the HLA-A26 allele, which is a minor population worldwide, we investigated the immunological responses of HLA-A26(+) /A26(+) cancer patients to four different CTL epitope peptides under personalized peptide vaccine regimens. In personalized peptide vaccine regimens, two to four peptides showing positive peptide-specific IgG responses in pre-vaccination plasma were selected from the four peptide candidates applicable for HLA-A26(+) /A26(+) cancer patients and administered s.c. Peptide-specific CTL and IgG responses along with cytokine levels were measured before and after vaccination. Cell surface markers in PBMCs and plasma cytokine levels were also measured. In this study, 21 advanced cancer patients, including seven lung, three breast, two pancreas, and two colon cancer patients, were enrolled. Their HLA-A26 genotypes were HLA-A26:01 (n = 24), HLA-A26:03 (n = 10), and HLA-A26:02 (n = 8). One, 14, and 6 patients received two, three, and four peptides, respectively. Grade 1 or 2 skin reactions at the injection sites were observed in the majority of patients, but no severe adverse events related to the vaccination were observed. Peptide-specific CTL responses were augmented in 39% or 22% of patients after one or two cycles of vaccination, respectively. Notably, peptide-specific IgG were augmented in 63% or 100% of patients after one or two cycles of vaccination, respectively. Personalized peptide vaccines with these four CTL epitope peptides could be feasible for HLA-A26(+) advanced cancer patients because of their safety and higher rates of immunological responses. © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.
Award Number: W81XWH-15-1-0311 TITLE: TNK2 Tyrosine Kinase as a Novel Therapeutic Target in Triple- Negative Breast Cancer PRINCIPAL...Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Triple-negative breast cancers (TNBCs) represent only 10%-15% of all breast cancers ; however... cancers (TNBC) represent 10-15% of all breast cancers . While significant advances have been made for targeted therapy of ER and HER2-positive breast
Cornelissen, J.B.W.J.; Giessen, van der J.W.B.; Takumi, K.; Teunis, P.F.M.; Wisselink, H.J.
High numbers of Toxoplasma gondii oocysts in the environment are a risk factor to humans. The environmental contamination might be reduced by vaccinating the definitive host, cats. An experimental challenge model is necessary to quantitatively assess the efficacy of a vaccine or drug treatment.
The FDA has approved a second vaccine to prevent cervical cancer and cervical precancers, the vaccine’s manufacturer, GlaxoSmithKline (GSK), announced last week. The approval is based on data from a large clinical trial showing that the vaccine, Cervarix, prevented precancerous lesions in 93 percent of those who received the full vaccine sequence of three injections over 6 months. |
Pampena, María Betina; Levy, Estrella Mariel
Vaccine-based cancer immunotherapy has generated highly variable clinical results due to differing methods of vaccine preparation and variation in patient populations among other lesser factors. Moreover, these clinical responses do not necessarily correspond with the induction of tumor-specific cytotoxic lymphocytes. Here, we review the participation of natural killer (NK) cells as alternative immune components that could cooperate in successful vaccination treatment. NK cells have been desc...
Holmstrøm, Kim; Pedersen, Ayako Wakatsuki; Claesson, Mogens Helweg
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...... difference at the level of miRNA induction between these two groups was observed, suggesting that quantitative evaluation of selected miRNAs potentially can predict the immunogenicity of DC vaccines....
Price, Rebecca Anhang; Koshiol, Jill; Kobrin, Sarah; Tiro, Jasmin A.
Background If women who receive the human papillomavirus (HPV) vaccine are unduly reassured about the cancer prevention benefits of vaccination, they may choose not to participate in screening, thereby increasing their risk for cervical cancer. This study assesses adult women’s knowledge of the need to continue cervical cancer screening after HPV vaccination, describes Pap test intentions of vaccinated young adult women, and evaluates whether knowledge and intentions differ across groups at greatest risk for cervical cancer. Methods Data were from the 2008 Health Information National Trends Survey (HINTS) and the 2008 National Health Interview Survey (NHIS), which initiated data collection approximately 18 months after the first FDA approval of an HPV vaccine. We calculated associations between independent variables and the outcomes using chi-square tests. Results Of 1,586 female HINTS respondents ages 18 through 74, 95.6% knew that HPV-vaccinated women should continue to receive Pap tests. This knowledge did not vary significantly by race/ethnicity, education, income, or healthcare access. Among 1,101 female NHIS respondents ages 18 to 26 who had ever received a Pap test, the proportion (12.7%; n = 139) who reported receipt of the HPV vaccine were more likely than those not vaccinated to plan to receive a Pap test within three years (98.1% vs. 92.5%, pknowledge and intention to participate in Pap testing after HPV vaccination. The vast majority of young adult women who received the HPV vaccine within its first two years on the market intend to participate in cervical cancer screening in the near future. Future studies are needed to examine whether those vaccinated in adolescence will become aware of, and adhere to, screening guidelines as they become eligible. PMID:21473953
Results from a pilot clinical trial found that TARP, or T-cell receptor gamma chain alternate reading frame protein, vaccination slowed prostate-specific antigen (PSA) rise in the majority of patients with early stage prostate cancer.
Suganya, K; Prem Kumar, A; Sekar, B; Sundaran, B
The protective effect of therapeutic immunization with heat inactivated Helicobacter pylori cells administered with aluminum phosphate as an adjuvant was evaluated with "Swiss albino mice" infected with H. pylori Sydney strain 1 (SS1). The presence of bacteria in histological sections of the stomach was evaluated to confirm the colonization of H. pylori. The infection dose was determined to be 1 × 10 8 cells which resulted to be the optimal concentration to sustain infection for required time. Systemic immunization of H. pylori 26695 and SS1 Whole cell heat inactivated vaccine were induced on mice. The IgG titer levels of high dose adjuvant vaccine of both strains were proportionate on the 7th and 14th day. Subsequently on the 21st and 28th day SS1 high dose adjuvant revealed a higher titer value. The Probability values were pylori infection in mice. These results represent strong evidence for feasibility of therapeutic use of whole cell based vaccine formulations against H. pylori infection in animal model. Copyright © 2016 International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.
Lamm, D.L.; Riggs, D.R.; DeHaven, J.I.; Bryner, R.W. (West Virginia Univ. School of Medicine, Morgantown (USA))
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.
Saxena, Mansi; Bhardwaj, Nina
Dendritic cells (DCs) are essential in immunity owing to their role in activating T cells, thereby promoting antitumor responses. Tumor cells, however, hijack the immune system, causing T cell exhaustion and DC dysfunction. Tumor-induced T cell exhaustion may be reversed through immune checkpoint blockade (ICB); however, this treatment fails to show clinical benefit in many patients. While ICB serves to reverse T cell exhaustion, DCs are still necessary to prime, activate, and direct the T cells to target tumor cells. In this review we provide a brief overview of DC function, describe mechanisms by which DC functions are disrupted by the tumor microenvironment, and highlight recent developments in DC cancer vaccines. Copyright © 2018 Elsevier Inc. All rights reserved.
Acanthomatous ameloblastoma is a locally invasive tumor arising in the gingiva that can progress rapidly, invade and destroy bone. If the lesion involves the upper jaw, surgical excision may not be possible and while local control is imperative, other therapies have not been fully evaluated. The primary author's personal cat, Gabriella, developed this tumor, with gingival masses around teeth in the upper jaw and evidence of widespread bony destruction of the hard palate. Because of his involvement with Immunophotonics Inc. as an advisor, the author was aware of an in situ autologous cancer vaccine (inCVAX) that is currently under development by the company. One session was performed in a veterinary clinic in Arkansas, and two follow-up sessions at the small animal hospital at the UC Davis veterinary school. No other therapy was provided. As of this writing, 3+ years after first treatment and 3 years, 4 months after presentation, Gabriella is well, with no evidence of disease.
Full Text Available Zhicheng Zhang, Fang Li, Tiansheng Sun, Dajiang Ren, Xiumei Liu PLA Institute of Orthopedics, Beijing Army General Hospital, Beijing, People's Republic of China Background: Many previous studies have focused on the effects of IN-1, a monoclonal antibody that neutralizes Nogo (a neurite growth inhibitory protein, on neurologic regeneration in spinal cord injury (SCI. However, safety problems and the short half-life of the exogenous antibody are still problematic. In the present study, the NogoA polypeptide was used as an antigen to make a therapeutic NogoA vaccine. Rats were immunized with this vaccine and were able to secrete the polyclonal antibody before SCI. The antibody can block NogoA within the injured spinal cord when the antibody gains access to the spinal cord due to a compromised blood–spinal cord barrier. Olfactory ensheathing glial cell transplantation has been used in a spinal cord contusion model to promote the recovery of SCI. The present study was designed to verify the efficacy and safety of NogoA polypeptide vaccine, the effects of immunotherapy with this vaccine, and the synergistic effects of the vaccine and olfactory ensheathing glial cells in repair of SCI. Methods: A 13-polypeptide fragment of NogoA was synthesized. This fragment was then coupled with keyhole limpet hemocyanin to improve the immunogenicity of the polypeptide vaccine. Immunization via injection into the abdominal cavity was performed in rats before SCI. The serum antibody level and ability of the vaccine to bind with Nogo were detected by enzyme-linked immunosorbent assay. The safety of the vaccine was evaluated according to the incidence and severity of experimental autoimmune encephalomyelitis. Olfactory ensheathing glia cells were obtained, purified, and subsequently implanted into a Wistar rat model of thoracic spinal cord contusion injury. The rats were divided into four groups, ie, an SCI model group, an olfactory ensheathing glia group, a vaccine
Ferris, Daron G; Waller, Jennifer; Dickinson, Ashley; McCracken, Courtney; Goebel, Angela
The objective of this study was to determine the impact of Pap test compliance and cervical cancer screening intervals on human papillomavirus (HPV) vaccination acceptance. A convenience sample of 499 women 21 to 65 years old completed a 37-question survey in Augusta and Savannah, GA. The survey assessed their knowledge about HPV, cervical cancer, and the HPV vaccine. The questionnaire also determined their Pap test compliance and how longer Pap test intervals would influence their willingness to receive the HPV vaccine. Differences between categorical variables and knowledge scores were examined using χ test and unequal-variance t tests, respectively. Pap test-noncompliant women were more likely to get the HPV vaccine if they only needed a Pap test every 10 years compared with Pap test-compliant women (27.6% vs 14.6%, p = .02). A greater number (83.5%) of Pap test-noncompliant women preferred the HPV vaccine plus every 10-year Pap test option compared with Pap test-compliant women (31.3%, p Pap testing. Women are receptive to getting the HPV vaccine in exchange for longer cervical cancer screening intervals. Moreover, Pap test-noncompliant women are more likely to get the HPV vaccine if Pap testing was needed less frequently. Increasing the Pap testing interval may be an excellent method to improving HPV vaccine acceptance in women at highest risk for cervical cancer.
Bungener, Laura Barbara
The aim of the study described in this thesis is the development of a therapeutic immunization strategy against cervical cancer and pre-malignant precursor lesions of cervical cancer (CIN lesions). Cervical cancer is caused by high risk human papillomavirus (HPV). Two of the early proteins of high
Skorstengaard, Malene; Thamsborg, Lise Holst; Lynge, Elsebeth
Denmark is one of the countries where Human papillomavirus (HPV)-vaccination at present includes only girls. However, the burden of HPV-related cancer in men is increasing, which would argue for gender-neutral vaccination. The aim of this study was to examine the burden of HPV-caused cancers in women and men, and to evaluate the potential of HPV-vaccination in cancer control. Data were retrieved from the literature on population prevalence of high risk (HR) HPV, on HR HPV-prevalence and genotypes in HPV-related cancers, and on number of cytology samples in cervical screening. Data on annual biopsies and conisations were retrieved from the Danish National Health Service Register and the Danish National Patient Register. Incidences of HPV-related cancers in Denmark were extracted from NORDCAN. Number of HPV-caused cancers was calculated from number of HPV-related cancers and the proportion known to be caused by high-risk (HR) HPV. In cross-sectional surveys in Denmark, one fifth of women and almost one third of men were found to be positive for HR HPV. Per year, 548 HPV-caused cancer cases were diagnosed in women and 234 in men, and twice as many cancers in women as in men were preventable with HPV vaccination. However, including screening prevented cervical cancers, the burden of cancers caused by HPV-infection would be 1300-2000 in women as compared to 234 in men. Taking screening prevented cervical cancers into account, the cancer control potential of HPV-vaccination is considerably higher in women than in men. HPV-vaccination could reduce the burden of screening on women and on health care resources. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.
Full Text Available Abstract Background Despite the fact that approximately 70% of Canadian women undergo cervical cancer screening at least once every 3 years, approximately 1,300 women were diagnosed with cervical cancer and approximately 380 died from it in 2008. This study estimates the effectiveness and cost-effectiveness of vaccinating 12-year old Canadian females with an AS04-adjuvanted cervical cancer vaccine. The indirect effect of vaccination, via herd immunity, is also estimated. Methods A 12-health-state 1-year-cycle Markov model was developed to estimate lifetime HPV related events for a cohort of 12-year old females. Annual transition probabilities between health-states were derived from published literature and Canadian population statistics. The model was calibrated using Canadian cancer statistics. From a healthcare perspective, the cost-effectiveness of introducing a vaccine with efficacy against HPV-16/18 and evidence of cross-protection against other oncogenic HPV types was evaluated in a population undergoing current screening practices. The base-case analysis included 70% screening coverage, 75% vaccination coverage, $135/dose for vaccine, and 3% discount rate on future costs and health effects. Conservative herd immunity effects were taken into account by estimated HPV incidence using a mathematical model parameterized by reported age-stratified sexual mixing data. Sensitivity analyses were performed to address parameter uncertainties. Results Vaccinating 12-year old females (n = 100,000 was estimated to prevent between 390-633 undiscounted cervical cancer cases (reduction of 47%-77% and 168-275 undiscounted deaths (48%-78% over their lifetime, depending on whether or not herd immunity and cross-protection against other oncogenic HPV types were included. Vaccination was estimated to cost $18,672-$31,687 per QALY-gained, the lower range representing inclusion of cross-protective efficacy and herd immunity. The cost per QALY-gained was most
Wiskemann, L; Durani, B; Hartschuh, W
A 50-year-old man with widespread manifestation of warts and distinct pruritus for the last 5 years was diagnosed with a reactivated human papillomavirus (HPV) infection by three, genetically verified types (6, 16, 18), which are included in the vaccine Gardasil®. Conventional treatment was not successful, but a rapid and significant reduction of the skin manifestation was observed after vaccination with Gardasil®. To what extent therapy-resistant infections with HPV can be influenced through an active HPV vaccination should be investigated in future trials.
Chen, Meihua; Xiang, Rong; Wen, Yuan; Xu, Guangchao; Wang, Chunting; Luo, Shuntao; Yin, Tao; Wei, Xiawei; Shao, Bin; Liu, Ning; Guo, Fuchun; Li, Meng; Zhang, Shuang; Li, Minmin; Ren, Kexing; Wang, Yongsheng; Wei, Yuquan
Cancer-associated fibroblasts (CAFs) are common components of the tumor-suppressive microenvironment, and are a major determinant of the poor outcome of therapeutic vaccination. In this study, we modified tumor cells to express the fibroblast activation protein (FAP), which is highly expressed by CAFs, to potentially improve whole-cell tumor vaccines by targeting both tumor cells and CAFs. Tumor cells were transfected with murine FAP plasmids bearing the cationic lipid DOTAP. Its antitumor effects were investigated in three established tumor models. Vaccination with tumor cells expressing FAP eliminated solid tumors and tumors resulting from hematogenous dissemination. This antitumor immune response was mediated by CD8+ T cells. Additionally, we found that CAFs were significantly reduced within the tumors. Furthermore, this vaccine enhanced the infiltration of CD8+ T lymphocytes, and suppressed the accumulation of immunosuppressive cells in the tumor microenvironment. Our results indicated that the FAP-modified whole-cell tumor vaccine induced strong antitumor immunity against both tumor cells and CAFs and reversed the immunosuppressive effects of tumors by decreasing the recruitment of immunosuppressive cells and enhancing the recruitment of effector T cells. This conclusion may have important implications for the clinical use of genetically modified tumor cells as cancer vaccines.
Full Text Available One of the potential threats to public health microbiology in 21st century is the increased mortality rate caused by Zika virus (ZIKV, a mosquito-borne flavivirus. The severity of ZIKV infection urged World Health Organization (WHO to declare this virus as a global concern. The limited knowledge on the structure, virulent factors, and replication mechanism of the virus posed as hindrance for vaccine development. Several vector and non-vector-borne mode of transmission are observed for spreading the disease. The similarities of the virus with other flaviviruses such as dengue and West Nile virus are worrisome; hence, there is high scope to undertake ZIKV research that probably provide insight for novel therapeutic intervention. Thus, this review focuses on the recent aspect of ZIKV research which includes the outbreak, genome structure, multiplication and propagation of the virus, current animal models, clinical manifestations, available treatment options (probable vaccines and therapeutics, and the recent advancements in computational drug discovery pipelines, challenges and limitation to undertake ZIKV research. The review suggests that the infection due to ZIKV became one of the universal concerns and an interdisciplinary environment of in vitro cellular assays, genomics, proteomics, and computational biology approaches probably contribute insights for screening of novel molecular targets for drug design. The review tried to provide cutting edge knowledge in ZIKV research with future insights required for the development of novel therapeutic remedies to curtail ZIKV infection.
Wallace, Lorraine S; Ache, Kevin A
To examine the content of human papillomavirus (HPV)-related vaccination information presented during nightly national television news broadcasts in the United States. A retrospective content analysis of HPV vaccination coverage on 5 major nightly US television networks from 2002 to 2007. The Vanderbilt Television News Archive was searched for keywords "Gardasil," "cervical cancer vaccination," "human papillomavirus vaccine," and "HPV vaccination." Each television news broadcast was categorized as follows: segment length (in seconds), network (American Broadcasting Company, Columbia Broadcasting Company, National Broadcasting Company, Cable News Network, or Fox Broadcasting Company), year of broadcast (2002-2007), and (4) presentation type. Air dates were plotted on a timeline to depict trends and linkages to 5 seminal events surrounding the development, efficacy, and controversy regarding HPV vaccination. During the 6-year period, a total of 27 HPV-related vaccination news broadcasts aired. News broadcasts ranged from 10 to 250 seconds, lasting an average of close to 2 minutes (mean +/- SD, 127.0 +/- 66.1 seconds). Most broadcasts presented information pertaining to HPV and cervical cancer, information on vaccine labeling, impact of the vaccine, and raised issues or concerns about the vaccine. More than half (66.7%) of news broadcasts were directly related to 5 seminal events surrounding the development, efficacy, and controversy regarding HPV vaccination. All 5 networks included within the Vanderbilt Television News Archive aired HPV vaccination content, with National Broadcasting Company and Columbia Broadcasting Company broadcasting most of the news stories during this time period. As compared with other medical-related information presented on national nightly television news during this time period, HPV vaccination received a modest amount of coverage.
de Goede, A L; Vulto, A G; Osterhaus, A D M E; Gruters, R A
HIV infection leads to a gradual loss CD4+ T lymphocytes comprising immune competence and progression to AIDS. Effective treatment with combined antiretroviral drugs (cART) decreases viral load below detectable levels but is not able to eliminate the virus from the body. The success of cART is frustrated by the requirement of expensive life-long adherence, accumulating drug toxicities and chronic immune activation resulting in increased risk of several non-AIDS disorders, even when viral replication is suppressed. Therefore there is a strong need for therapeutic strategies as an alternative to cART. Immunotherapy, or therapeutic vaccination, aims to increase existing immune responses against HIV or induce de novo immune responses. These immune responses should provide a functional cure by controlling viral replication and preventing disease progression in the absence of cART. The key difficulty in the development of an HIV vaccine is our ignorance of the immune responses that control of viral replication, and thus how these responses can be elicited and how they can be monitored. Part one of this review provides an extensive overview of the (patho-) physiology of HIV infection. It describes the structure and replication cycle of HIV, the epidemiology and pathogenesis of HIV infection and the innate and adaptive immune responses against HIV. Part two of this review discusses therapeutic options for HIV. Prevention modalities and antiretroviral therapy are briefly touched upon, after which an extensive overview on vaccination strategies for HIV is provided, including the choice of immunogens and delivery strategies. Copyright © 2014 Elsevier Masson SAS. All rights reserved.
Coleman, Hannah N; Greenfield, William W; Stratton, Shawna L; Vaughn, Rita; Kieber, Alexander; Moerman-Herzog, Andrea M; Spencer, Horace J; Hitt, Wilbur C; Quick, Charles Matthew; Hutchins, Laura F; Mackintosh, Samuel G; Edmondson, Ricky D; Erickson, Stephen W; Nakagawa, Mayumi
In the dose-escalation phase of a Phase I clinical trial in which six subjects each were vaccinated with PepCan at the 50, 100, 250, and 500 μg per peptide dose, the 50 μg dose showed the best histological regression rate. Ten additional subjects were vaccinated at this dose in the final dose phase. As with the dose-escalation phase, no dose-limiting toxicities were observed. Overall, the histological regression rates were 50% at the 50 μg dose (7 of 14) and 100 μg dose (3 of 6), and 45 % overall (14 of 31). Of subjects in whom HPV type 16 (HPV 16) was detected at entry, it became undetectable in three subjects after vaccination, and the viral loads significantly decreased in nine subjects in whom HPV 16 infection was detected at entry and exit (p = 0.008). Immune profiling revealed increased T-helper type 1 cells after vaccinations (p = 0.02 and 0.0004 after 2 and 4 vaccinations, respectively). T-helper type 2 cells initially increased after two vaccinations (p = 0.01), but decreased below the baseline level after four vaccinations although not significantly. Pre-vaccination regulatory T cell levels were significantly lower in histological responders compared to non-responders (p = 0.03). Feasibility of testing plasma for multiplex cytokine/chemokine analysis and of performing proteomic analysis of PBMCs was examined for potentially identifying biomarkers in the future. While these analyses are feasible to perform, attention needs to be given to how soon the blood samples would be processed after phlebotomy. As sufficient safety of PepCan has been demonstrated, enrollment for the Phase II clinical trial has been opened.
Zlatkov, V; Kostova, P
The aim of this review is to present the benefits and risks of the implementation of prophylactic vaccines for cervical cancer. The classical understanding of human papilloma virus (HPV) infection and its role for the cervical oncogenesis, as well as, the place of prophylactic HPV vaccines are discussed. Results concerning the effectiveness of vaccines 10 years after their introduction and data about their safety are presented. Reports of the use in practice of the new 9-valent HPV vaccine and the first results of its implementation are studied.
Nizard, Mevyn; Roussel, Hélène; Diniz, Mariana O; Karaki, Soumaya; Tran, Thi; Voron, Thibault; Dransart, Estelle; Sandoval, Federico; Riquet, Marc; Rance, Bastien; Marcheteau, Elie; Fabre, Elizabeth; Mandavit, Marion; Terme, Magali; Blanc, Charlotte; Escudie, Jean-Baptiste; Gibault, Laure; Barthes, Françoise Le Pimpec; Granier, Clemence; Ferreira, Luis C S; Badoual, Cecile; Johannes, Ludger; Tartour, Eric
Tissue-resident memory T cells (Trm) represent a new subset of long-lived memory T cells that remain in tissue and do not recirculate. Although they are considered as early immune effectors in infectious diseases, their role in cancer immunosurveillance remains unknown. In a preclinical model of head and neck cancer, we show that intranasal vaccination with a mucosal vector, the B subunit of Shiga toxin, induces local Trm and inhibits tumour growth. As Trm do not recirculate, we demonstrate their crucial role in the efficacy of cancer vaccine with parabiosis experiments. Blockade of TFGβ decreases the induction of Trm after mucosal vaccine immunization, resulting in the lower efficacy of cancer vaccine. In order to extrapolate this role of Trm in humans, we show that the number of Trm correlates with a better overall survival in lung cancer in multivariate analysis. The induction of Trm may represent a new surrogate biomarker for the efficacy of cancer vaccine. This study also argues for the development of vaccine strategies designed to elicit them.
Walsh, Louise; Gallagher, William M; O'Connor, Darran P; Ní Chonghaile, Tríona
Breast cancer is the most common cancer in women and great advancements have been made for individualised patient treatment. Through understanding the underlying altered biology in the different subtypes of breast cancer, targeted therapeutics have been developed. Unfortunately, resistance to targeted therapy, intrinsic or acquired, is a recurring theme in cancer treatment. Epigenetic-mediated resistance to targeted therapy has been identified across different types of cancer. In addition, tumorigenesis has also been linked to altered expression of epigenetic modifiers. Due to the reversible nature of epigenetic modifications, epigenetic proteins are appealing as therapeutic targets in both the primary and relapsed/resistant setting. In this review, we will discuss the current state of targetable epigenetic histone modifications and their diagnostic and therapeutic implications in breast cancer.
María Betina Pampena
Full Text Available Vaccine-based cancer immunotherapy has generated highly variable clinical results due to differing methods of vaccine preparation and variation in patient populations, among other lesser factors. Moreover, these clinical responses do not necessarily correspond with the induction of tumor-specific cytotoxic lymphocytes. Here we review the participation of natural killer (NK cells as alternative immune components that could cooperate in successful vaccination treatment. NK cells have been described as helper cells in dendritic cell-based cancer vaccines, but the role in other kinds of vaccination strategies (whole cells, peptide or DNA- based vaccines is poorly understood. In this article we address the following issues regarding the role of NK cells in cancer vaccines: NK cell anti-tumor action sites, and the loci of NK cell interaction with other immune cells; descriptions of new data on the memory characteristics of NK cells described in infectious diseases; and finally phenotypical and functional changes after vaccination measured by immunomonitoring in preclinical and clinical settings.
Park, Geon-Tae; Choi, Kyung-Chul
The field of therapeutic stem cell and oncolytic virotherapy for cancer treatment has rapidly expanded over the past decade. Oncolytic viruses constitute a promising new class of anticancer agent because of their ability to selectively infect and destroy tumor cells. Engineering of viruses to express anticancer genes and specific cancer targeting molecules has led to the use of these systems as a novel platform of metastatic cancer therapy. In addition, stem cells have a cancer specific migra...
Rahman, Mohammad Aminur; Shin, Dong M
In their review article published in the March 1, 2008, issue of Clinical Cancer Research, Cho and colleagues presented the strong potential of nanotechnology in cancer. This commentary discusses the latest advances in nanotechnology, which provide novel approaches for cancer diagnosis, imaging, drug delivery, and personalized therapy; highlights the perspectives for therapeutic nanoparticles; and describes the advantages and challenges of their multifunctionalities. ©2015 American Association for Cancer Research.
Park, Jong Ho; Zo, Jae Ill; Baek, Hee Jong; Jung, Jin Haeng; Lee, Jae Cheol; Ryoo, Baek Yeol; Kim, Mi Sook; Choi, Du Hwan; Park, Sun Young; Lee, Hae Young
The aims of this study were to make the lung cancer clinics in Korea Cancer Center Hospital, and to establish new therapeutic methods of lung cancer for increasing the cure rate and survival rate of patients. Also another purpose of this study was to establish a common treatment method in our hospital. All patients who were operated in Korea Cancer Center Hospital from 1987 due to lung cancer were followed up and evaluated. And we have been studied the effect of postoperative adjuvant therapy in stage I, II, IIIA non-small cell lung cancer patients from 1989 with the phase three study form. Follow-up examinations were scheduled in these patients and interim analysis was made. Also we have been studied the effect of chemo-therapeutic agents in small cell lung cancer patients from 1997 with the phase two study form. We evaluated the results of this study. Some important results of this study were as follows. 1. The new therapeutic method (surgery + MVP chemotherapy) was superior to the standard therapeutic one in stage I Non-small cell lung cancer patients. So, we have to change the standard method of treatment in stage I NSCLC. 2. Also, this new therapeutic method made a good result in stage II NSCLC patients. And this result was reported in The Annals of Thoracic Surgery. 3. However, this new therapeutic method was not superior to the standard treatment method (surgery only) in stage IIIA NSCLC patients. So, we must develop new chemo-therapeutic agents in the future for advanced NSCLC patients. 4. In the results of the randomized phase II studies about small cell lung cancer, there was no difference in survival between Etoposide + Carboplatin + Ifosfamide + Cisplatin group and Etoposide + Carboplatin + Ifosfamide + Cisplatin + Tamoxifen group in both the limited and extended types of small cell lung cancer patients.
.... Our aims are first to develop a model of anti-S14 breast cancer therapy in mice. Intratumoral adenoviral delivery of an S14-antisense gene into human breast cancer cell xenografts caused a significant inhibition of tumor growth...
Pathways: Involving Microenvironment Damage Responses in Cancer Therapy Resistance. Clin Cancer Res. 18: 4019-4025. Sun, Y ., Campisi, J., Higano, C...regulates response to chemotherapy. Cancer Discov. 1, 54–67 (2011). 45. Chien, Y . et al. Control of the senescence-associated secretory phenotype by...domain-like IL-1-converting enzyme-like inhibitory protein-long confers resistance to CD95 - induced apoptosis in hematopoietic cancer cell lines. J Immunol
Razungles , Julie; Cavaillès , Vincent; Jalaguier , Stéphan; Teyssier , Catherine
International audience; Cancer cell metabolism described by Otto Warburg in the thirties became a cancer specific hallmark, also called "Warburg effect". Cancer cells use essentially glucose as fuel, through glycolysis, in order to meet their energy and biomass needs to insure their cell proliferation. Recent advances describe Warburg effect regulation by oncogenes and tumor suppressor genes. Moreover, mutations in some glycolysis enzymes are found in various cancers, highlighting the role of...
Basu, Gargi D; Tinder, Teresa L; Bradley, Judy M; Tu, Tony; Hattrup, Christine L; Pockaj, Barbara A; Mukherjee, Pinku
We report that administration of celecoxib, a specific cyclooxygenase-2 (COX-2) inhibitor, in combination with a dendritic cell-based cancer vaccine significantly augments vaccine efficacy in reducing primary tumor burden, preventing metastasis, and increasing survival. This combination treatment was tested in MMTV-PyV MT mice that develop spontaneous mammary gland tumors with metastasis to the lungs and bone marrow. Improved vaccine potency was associated with an increase in tumor-specific CTLs. Enhanced CTL activity was attributed to a significant decrease in levels of tumor-associated IDO, a negative regulator of T cell activity. We present data suggesting that inhibiting COX-2 activity in vivo regulates IDO expression within the tumor microenvironment; this is further corroborated in the MDA-MB-231 human breast cancer cell line. Thus, a novel mechanism of COX-2-induced immunosuppression via regulation of IDO has emerged that may have implications in designing future cancer vaccines.
Kobetz, E; Menard, J; Hazan, G; Koru-Sengul, T; Joseph, T; Nissan, J; Barton, B; Blanco, J; Kornfeld, J
Women in Haiti and throughout the Haitian Diaspora shoulder a disproportionate burden of cervical cancer morbidity and mortality. The widespread Human Papillomavirus (HPV) vaccination holds promise for helping to attenuate this disparity. However, previous research has not fully examined Haitian women's perceptions of, and barriers to, HPV vaccination, which is essential for informing future intervention. The current paper aims to fill this gap. As part of ongoing Community-Based Participatory Research (CBPR) efforts, we conducted a series of focus groups with Haitian immigrant women in Little Haiti, the predominantly Haitian neighborhood in Miami, Florida, U.S. Focus group questions assessed women's knowledge and beliefs about cervical cancer and HPV, their opinions of vaccines in general, their knowledge and perceptions of the HPV vaccine specifically and health communications preferences for cervical cancer prevention. Among the participants who had heard of HPV, many held misconceptions about virus transmission and did not understand the role of HPV in the development of cervical cancer. Virtually all participants expressed support for vaccines in general as beneficial for health. Some women had heard of the HPV vaccine, primarily as the result of a contemporary popular media campaign promoting the Gardasil® vaccine. Physician recommendation was commonly mentioned as a reason for vaccination, in addition to having more than one sex partner. Women felt the HPV vaccine was less appropriate for adolescent girls who are presumed as not sexually active. Women indicated a strong preference to obtain health information through trusted sources, such as Haitian physicians, Haitian Community Health Workers, and especially Kreyol-language audiovisual media. Study findings indicate a need for culturally and linguistically appropriate educational initiatives to promote awareness of HPV and its role in cervical cancer, the importance of vaccination against the virus
Keijer, J.; Dartel, van D.A.M.
Metabolism in cancer cells is reprogrammed. Cancer cells largely depend on glycolysis for ATP production. The metabolic alterations in cancer cells facilitate resistance to cell death as well as biosynthesis of nucleotides and lipids, building blocks for growth. The reprogrammed metabolism is
Chaiswing, Luksana; St Clair, William H; St Clair, Daret K
Cancer cells that are resistant to radiation and chemotherapy are a major problem limiting the success of cancer therapy. Aggressive cancer cells depend on elevated intracellular levels of reactive oxygen species (ROS) to proliferate, self-renew, and metastasize. As a result, these aggressive cancers maintain high basal levels of ROS compared with normal cells. The prominence of the redox state in cancer cells led us to consider whether increasing the redox state to the condition of oxidative stress could be used as a successful adjuvant therapy for aggressive cancers. Recent Advances: Past attempts using antioxidant compounds to inhibit ROS levels in cancers as redox-based therapy have met with very limited success. However, recent clinical trials using pro-oxidant compounds reveal noteworthy results, which could have a significant impact on the development of strategies for redox-based therapies. The major objective of this review is to discuss the role of the redox state in aggressive cancers and how to utilize the shift in redox state to improve cancer therapy. We also discuss the paradox of redox state parameters; that is, hydrogen peroxide (H 2 O 2 ) as the driver molecule for cancer progression as well as a target for cancer treatment. Based on the biological significance of the redox state, we postulate that this system could potentially be used to create a new avenue for targeted therapy, including the potential to incorporate personalized redox therapy for cancer treatment. Antioxid. Redox Signal. 00, 000-000.
AWARD NUMBER: W81XWH-13-1-0238 TITLE: Developing Inhibitors of Translesion DNA Synthesis as Therapeutic Agents against Lung Cancer PRINCIPAL...of Translesion DNA Synthesis as Therapeutic Agents against Lung Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S...Oxygen-rich environments can create pro- mutagenic DNA lesions such as 8-oxoguanine (8-oxo-G) that can be misreplicated during translesion DNA synthesis
Cekanova, Maria; Rathore, Kusum
Cancer is the term used to describe over 100 diseases that share several common hallmarks. Despite prevention, early detection, and novel therapies, cancer is still the second leading cause of death in the USA. Successful bench-to-bedside translation of basic scientific findings about cancer into therapeutic interventions for patients depends on the selection of appropriate animal experimental models. Cancer research uses animal and human cancer cell lines in vitro to study biochemical pathways in these cancer cells. In this review, we summarize the important animal models of cancer with focus on their advantages and limitations. Mouse cancer models are well known, and are frequently used for cancer research. Rodent models have revolutionized our ability to study gene and protein functions in vivo and to better understand their molecular pathways and mechanisms. Xenograft and chemically or genetically induced mouse cancers are the most commonly used rodent cancer models. Companion animals with spontaneous neoplasms are still an underexploited tool for making rapid advances in human and veterinary cancer therapies by testing new drugs and delivery systems that have shown promise in vitro and in vivo in mouse models. Companion animals have a relatively high incidence of cancers, with biological behavior, response to therapy, and response to cytotoxic agents similar to those in humans. Shorter overall lifespan and more rapid disease progression are factors contributing to the advantages of a companion animal model. In addition, the current focus is on discovering molecular targets for new therapeutic drugs to improve survival and quality of life in cancer patients.
Jonathan Z Li
Full Text Available In the placebo-controlled trial ACTG A5197, a trend favoring viral suppression was seen in the HIV-1-infected subjects who received a recombinant Ad5 HIV-1 gag vaccine.To identify individuals with initial viral suppression (plasma HIV-1 RNA set point <3.0 log(10 copies/ml during the analytic treatment interruption (ATI and evaluate the durability and correlates of virologic control and characteristics of HIV sequence evolution.HIV-1 gag and pol RNA were amplified and sequenced from plasma obtained during the ATI. Immune responses were measured by flow cytometric analysis and intracellular cytokine expression assays. Characteristics of those with and without initial viral suppression were compared using the Wilcoxon rank sum and Fisher's exact tests.Eleven out of 104 participants (10.6% were classified as initial virologic suppressors, nine of whom had received the vaccine. Initial virologic suppressors had significantly less CD4+ cell decline by ATI week 16 as compared to non-suppressors (median 7 CD4+ cell gain vs. 247 CD4+ cell loss, P = 0.04. However, of the ten initial virologic suppressors with a pVL at ATI week 49, only three maintained pVL <3.0 log(10 copies/ml. HIV-1 Gag-specific CD4+ interferon-γ responses were not associated with initial virologic suppression and no evidence of vaccine-driven HIV sequence evolution was detected. Participants with initial virologic suppression were found to have a lower percentage of CD4+ CTLA-4+ cells prior to treatment interruption, but a greater proportion of HIV-1 Gag-reactive CD4+ TNF-α+ cells expressing either CTLA-4 or PD-1.Among individuals participating in a rAd5 therapeutic HIV-1 gag vaccine trial, initial viral suppression was found in a subset of patients, but this response was not sustained. The association between CTLA-4 and PD-1 expression on CD4+ T cells and virologic outcome warrants further study in trials of other therapeutic vaccines in development.ClinicalTrials.gov NCT
Full Text Available Abstract Background In our recent study, Periostin was up-regulated in prostate cancer(PCa compared with benign prostate hyperplasia (BPH by proteomics analysis of prostate biopsies. We investigated the effect of sliencing Periostin by RNA interference (RNAi on the proliferation and migration of PCa LNCap cell line. Methods All the prostate biopsies from PCa, BPH and BPH with local prostatic intraepithelial neoplasm(PIN were analyzed by iTRAQ(Isobaric tags for relative and absolute quantification technology. Western blotting and immunohistochemical staining were used to verify Periostin expression in the tissues of PCa. Periostin expression in different PCa cell lines was determined by immunofluorescence staining, western blotting and reverse transcription PCR(RT-PCR. The LNCap cells with Periostin expression were used for transfecting shRNA-Periostin lentiviral particles. The efficancy of transfecting shRNA lentiviral particles was evaluated by immunofluorescence, western blotting and Real-time PCR. The effect of silencing Periostin expression by RNAi on proliferation of LNCap cells was determined by MTT assay and tumor xenografts. The tissue slices from theses xenografts were analyzed by hematoxylin and eosin(HE staining. The expression of Periostin in the xenografts was deteminned by Immunohistochemical staining and western blotting. The migration of LNCap cells after silencing Periostin gene expression were analyzed in vitro. Results Periostin as the protein of interest was shown 9.12 fold up-regulation in PCa compared with BPH. The overexpression of Periostin in the stroma of PCa was confirmed by western blotting and immunohistochemical staining. Periostin was only expressed in PCa LNCap cell line. Our results indicated that the transfection ratio was more than 90%. As was expected, both the protein level and mRNA level of Periostin in the stably expressing shRNA-Periostin LNCap cells were significantly reduced. The stably expressing sh
Full Text Available Breast cancer is the most common type of cancer among American women, and remains the second leading cause of cancer-related death for female in the United States. It has been known that several signaling pathways and various factors play critical roles in the development and progression of breast cancer, such as estrogen receptor, Notch, PTEN, Her2, PI3K/Akt, BRCA1 and BRCA2. Emerging evidence has shown that the F-box protein Skp2 (S-phase kinase associated protein 2 also plays an important role in the pathogenesis of breast cancer. Therefore, in this brief review, we summarize the novel functions of Skp2 in the pathogenesis of breast cancer. Moreover, we provide further evidence regarding the state of our knowledge toward the development of novel Skp2 inhibitors especially natural chemopreventive agents as targeted approach for the prevention and/or treatment of breast cancer.
Shtivelman, Emma; Hensing, Thomas; Simon, George R.; Dennis, Phillip A.; Otterson, Gregory A.; Bueno, Raphael; Salgia, Ravi
Lung cancer is still the leading cause of cancer death worldwide. Both histologically and molecularly lung cancer is heterogeneous. This review summarizes the current knowledge of the pathways involved in the various types of lung cancer with an emphasis on the clinical implications of the increasing number of actionable molecular targets. It describes the major pathways and molecular alterations implicated in the development and progression of non-small cell lung cancer (adenocarcinoma and squamous cancer), and of small cell carcinoma, emphasizing the molecular alterations comprising the specific blueprints in each group. The approved and investigational targeted therapies as well as the immune therapies, and clinical trials exploring the variety of targeted approaches to treatment of lung cancer are the main focus of this review. PMID:24722523
Full Text Available Colon cancer is a world-wide health problem and the second-most dangerous type of cancer, affecting both men and women. The modern diet and lifestyles, with high meat consumption and excessive alcohol use, along with limited physical activity has led to an increasing mortality rate for colon cancer worldwide. As a result, there is a need to develop novel and environmentally benign drug therapies for colon cancer. Currently, nutraceuticals play an increasingly important role in the treatment of various chronic diseases such as colon cancer, diabetes and Alzheimer׳s disease. Nutraceuticals are derived from various natural sources such as medicinal plants, marine organisms, vegetables and fruits. Nutraceuticals have shown the potential to reduce the risk of colon cancer and slow its progression. These dietary substances target different molecular aspects of colon cancer development. Accordingly, this review briefly discusses the medicinal importance of nutraceuticals and their ability to reduce the risk of colorectal carcinogenesis.
Kuppusamy, Palaniselvam; Yusoff, Mashitah M; Maniam, Gaanty Pragas; Ichwan, Solachuddin Jauhari Arief; Soundharrajan, Ilavenil; Govindan, Natanamurugaraj
Colon cancer is a world-wide health problem and the second-most dangerous type of cancer, affecting both men and women. The modern diet and lifestyles, with high meat consumption and excessive alcohol use, along with limited physical activity has led to an increasing mortality rate for colon cancer worldwide. As a result, there is a need to develop novel and environmentally benign drug therapies for colon cancer. Currently, nutraceuticals play an increasingly important role in the treatment of various chronic diseases such as colon cancer, diabetes and Alzheimer׳s disease. Nutraceuticals are derived from various natural sources such as medicinal plants, marine organisms, vegetables and fruits. Nutraceuticals have shown the potential to reduce the risk of colon cancer and slow its progression. These dietary substances target different molecular aspects of colon cancer development. Accordingly, this review briefly discusses the medicinal importance of nutraceuticals and their ability to reduce the risk of colorectal carcinogenesis.
Kostinov, M P; Zhestkov, A V; Protasov, A D; Magarshak, O O; Kostinova, T A
To estimate the indicators of the therapeutic effect of combination vaccination against pneumococcal, Haemophilus influenzae type b infection, and influenza in patients with chronic obstructive pulmonary disease (COPD). Clinical, bacteriological, and immunological studies, by determining the quality of life (QL), were conducted in COPD patients during a year after combination vaccination against pneumococcal, Haemophilus influenza type b infection, and influenza. One year after the vaccination, there were reductions in the number of COPD exacerbations by 3.7 times, in that of antibiotic therapy cycles by 3.4 times, in the levels of inflammatory mediators of interleukins 2 and 8 and interferon-γ, and in the synthesis of IgG antibodies to Streptococcus pneumoniae, Haemophilus influenzae type b, and influenza virus strains as compared to the baseline values. Combination vaccination against bacterial and viral infections substantially improves the major clinical parameters of COPD, positively affecting LQ indicators that generally characterize the therapeutic effect of immunization.
Coleman, Hannah N.; Greenfield, William W.; Stratton, Shawna L.; Vaughn, Rita; Kieber, Alexander; Moerman-Herzog, Andrea M.; Spencer, Horace J.; Hitt, Wilbur. C.; Quick, Charles Matthew; Hutchins, Laura F.; Mackintosh, Samuel G.; Edmondson, Ricky D.; Erickson, Stephen W.; Nakagawa, Mayumi
In the dose-escalation phase of a Phase I clinical trial in which six subjects each were vaccinated with PepCan at the 50, 100, 250, and 500μg per peptide dose, the 50μg dose showed the best histological regression rate. Ten additional subjects were vaccinated at this dose in the final dose phase. As with the dose-escalation phase, no dose-limiting toxicities were observed. Overall, the histological regression rates were 50% at the 50μg dose (7 of 14) and 100μg dose (3 of 6), and 45% overall ...
Botha, M H; van der Merwe, F H; Snyman, L C; Dreyer, G
The incidence of cervical cancer in South Africa (SA) remains high, and the current screening programme has had limited success. New approaches to prevention and screening tactics are needed. To investigate acceptance of school-based human papillomavirus (HPV) vaccination, as well as the information provided, methods of obtaining consent and assent, and completion rates achieved. Information on cervical cancer and HPV vaccination was provided to 19 primary schools in Western Cape and Gauteng provinces participating in the study. Girls with parental consent and child assent were vaccinated during school hours at their schools. A total of 3 465 girls were invited to receive HPV vaccine, of whom 2 046 provided written parental consent as well as child assent. At least one dose of vaccine was delivered to 2 030 girls (99.2% of the consented cohort), while a total of 1 782 girls received all three doses. Sufficient vaccination was achieved in 91.6% of the vaccinated cohort. Of all invited girls, 56.9% in Gauteng and 50.7% in the Western Cape were sufficiently vaccinated. This implementation project demonstrated that HPV vaccination is practical and safe in SA schools. Political and community acceptance was good, and positive attitudes towards vaccination were encountered. During the study, which mimicked a governmental vaccine roll-out programme, high completion rates were achieved in spite of several challenges encountered.
Silver, Daniel J; Sinyuk, Maksim; Vogelbaum, Michael A; Ahluwalia, Manmeet S; Lathia, Justin D
During brain neoplasia, malignant cells subjugate the immune system to provide an environment that favors tumor growth. These mechanisms capitalize on tumor-promoting functions of various immune cell types and typically result in suppression of tumor immune rejection. Immunotherapy efforts are underway to disrupt these mechanisms and turn the immune system against developing tumors. While many of these therapies are already in early-stage clinical trials, understanding how these therapies impact various tumor cell populations, including self-renewing cancer stem cells, may help to predict their efficacy and clarify their mechanisms of action. Moreover, interrogating the biology of glioma cell, cancer stem cell, and immune cell interactions may provide additional therapeutic targets to leverage against disease progression. In this review, we begin by highlighting a series of investigations into immune cell-mediated tumor promotion that do not parse the tumor into stem and non-stem components. We then take a closer look at the immune-suppressive mechanisms derived specifically from cancer stem cell interactions with the immune system and end with an update on immunotherapy and cancer stem cell-directed clinical trials in glioblastoma. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: email@example.com.
Mayu O Frank
Full Text Available Studies of patients with paraneoplastic neurologic disorders (PND have revealed that apoptotic tumor serves as a potential potent trigger for the initiation of naturally occurring tumor immunity. The purpose of this study was to assess the feasibility, safety, and immunogenicity of an apoptotic tumor-autologous dendritic cell (DC vaccine.We have modeled PND tumor immunity in a clinical trial in which apoptotic allogeneic prostate tumor cells were used to generate an apoptotic tumor-autologous dendritic cell vaccine. Twenty-four prostate cancer patients were immunized in a Phase I, randomized, single-blind, placebo-controlled study to assess the safety and immunogenicity of this vaccine. Vaccinations were safe and well tolerated. Importantly, we also found that the vaccine was immunogenic, inducing delayed type hypersensitivity (DTH responses and CD4+ and CD8+ T cell proliferation, with no effect on FoxP3+ regulatory T cells. A statistically significant increase in T cell proliferation responses to prostate tumor cells in vitro (p = 0.002, decrease in prostate specific antigen (PSA slope (p = 0.016, and a two-fold increase in PSA doubling time (p = 0.003 were identified when we compared data before and after vaccination.An apoptotic cancer cell vaccine modeled on naturally occurring tumor immune responses in PND patients provides a safe and immunogenic tumor vaccine.ClinicalTrials.gov NCT00289341.
Kawano, Kouichiro; Tsuda, Naotake; Matsueda, Satoko; Sasada, Tetsuro; Watanabe, Noriko; Ushijima, Kimio; Yamaguchi, Tomohiko; Yokomine, Masato; Itoh, Kyogo; Yamada, Akira; Kamura, Toshiharu
To develop a personalized peptide vaccine (PPV) for recurrent ovarian cancer patients and evaluate its efficacy from the point of view of overall survival (OS), Phase II study of PPV was performed. Forty-two patients, 17 with platinum-sensitive and 25 with platinum-resistant recurrent ovarian cancer, were enrolled in this study and received a maximum of four peptides based on HLA-A types and IgG responses to the peptides in pre-vaccination plasma. Expression of 13 of the 15 parental tumor-associated antigens encoding the vaccine peptides, with the two prostate-related antigens being the exceptions, was confirmed in the ovarian cancer tissues. No vaccine-related systemic severe adverse events were observed in any patients. Boosting of cytotoxic T lymphocytes or IgG responses specific for the peptides used for vaccination was observed in 18 or 13 of 42 cases at 6th vaccination, and 19 or 29 of 30 cases at 12th vaccination, respectively. The median survival time (MST) values of the platinum-sensitive- and platinum-resistant recurrent cases were 39.3 and 16.2 months, respectively. The MST of PPV monotherapy or PPV in combination with any chemotherapy during the 1st to 12th vaccination of platinum-sensitive cases was 39.3 or 32.2 months, and that of platinum-resistant cases was 16.8 or 16.1 months, respectively. Importantly, lymphocyte frequency and epitope spreading were significantly prognostic of OS. Because of the safety and possible prolongation of OS, a clinical trial of PPV without chemotherapy during the 1st to 12th vaccination in recurrent ovarian cancer patients is merited.
Dervillez, Xavier; Gottimukkala, Chetan; Kabbara, Khaled W.; Nguyen, Chelsea; Badakhshan, Tina; Kim, Sarah M.; Nesburn, Anthony B.; Wechsler, Steven L.; BenMohamed, Lbachir
Summary Considering the limited success of the recent herpes clinical vaccine trial , new vaccine strategies are needed. Infections with herpes simplex virus type 1 and type 2 (HSV-1 & HSV-2) in the majority of men and women are usually asymptomatic and results in lifelong viral latency in neurons of sensory ganglia (SG). However, in a minority of men and women HSV spontaneous reactivation can cause recurrent disease (i.e., symptomatic individuals). Our recent findings show that T cells from symptomatic and asymptomatic men and women (i.e. those with and without recurrences, respectively) recognize different herpes epitopes. This finding breaks new ground and opens new doors to assess a new vaccine strategy: mucosal immunization with HSV-1 & HSV-2 epitopes that induce strong in vitro CD4 and CD8 T cell responses from PBMC derived from asymptomatic men and women (designated here as “asymptomatic” protective epitopes”) could boost local and systemic “natural” protective immunity, induced by wild-type infection. Here we highlight the rationale and the future of our emerging “asymptomatic” T cell epitope-based mucosal vaccine strategy to decrease recurrent herpetic disease. PMID:22701511
Berzofsky, Jay A.; Terabe, Masaki; Oh, SangKon; Belyakov, Igor M.; Ahlers, Jeffrey D.; Janik, John E.; Morris, John C.
In recent years, great strides in understanding and regulating the immune system have led to new hope for harnessing its exquisite specificity to destroy cancer cells without affecting normal tissues. This review examines the fundamental immunologic advances and the novel vaccine strategies arising from these advances, as well as the early clinical trials studying new approaches to treat or prevent cancer.
Mohammad A. Rafi
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.
Nizard, Mevyn; Roussel, Hélène; Tartour, Eric
Cancer vaccine boost via the cervicovaginal rather than the intramuscular route of immunization appears to be crucial to induce genital CD8(+) T cells and tumor regression. This clinical activity is correlated with the ability of the mucosal boost to elicit resident memory T cells in the genital tract. ©2015 American Association for Cancer Research.
Karlsson, Ingrid; Kløverpris, Henrik; Jensen, Kristoffer Jarlov
of a universal epitope peptide-based T cell vaccine with relevance for any geographic locations. The two major obstacles when designing such a vaccine are the high diversities of the HIV-1 genome and of the human major histocompatibility complex (MHC) class I. We selected 15 CD8-restricted epitopes predicted......-specific, HLA-restricted T cell specificities using peptide-MHC class I tetramer labeling of CD8(+) T cells from HIV-1-infected individuals. The selected vaccine epitopes are infrequently targeted in HIV-1-infected individuals from both locations. Moreover, we HLA-typed HIV-1-infected individuals......The high HIV-1 prevalence, up to 4.6% in Guinea-Bissau, West Africa, makes it a relevant location for testing of therapeutic vaccines. With the aim of performing a clinical study in Guinea-Bissau, after first testing the vaccine for safety in Denmark, Europe, we here describe the design...
Sanada, Yukinari; Yakushijin, Kimikazu; Nomura, Tetsuhiko; Chayahara, Naoko; Toyoda, Masanori; Minami, Yosuke; Kiyota, Naomi; Mukohara, Toru; Kawamoto, Shinichiro; Ito, Mitsuhiro; Matsuoka, Hiroshi; Minami, Hironobu
Cancer patients receiving chemotherapy are at risk of acquiring influenza infections. Two-dose vaccination is a proposed strategy for increasing vaccination efficacy; however, this has yet to be confirmed in this population. The purpose of this study was to clarify the efficacy and safety of this strategy. We conducted a multicentre prospective study on a two-dose vaccination regimen in cancer patients receiving chemotherapy. Second vaccinations were performed in patients who did not respond to all three viral strains after the first vaccination. Serum haemagglutination inhibition titres were measured to determine the patients' immunological response, 2 weeks prior to the first vaccination, 3-5 weeks after each vaccination, and at the end of the influenza season. We enrolled 109 patients, including 70 with solid tumours, 36 with haematological malignancies, and 3 with both cancer types. Among the total patients, the proportion of patients with protective titres against the three viral strains increased significantly from 3 to 27% (P vaccination. Among the 79 patients who received a second vaccination, the proportion of those with protective titres against the individual strains increased by 10% (H1N1), 8% (H3N2), and 3% (B) compared with after the first vaccination. Serious adverse events were not observed. We recommend influenza vaccinations for cancer patients, including those receiving chemotherapy. Also, the additional benefit of the second vaccination may be limited. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: firstname.lastname@example.org.
Brusic, Ana; Wu, Catherine J
Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only truly effective curative treatment for refractory hematological malignancies. Unfortunately, relapse and transplant rejection continue to be of major concern. In order to enhance the effectiveness of the HSCT, various strategies have been explored to amplify the graft versus leukemia (GvL) effect. Cancer vaccines have emerged in recent years as a promising strategy for the immunotherapeutic treatment of cancer. Evidence shows that they are most likely to have the greatest effect in the setting of minimal residual disease and as adjuvant agents. With this in mind, researchers have begun to explore the use of cancer vaccines in conjunction with HSCT, with exciting results. There has also been recent work examining the effect of novel adjuvants or blockers of negative immune regulation to augment the effect of cancer vaccines in both the transplant and non-transplant settings. The addition of these agents may prove.
Home; Journals; Journal of Biosciences; Volume 39; Issue 3. Novel inhibitor of DNA ligase IV with a promising cancer therapeutic potential. Ashwin Kotnis Rita Mulherkar. Clipboards Volume 39 Issue 3 June 2014 pp 339-340 ... Keywords. Anti-cancer drug; DNA repair; ligase IV; non-homologous end-joining ...
Mo, Lijun; Chen, Qianmei; Zhang, Xinji; Shi, Xiaojun; Wei, Lili; Zheng, Dianpeng; Li, Hongwei; Gao, Jimin; Li, Jinlong; Hu, Zhiming
ICOS + Treg cells exert important immunosuppressive effects in tumor immunity. We adopt a combination approach of ICOS + Treg cells depletion with tumor cell vaccine to evaluate anti-tumor immunity in mouse prostate cancer model. Streptavidin (SA)-mGM-CSF surface-modified RM-1 cells were prepared as the vaccine and the mouse subcutaneous prostate tumor model was used to evaluate the immunity. Tumor growth, flow cytometry, immunohistochemistry, immunofluorescence and enzyme linked immunosorbent assay (ELISA) were performed to evaluate the therapeutic effects. Our results demonstrated that SA-mGM-CSF vaccine was prepared successfully and tumor growth was inhibited. The tumor size in the combination group was much smaller than that in the vaccine with IgG mAb group. The portions of dendritic cells, CD8 + and CD4 + T cells in the mice blood and tumor tissues were increased after treatment with vaccine. There were more immune-suppressing Tregs infiltrated into tumor after treatment with tumor cell vaccine, and ICOS blocking could deplete the infiltrated Tregs, and T lymphocytes increased more dramatically in the combination therapy group. The concentrations of interferon-γ were increased in all vaccine group, the concentrations of Interleukin-10 and Interleukin-4 were much lower in the combination group. Our study demonstrated that ICOS blocking could deplete the tumor-infiltrated ICOS + Treg cells. Combining GM-CSF surface-modified RM-1 cell vaccine with Anti-ICOS antibody could induce better antitumor immunity than a vaccine alone. Copyright © 2017 Elsevier Ltd. All rights reserved.
Hong Im Kim
Full Text Available Ornithine Decarboxylase (ODC a key enzyme in polyamine biosynthesis is often overexpressed in cancers and contributes to polyamine-induced cell proliferation. We noted ubiquitous expression of ODC1 in our published endometrial cancer gene array data and confirmed this in the cancer genome atlas (TCGA with highest expression in non-endometrioid, high grade, and copy number high cancers, which have the worst clinical outcomes. ODC1 expression was associated with worse overall survival and increased recurrence in three endometrial cancer gene expression datasets. Importantly, we confirmed these findings using quantitative real-time polymerase chain reaction (qRT-PCR in a validation cohort of 60 endometrial cancers and found that endometrial cancers with elevated ODC1 had significantly shorter recurrence-free intervals (KM log-rank p = 0.0312, Wald test p = 5.59e-05. Difluoromethylornithine (DFMO a specific inhibitor of ODC significantly reduced cell proliferation, cell viability, and colony formation in cell line models derived from undifferentiated, endometrioid, serous, carcinosarcoma (mixed mesodermal tumor; MMT and clear cell endometrial cancers. DFMO also significantly reduced human endometrial cancer ACI-98 tumor burden in mice compared to controls (p = 0.0023. ODC-regulated polyamines (putrescine [Put] and/or spermidine [Spd] known activators of cell proliferation were strongly decreased in response to DFMO, in both tumor tissue ([Put] (p = 0.0006, [Spd] (p<0.0001 and blood plasma ([Put] (p<0.0001, [Spd] (p = 0.0049 of treated mice. Our study indicates that some endometrial cancers appear particularly sensitive to DFMO and that the polyamine pathway in endometrial cancers in general and specifically those most likely to suffer adverse clinical outcomes could be targeted for effective treatment, chemoprevention or chemoprevention of recurrence.
Kim, In Gyu; Kim, Kugchan; Jung, Il Lae; Kim, Seo Yeon; Choi, Su Im; Lee, Jae Ha
This study focuses on developing an efficient bioprocess for large-scale production of fibulin-3 using Chinese Hamster Ovary cell expression system and evaluating its therapeutic potential for the treatment of cancer. The specific aims are as follows: Isolation and establishment of CSCs using FACS based on cell surface markers and high ALDH1 activity. Identification and characterization of lung cancer stem cells that acquire features of CSC upon exposure to ionizing radiation. Evaluation of the fibulin-3 effects on the stem traits and signaling pathways required for the generation and maintenance of CSCs. In vivo validation of fivulin-3 for tumor prognosis and therapeutic efficacy against lung cancer using animal model.
Jelveh, Salomeh; Chithrani, Devika B.
The field of nanotechnology is currently undergoing explosive development on many fronts. The technology is expected to generate innovations and play a critical role in cancer therapeutics. Among other nanoparticle (NP) systems, there has been tremendous progress made in the use of spherical gold NPs (GNPs), gold nanorods (GNRs), gold nanoshells (GNSs) and gold nanocages (GNCs) in cancer therapeutics. In treating cancer, radiation therapy and chemotherapy remain the most widely used treatment options and recent developments in cancer research show that the incorporation of gold nanostructures into these protocols has enhanced tumor cell killing. These nanostructures further provide strategies for better loading, targeting, and controlling the release of drugs to minimize the side effects of highly toxic anticancer drugs used in chemotherapy and photodynamic therapy. In addition, the heat generation capability of gold nanostructures upon exposure to UV or near infrared light is being used to damage tumor cells locally in photothermal therapy. Hence, gold nanostructures provide a versatile platform to integrate many therapeutic options leading to effective combinational therapy in the fight against cancer. In this review article, the recent progress in the development of gold-based NPs towards improved therapeutics will be discussed. A multifunctional platform based on gold nanostructures with targeting ligands, therapeutic molecules, and imaging contrast agents, holds an array of promising directions for cancer research. PMID:24212654
Bakhtiar, Athirah; Sayyad, Mustak; Rosli, Rozita; Maruyama, Atsushi; Chowdhury, Ezharul H
Conventional therapies for malignant cancer such as chemotherapy and radiotherapy are associated with poor survival rates owing to the development of cellular resistance to cancer drugs and the lack of targetability, resulting in unwanted adverse effects on healthy cells and necessitating the lowering of therapeutic dose with consequential lower efficacy of the treatment. Gene therapy employing different types of viral and non-viral carriers to transport gene(s) of interest and facilitating production of the desirable therapeutic protein(s) has tremendous prospects in cancer treatments due to the high-level of specificity in therapeutic action of the expressed protein(s) with diminished off-target effects, although cancer cell-specific delivery of transgene(s) still poses some challenges to be addressed. Depending on the potential therapeutic target genes, cancer gene therapy could be categorized into tumor suppressor gene replacement therapy, immune gene therapy and enzyme- or prodrug-based therapy. This review would shed light on the current progress of delivery of potentially therapeutic genes into various cancer cells in vitro and animal models utilizing a variety of viral and non-viral vectors.
Jelveh, Salomeh [Ontario Cancer Institute, Princess Margaret Hospital, University Health Network, Toronto, ON (Canada); Department of Radiation Physics, Princess Margaret Hospital, Toronto, ON (Canada); Chithrani, Devika B., E-mail: email@example.com [Department of Radiation Physics, Princess Margaret Hospital, Toronto, ON (Canada); STTARR Innovation Centre, Toronto Medical Discovery Tower, Toronto, ON (Canada)
The field of nanotechnology is currently undergoing explosive development on many fronts. The technology is expected to generate innovations and play a critical role in cancer therapeutics. Among other nanoparticle (NP) systems, there has been tremendous progress made in the use of spherical gold NPs (GNPs), gold nanorods (GNRs), gold nanoshells (GNSs) and gold nanocages (GNCs) in cancer therapeutics. In treating cancer, radiation therapy and chemotherapy remain the most widely used treatment options and recent developments in cancer research show that the incorporation of gold nanostructures into these protocols has enhanced tumor cell killing. These nanostructures further provide strategies for better loading, targeting, and controlling the release of drugs to minimize the side effects of highly toxic anticancer drugs used in chemotherapy and photodynamic therapy. In addition, the heat generation capability of gold nanostructures upon exposure to UV or near infrared light is being used to damage tumor cells locally in photothermal therapy. Hence, gold nanostructures provide a versatile platform to integrate many therapeutic options leading to effective combinational therapy in the fight against cancer. In this review article, the recent progress in the development of gold-based NPs towards improved therapeutics will be discussed. A multifunctional platform based on gold nanostructures with targeting ligands, therapeutic molecules, and imaging contrast agents, holds an array of promising directions for cancer research.
Full Text Available HPV is closely associated with cervical cancer that the incidence of this tumor is regarded as a surrogate marker for HPV infection in countries lacking epidemiological studies. HPV is also implicated in subsets of anogenital and oro-pharyngeal cancers. Although cervical cancer is the third most common cancer in women worldwide, its reported incidence is low in Saudi Arabia, ranking number 12 between all cancers in females and accounts only for 2.4% of all new cases, despite the lack of national screening programs. However, the limited available studies from Saudi Arabia indicate that HPV prevalence and genotypes’ distribution in invasive cervical cancer show similar pattern as in the world. Cytology screening (Pap Smear and HPV vaccinations are the two preventive measures against cervical cancer. The two available vaccines are effective against the two most common HPV genotypes (HPV-16 and 18. Since 92% of cervical tumors in the Kingdom are infected with HPV of which 78% are HPV-16 and 18 genotypes, vaccination is expected to protect against more than two-third of cervical cancers in Saudi Arabia. Nevertheless, due to its low incidence (2.1/100,000 women, a proper cost-effectiveness analysis is required to justify the implementation of a costly vaccine bearing in mind that HPV could potentially be associated with about 3% of all cancers. However, further studies are needed to ascertain the real prevalence of HPV at the population level at large, its association with various types of cancers and also the impact of local tradition and emerging behavioral trends that could affect HPV transmission and consequently the effectiveness of applying national vaccination program.
WANG, MIN-CONG; LI, CHUN-LI; CUI, JIE; JIAO, MIN; WU, TAO; JING, LI; NAN, KE-JUN
BMI-1 oncogene is a member of the polycomb-group gene family and a transcriptional repressor. Overexpression of BMI-1 has been identified in various human cancer tissues and is known to be involved in cancer cell proliferation, cell invasion, distant metastasis, chemosensitivity and patient survival. Accumulating evidence has revealed that BMI-1 is also involved in the regulation of self-renewal, differentiation and tumor initiation of cancer stem cells (CSCs). However, the molecular mechanisms underlying these biological processes remain unclear. The present review summarized the function of BMI-1 in different human cancer types and CSCs, and discussed the signaling pathways in which BMI-1 is potentially involved. In conclusion, BMI-1 may represent a promising target for the prevention and therapy of various cancer types. PMID:26622537
Muthana, Saddam M; Gulley, James L; Hodge, James W; Schlom, Jeffrey; Gildersleeve, Jeffrey C
Immunotherapies for cancer are transforming patient care, but clinical responses vary considerably from patient to patient. Simple, inexpensive strategies to target treatment to likely responders could substantially improve efficacy while simultaneously reducing health care costs, but identification of reliable biomarkers has proven challenging. Previously, we found that pre-treatment serum IgM to blood group A (BG-A) correlated with survival for patients treated with PROSTVAC-VF, a therapeutic cancer vaccine in phase III clinical trials for the treatment of prostate cancer. These results suggested that ABO blood type might influence efficacy. Unfortunately, blood types were not available in the clinical records for all but 8 patients and insufficient amounts of sera were left for standard blood typing methods. To test the hypothesis, therefore, we developed a new glycan microarray-based method for determining ABO blood type. The method requires only 4 μL of serum, provides 97% accuracy, and allows simultaneous profiling of many other serum anti-glycan antibodies. After validation with 220 healthy subjects of known blood type, the method was then applied to 74 PROSTVAC-VF patients and 37 control patients from a phase II trial. In this retrospective study, we found that type B and O PROSTVAC-VF patients demonstrated markedly improved clinical outcomes relative to A and AB patients, including longer median survival, longer median survival relative to Halabi predicted survival, and improved overall survival via Kaplan-Meier survival analysis (p = 0.006). Consequently, blood type may provide an inexpensive screen to pre-select patients likely to benefit from PROSTVAC-VF therapy.
Full Text Available Abstract Background The cervical cancer screening program implemented in Hungary to date has not been successful. Along with screening, vaccination is an effective intervention to prevent cervical cancer. The aim of this study was to assess the cost-effectiveness of adding vaccination with the human papillomavirus 16/18 vaccine to the current cervical cancer screening program in Hungary. Methods We developed a cohort simulation state-transition Markov model to model the life course of 12-year-old girls. Eighty percent participation in the HPV vaccination program at 12 years of age was assumed. Transitional probabilities were estimated using data from the literature. Local data were used regarding screening participation rates, and the costs were estimated in US $. We applied the purchasing power parity exchange rate of 129 HUF/$ to the cost data. Only direct health care costs were considered. We used a 3.7% discount rate for both the cost and quality-adjusted life years (QALYs. The time horizon was 88 years. Results Inclusion of HPV vaccination at age 12 in the cervical cancer prevention program was predicted to be cost-effective. The incremental cost-effectiveness ratio (ICER of adding HPV vaccination to the current national cancer screening program was estimated to be 27 588 $/QALY. The results were sensitive to the price of the vaccine, the discount rate, the screening participation rate and whether herd immunity was taken into account. Conclusions Our modeling analysis showed that the vaccination of 12-year-old adolescent girls against cervical cancer with the AS04-adjuvanted human papillomavirus 16/18 vaccine would be a cost-effective strategy to prevent cervical cancer in Hungary.
Full Text Available The objective of the present review is to study the relationship between flavonoids and lung cancer, proposing that their regular consumption in Western diets could be beneficial for protecting patients against lung cancer. An extensive search of the scientific literature was performed in the following electronic specialized databases (PubMed central (PMC-NBCI, Elsevier Journal, SciELO Spain, Scirus, Science Direct, including studies in animals, cells, and humans, in order to establish the effect of flavonoids in the prevention and development of lung cancer. Although in vitro and animal studies show the potential ability of flavonoids to act against different types of cancers, especially against lung cancers, the diverse results reported within epidemiological studies, together with the lack of experiments in humans, are the major factors in limiting making dietary recommendations based on scientific evidence for the management of patients with lung cancer. Therefore, the authors of the present study recommend following the dietary health practice guidelines which promotes the consumption of food enriched in flavonoids and reflects the current state of knowledge of an effective and appropriate diet in lung cancer patients.Erratum in: Rev Esp Nutr Hum Diet. 2013;17(2:91-92Link: http://www.renhyd.org/index.php/renhyd/article/view/6/17
Apaydin, Kaan Z; Fontenot, Holly B; Shtasel, Derri L; Mayer, Kenneth H; Keuroghlian, Alex S
Human papillomavirus (HPV) vaccination and anal cancer screening are valuable, yet underutilized, tools in prevention of HPV-related cancers among sexual and gender minority (SGM) populations. The aim of this study was to characterize primary care providers' (PCPs) practices and perceptions pertaining to HPV vaccination and anal cancer screening. A survey assessing self-reported practice characteristics related to HPV vaccination and anal cancer screening, as well as perceived barriers to vaccination and anal cancer screening at the patient-, provider-, and system-level was distributed to PCPs at a Federally-Qualified Health Center that specializes in care for SGM populations in the greater Boston area. A total of 33 PCPs completed the survey. All PCPs strongly recommended HPV vaccination to their patients by emphasizing that the vaccine is extremely important or very important. Most PCPs told their patients that the HPV vaccine prevents cervical cancer (96.9%), anal cancer (96.9%), oropharyngeal cancer (72.7%), penile cancer (57.5%), and genital warts (63.6%). There is substantial variability among providers regarding recommendations for anal cancer screening and follow-up. Most PCPs perceived that patient-level factors such as poverty, mental illness, and substance use disorders were barriers to HPV vaccination and anal cancer screening. Systems-level barriers such as lack of clinical time with each patient and lack of staffing were also described as barriers to vaccination and screening. Patient-, provider- and systems-level improvements are important to increase HPV vaccination and anal cancer screening rates.
Rathfisch, Gülay; Güngör, İlkay; Uzun, Ece; Keskin, Özlem; Tencere, Zeliha
The aim of this study was to evaluate awareness, knowledge, and risk perception about human papillomavirus (HPV), cervical cancer, and HPV vaccines among undergraduate students in Turkey. The convenience sample of this descriptive cross-sectional study consisted of 605 undergraduate students in Istanbul University during a semester. Demographic characteristics of students, their reproductive health and lifestyle behaviors, and knowledge of HPV and HPV vaccine were questioned using self-administered forms. The overall proportion of students who had heard about HPV infection was 48.8%, while the proportion of students who had heard of the HPV vaccine was 44.5%. Forty eight percent of females and 60% of males reported never having heard of the HPV. Only 45.7% of females had knowledge about HPV as a cause of genital warts, and 58.1% correctly indicated that HPV caused cervical cancer. The majority of students in both genders (>80%) knew that the infection is primarily transmitted through sexual intercourse. Females were more concerned than males about having cervical/penile cancer associated with HPV in the future. Only 46.4% of females and 39% of males reported having heard of the HPV vaccine. The majority of the female and male students did not know who should get the HPV vaccine and when to get vaccinated. Among males, 25.8% reported that they would consider getting vaccinated (if available) and 38.4% intended to vaccinate their children. Turkish undergraduate students had a low to moderate level of knowledge regarding HPV infection and HPV vaccine. In order to increase awareness about HPV and develop positive behaviors, young people should be provided with accurate information through educational activities in the community and health care services.
Kleinerman, Ruth A. [National Institutes of Health, Division of Cancer Epidemiology and Genetics, National Cancer Institute, EPS 7044, Rockville, MD (United States)
The growing use of interventional and fluoroscopic imaging in children represents a tremendous benefit for the diagnosis and treatment of benign conditions. Along with the increasing use and complexity of these procedures comes concern about the cancer risk associated with ionizing radiation exposure to children. Children are considerably more sensitive to the carcinogenic effects of ionizing radiation than adults, and children have a longer life expectancy in which to express risk. Numerous epidemiologic cohort studies of childhood exposure to radiation for treatment of benign diseases have demonstrated radiation-related risks of cancer of the thyroid, breast, brain and skin, as well as leukemia. Many fewer studies have evaluated cancer risk following diagnostic radiation exposure in children. Although radiation dose for a single procedure might be low, pediatric patients often receive repeated examinations over time to evaluate their conditions, which could result in relatively high cumulative doses. Several cohort studies of girls and young women subjected to multiple diagnostic radiation exposures have been informative about increased mortality from breast cancer with increasing radiation dose, and case-control studies of childhood leukemia and postnatal diagnostic radiation exposure have suggested increased risks with an increasing number of examinations. Only two long-term follow-up studies of cancer following cardiac catheterization in childhood have been conducted, and neither reported an overall increased risk of cancer. Most cancers can be induced by radiation, and a linear dose-response has been noted for most solid cancers. Risks of radiation-related cancer are greatest for those exposed early in life, and these risks appear to persist throughout life. (orig.)
Cancer is a leading cause of death worldwide although extensive research in human cancer medicine is carried out. To develop and improve molecular anticancer therapies, the characterisation of the structure and function of cancer-related genes and proteins is essential. The dog is one of the companion animals being considered as an invaluable model system. The spontaneous development of tumours in the context of an intact immune system in dogs and the striking similarities to human neoplasias...
Wheeler, Cosette M.; Hunt, William C.; Joste, Nancy E.; Key, Charles R.; Quint, Wim G. V.; Castle, Philip E.
Background Limited data are available describing human papillomavirus (HPV) genotype distributions in cervical cancer in the United States. Such studies are needed to predict how HPV vaccination and HPV-based screening will influence cervical cancer prevention. Methods We used the New Mexico Surveillance, Epidemiology, and End Results Registry to ascertain cases of in situ (n = 1213) and invasive (n = 808) cervical cancer diagnosed during 1985?1999 and 1980?1999, respectively, in the state of...
New cancer therapies are urgently needed, since available treatment options today have negative side effects, and cure only about half of the patients with invasive cancer. One, relatively new, option is to vaccinate against cancer, by introducing an antigen that is present on the tumor cells into the patient to stimulate specific immunity against the tumor. For this purpose viral capsid proteins, which can self-assemble into so called virus-like particles (VLPs), can be e...
Cross-sectional and longitudinal analysis of cancer vaccination trials registered on the US Clinical Trials Database demonstrates paucity of immunological trial endpoints and decline in registration since 2008.
Lu, Liangjian; Yan, Haixi; Shyam-Sundar, Vijay; Janowitz, Tobias
Cancer vaccination has been researched as a means of treating and preventing cancer, but successful translational efforts yielding clinical therapeutics have been limited. Numerous reasons have been offered in explanation, pertaining both to the vaccine formulation, and the clinical trial methodology used. This study aims to characterize the tumor vaccine clinical trial landscape quantitatively, and explore the possible validity of the offered explanations including the translational obstacles posed by the current common endpoints. We performed a detailed cross-sectional and longitudinal analysis of tumor vaccine trials (n=955) registered in the US Clinical Trials database. The number of tumor vaccine trials initiated per annum has declined 30% since a peak in 2008. In terms of vaccine formulation, 25% of trials use tumor cell/lysate preparations; whereas, 73% of trials vaccinate subjects against defined protein/peptide antigens. Also, 68% of trials do not use vectors for antigen delivery. Both these characteristics of tumor vaccines have remained unchanged since 1996. The top five types of cancer studied are: melanoma (22.6%); cervical cancer (13.0%); breast cancer (11.3%); lung cancer (9.5%); and prostate cancer (9.4%). In addition, 86% of the trials are performed where there is established disease rather than prophylactically, of which 67% are performed exclusively in the adjuvant setting. Also, 42% of Phase II trials do not measure any survival-related endpoint, and only 23% of Phase III trials assess the immune response to vaccination. The clinical trial effort in tumor vaccination is declining, necessitating a greater urgency in identifying and removing the obstacles to clinical translation. These obstacles may include: 1) vaccination against a small range of antigens; 2) naked delivery of antigen; 3) investigation of less immunogenic cancer types; and 4) investigation in the setting of established disease. In addition, the prevalence of late phase failure
Boone, Stephanie D; Pinkston, Christina M; Baumgartner, Kathy B; Baumgartner, Richard N; Harper, Sean M; Bonham, Aaron J; Paynter, Christopher A; Harper, Diane M
Cervical cancer screening, regardless of HPV vaccination, is a cornerstone of cancer prevention. This study evaluated associations between prior HPV vaccine doses and initiation and continued participation of screening by age at vaccination. Using electronic medical records for a safety net healthcare system (Truman Medical Center), women aged 14-26y vaccinated (n=1123) between 07/01/2006 and 10/1/2009 were randomly selected and matched on birth year and health campus to unvaccinated (n=1123) women. Frequency of screening was determined through 07/01/2013. Hazard ratios (HR) for screening were estimated using Cox proportional hazards regression. Screening rates were higher after vaccination: unvaccinated (53%), first (62%), second (59%) or third (61%) doses. Women who initiated screening were less likely to complete the vaccine series, regardless of age. Women receiving one dose were more likely than unvaccinated women to initiate screening (HR=2.98 95% Confidence Interval (CI):2.45-3.61) and were more likely to screen than those receiving two (1 vs. 2, HR=2.94 95% CI:2.09-4.14) or three doses (1 vs. 3, HR=3.15 95% CI:2.21-4.48). Compared to unvaccinated women, women vaccinated women ≥21y were more likely to screen regardless of number of doses (pvaccinated were more likely to screen than unvaccinated women; screening rate was highest after and occurred closest to the first vaccine dose. Research evaluating the efficacy of a one-dose vaccine is warranted and may provide both higher vaccination and screening rates. Copyright © 2016 Elsevier Ltd. All rights reserved.
Diane M Harper
Full Text Available OBJECTIVE: Only a portion of the US population is willing to consider HPV vaccination to date. The primary aim of this study is to determine the decisional satisfaction associated with HPV vaccination. STUDY DESIGN: This is a prospective survey conducted at an urban college where women 18-26 years old completed a decisional satisfaction survey about their HPV vaccine experience. RESULTS: Regardless of the decision to accept or reject HPV vaccination, the decisional satisfaction was very high (mean 5-item score = 21.2 (SD 3.8. Women without HPV vaccination were decisionally neutral significantly more often than those already vaccinated; 22% were decisionally neutral for the option to accept HPV vaccination at that visit. Cervical cancer prevention was preferred significantly more often than genital wart prevention in all analyses. CONCLUSIONS: Targeting those who are decisionally neutral about HPV vaccination may result in a higher uptake of HPV vaccination.
Roelands, Jessica; Kuppen, Peter J. K.; Vermeulen, Louis; Maccalli, Cristina; Decock, Julie; Wang, Ena; Marincola, Francesco M.; Bedognetti, Davide; Hendrickx, Wouter
The immune system has a substantial effect on colorectal cancer (CRC) progression. Additionally, the response to immunotherapeutics and conventional treatment options (e.g., chemotherapy, radiotherapy and targeted therapies) is influenced by the immune system. The molecular characterization of
Laghi, Luigi; Malesci, Alberto
Microsatellite instability (MSI), the molecular phenotype of colorectal cancers with mismatch repair defects was discovered in the last decade of the previous century. As a field of investigation which successfully joins basic and clinical science, MSI is an example of real translational science, starting from the molecular basis of a disease and extending to the clinical arena. In clinical settings, MSI is a diagnostic biomarker leading to the diagnosis of hereditary nonpolyposis colorectal cancer. However, the clinical implication of MSI testing extends to the role of prognostic marker, due to the better outcome of patients with MSI colorectal cancer. Additionally, MSI identified a general lack of response to neo-adjuvant therapy employing 5-fluorouracil. Like predictive markers of response to chemotherapy, the role of MSI is likely not exhausted, as chemotherapy regimens need to take into account the peculiar biological and clinical behavior of MSI cancers. Copyright © 2012 S. Karger AG, Basel.
Vyas, Vivek Kumar; Brahmbhatt, Keyur; Bhatt, Hardik; Parmar, Utsav
Many active secretions produced by animals have been employed in the development of new drugs to treat diseases such as hypertension and cancer. Snake venom toxins contributed significantly to the treatment of many medical conditions. There are many published studies describing and elucidating the anti-cancer potential of snake venom. Cancer therapy is one of the main areas for the use of protein peptides and enzymes originating from animals of different species. Some of these proteins or peptides and enzymes from snake venom when isolated and evaluated may bind specifically to cancer cell membranes, affecting the migration and proliferation of these cells. Some of substances found in the snake venom present a great potential as anti-tumor agent. In this review, we presented the main results of recent years of research involving the active compounds of snake venom that have anticancer activity. PMID:23593597
Cheong, Heesun; Lu, Chao; Lindsten, Tullia; Thompson, Craig B.
The metabolism of cancer cells is reprogrammed by oncogene signaling and/or mutations in metabolic enzymes. These metabolic alterations support cell proliferation and survival, but leave cancer cells dependent on continuous support of the nutrients that fuel their altered metabolism. Thus, in addition to core oncogenic pathways, many metabolic enzymes have become targets for novel therapies. Two novel processes- isoform-specific expression of metabolic enzymes and autophagy- have recently been shown to play critical roles in the adaptation of tumor cells to changes in nutrient availability and the cell's ability to sense and adapt to depletion of critical nutrients. These findings suggest that a better understanding of the molecular basis of cancer-associated metabolic changes has the potential to provide insights to enhance cancer therapy. PMID:22781696
Hong, Waun K; Lotan, Reuben; Stewart, David
.... In addition, the clinical trials that will be conducted in the VITAL Research Program will demonstrate the true rate of lung cancer recurrence and second primary tumor incidence in patients at high...
The objects of this project are to develop a high-throughput method for screening potential inhibitors of breast cancer cell migration, and to apply this method to identify signaling events mediating...
.... We also proposed to examine the role of CDK5 activity in growth of prostate cancer metastatic to bone, using PC3 based bioluminescent cell clones, and to explore the potential for CDK5 inhibition...
Luo, Yunping; Zhou, He; Mizutani, Masato; Mizutani, Noriko; Reisfeld, Ralph A.; Xiang, Rong
Protection against breast cancer was achieved with a DNA vaccine against murine transcription factor Fos-related antigen 1, which is overexpressed in aggressively proliferating D2F2 murine breast carcinoma. Growth of primary s.c. tumor and dissemination of pulmonary metastases was markedly suppressed by this oral DNA vaccine, carried by attenuated Salmonella typhimurium, encoding murine Fos-related antigen 1, fused with mutant polyubiquitin, and cotransformed with secretory murine IL-18. The life span of 60% of vaccinated mice was tripled in the absence of detectable tumor growth after lethal tumor cell challenge. Immunological mechanisms involved activation of T, natural killer, and dendritic cells, as indicated by up-regulation of their activation markers and costimulatory molecules. Markedly increased specific target cell lysis was mediated by both MHC class I-restricted CD8+ T cells and natural killer cells isolated from splenocytes of vaccinated mice, including a significant release of proinflammatory cytokines IFN- and IL-2. Importantly, fluorescence analysis of fibroblast growth factor 2 and tumor cell-induced vessel growth in Matrigel plugs demonstrated marked suppression of angiogenesis only in vaccinated animals. Taken together, this multifunctional DNA vaccine proved effective in protecting against growth and metastases of breast cancer by combining the action of immune effector cells with suppression of tumor angiogenesis. vaccine | tumor | metastases | antiangiogenesis
Wheeler, Christopher J; Black, Keith L; Liu, Gentao; Mazer, Mia; Zhang, Xiao-xue; Pepkowitz, Samuel; Goldfinger, Dennis; Ng, Hiushan; Irvin, Dwain; Yu, John S
Cancer vaccine trials have failed to yield robust immune-correlated clinical improvements as observed in animal models, fueling controversy over the utility of human cancer vaccines. Therapeutic vaccination represents an intriguing additional therapy for glioblastoma multiforme (GBM; grade 4 glioma), which has a dismal prognosis and treatment response, but only early phase I vaccine trial results have been reported. Immune and clinical responses from a phase II GBM vaccine trial are reported here. IFN-gamma responsiveness was quantified in peripheral blood of 32 GBM patients given therapeutic dendritic cell vaccines. Posttreatment times to tumor progression (TTP) and survival (TTS) were compared in vaccine responders and nonresponders and were correlated with immune response magnitudes. GBM patients (53%) exhibited >or=1.5-fold vaccine-enhanced cytokine responses. Endogenous antitumor responses of similar magnitude occurred in 22% of GBM patients before vaccination. Vaccine responders exhibited significantly longer TTS and TTP relative to nonresponders. Immune enhancement in vaccine responders correlated logarithmically with TTS and TTP spanning postvaccine chemotherapy, but not with initial TTP spanning vaccination alone. This is the first report of a progressive correlation between cancer clinical outcome and T-cell responsiveness after therapeutic vaccination in humans and the first tracing of such correlation to therapeutically exploitable tumor alteration. As such, our findings offer unique opportunities to identify cellular and molecular components of clinically meaningful antitumor immunity in humans.
11/09/2016 University of Wisconsin-Madison, Cancer Biology Seminar Series, Madison, WI, “From Epigenetic Mechanism to Targeted Therapy” 12/22/2016...Transcription” 02/16/2017 Purdue University Cancer Center, West Lafayette, IN, “From Epigenetic Structural Mechanism to Targeted Therapy” 7 Binhua P...171,284/yr, d.c. “Structure and Mechanism of Protein Modules in Chromatin Biology” This project aims to conduct structural and biochemical analyses
Guerrero, Anna Melissa; Genuino, Anne Julienne; Santillan, Melanie; Praditsitthikorn, Naiyana; Chantarastapornchit, Varit; Teerawattananon, Yot; Alejandria, Marissa; Toral, Jean Anne
Cervical cancer is the second leading cause of cancer cases and deaths among Filipino women because of inadequate access to screening and treatment services. This study aims to evaluate the health and economic benefits of HPV vaccination and its combination with different screening strategies to find the most optimal preventive strategy in the Philippines. A cost-utility analysis was conducted using an existing semi-Markov model to evaluate different screening (i.e., Pap smear, visual inspection with acetic acid) and vaccination strategies against HPV infection implemented alone or as part of a combination strategy at different coverage scenarios. The model was run using country-specific epidemiologic, cost and clinical parameters from a health system perspective. Sensitivity analysis was performed for vaccine efficacy, duration of protection and costs of vaccination, screening and treatment. Across all coverage scenarios, VIA has been shown to be a dominant and cost-saving screening strategy with incremental cost-effectiveness ratio (ICER) ranging from dominant to Php 61,059 (1443 USD) per QALY gained. VIA can reduce cervical cancer cases and deaths by 25%. Pap smear screening was found to be not cost-effective due to its high cost in the Philippines. Adding HPV vaccination at a cost of 54 USD per vaccinated girl on top of VIA screening was found to be potentially cost-effective using a threshold of 1 GDP per capita (i.e., Php 120,000 or 2835 USD/ QALY) with the most favorable assumption of providing lifelong immunity against high-risk oncogenic HPV types 16/18. The highest incremental QALY gain was achieved with 80% coverage of the combined strategy of VIA at 35 to 45 years old done every five years following vaccination at 11 years of age with an ICER of Php 33,126 (783 USD). This strategy may result in a two-thirds reduction in cervical cancer burden. HPV vaccination is not cost-effective when vaccine protection lasts for less than 20 years. High VIA coverage
Full Text Available Maria Cekanova, Kusum Rathore Department of Small Animal Clinical Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN, USA Abstract: Cancer is the term used to describe over 100 diseases that share several common hallmarks. Despite prevention, early detection, and novel therapies, cancer is still the second leading cause of death in the USA. Successful bench-to-bedside translation of basic scientific findings about cancer into therapeutic interventions for patients depends on the selection of appropriate animal experimental models. Cancer research uses animal and human cancer cell lines in vitro to study biochemical pathways in these cancer cells. In this review, we summarize the important animal models of cancer with focus on their advantages and limitations. Mouse cancer models are well known, and are frequently used for cancer research. Rodent models have revolutionized our ability to study gene and protein functions in vivo and to better understand their molecular pathways and mechanisms. Xenograft and chemically or genetically induced mouse cancers are the most commonly used rodent cancer models. Companion animals with spontaneous neoplasms are still an underexploited tool for making rapid advances in human and veterinary cancer therapies by testing new drugs and delivery systems that have shown promise in vitro and in vivo in mouse models. Companion animals have a relatively high incidence of cancers, with biological behavior, response to therapy, and response to cytotoxic agents similar to those in humans. Shorter overall lifespan and more rapid disease progression are factors contributing to the advantages of a companion animal model. In addition, the current focus is on discovering molecular targets for new therapeutic drugs to improve survival and quality of life in cancer patients. Keywords: mouse cancer model, companion animal cancer model, dogs, cats, molecular targets
Full Text Available Abstract Background Ten cancer patients (Six renal cell carcinoma and four breast cancer patients were treated in a phase I/II study with a vaccine composed of autologous dendritic cells (DCs and IL-2 to evaluate the DC vaccine-related toxicity and antigen-specific immune alteration. Methods Cancer patients were treated twice with autologous CD34+ hematopoietic stem cell-derived, GM-CSF/IFN-γ-differentiated DCs pulsed with autologous tumor lysate and KLH, by 4-week interval. Following each subcutaneous injection of therapeutic DCs, low-dose (200 MIU IL-2 was introduced for 14 consecutive days as an immune adjuvant. To determine the DC vaccine-induced immunological alterations, the KLH-specific lymphocyte proliferation, number of IFN-γ secreting T cells (ELISPOT assay, NK activity and the cytokine modulation were measured. Results Cultured-DCs expressing HLA-DR, CD11c, CD83, and B7.1/B7.2 produced IL-12p70. After vaccination, the patients tolerated it. Clinical response was observed in one RCC patient as stable disease. However DC-vaccine related antigen-specific immune responses including peripheral blood lymphocyte proliferation and the number of IFN-r secreting cells were induced in six patients without clear correlation with clinical responses. Also NK activity was induced significantly in six patients after vaccination. DC vaccine-related decrease of TGF-β level or increase of IL-12p70 level and decline of CD4+CD25+ T cells were observed in three patients. However only in the RCC patient whose disease stabilized, combination of stimulatory as well as inhibitory immune alterations including induction of IFN-γ secreting T cell with reduction of CD4+ CD25+ T cell were correlated with clinical responses. Conclusion Data indicated that DC vaccine combined with IL-2 is well tolerated without major side effects. DC vaccine induced the specific immunity against introduced antigen. Combinatorial alterations of immunological parameters indicating
Full Text Available Development of solid cancer depends on escape from host immunosurveillance. Various types of immune cells contribute to tumor-induced immune suppression, including tumor associated macrophages, regulatory T cells, type 2 NKT cells, and myeloid-derived suppressor cells (MDSCs. Growing body of evidences shows that MDSCs play pivotal roles among these immunosuppressive cells in multiple steps of cancer progression. MDSCs are immature myeloid cells that arise from myeloid progenitor cells and comprise a heterogeneous immune cell population. MDSCs are characterized by the ability to suppress both adaptive and innate immunities mainly through direct inhibition of the cytotoxic functions of T cells and NK cells. In clinical settings, the number of circulating MDSCs is associated with clinical stages and response to treatment in several cancers. Moreover, MDSCs are reported to contribute to chemoresistant phenotype. Collectively, targeting MDSCs could potentially provide a rationale for novel treatment strategies in cancer. This review summarizes recent understandings of MDSCs in cancer and discusses promissing clinical approaches in cancer patients.
Turriziani, Mario; Fantini, Massimo; Benvenuto, Monica; Izzi, Valerio; Masuelli, Laura; Sacchetti, Pamela; Modesti, Andrea; Bei, Roberto
Carcinoembryonic antigen (CEA), a glycosylated protein of MW 180 kDa, is overexpressed in a wide range of human carcinomas, including colorectal, gastric, pancreatic, non-small cell lung and breast carcinomas. Accordingly, CEA is one of several oncofetal antigens that may serve as a target for active anti-cancer specific immunotherapy. Experimental results obtained by employing animal models have supported the design of clinical trials using a CEA-based vaccine for the treatment of different types of human cancers. This review reports findings from experimental models and clinical evidence on the use of a CEA-based vaccine for the treatment of cancer patients. Among the diverse CEA-based cancer vaccines, DCs- and recombinant viruses-based vaccines seem the most valid. However, although vaccination was shown to induce a strong immune response to CEA, resulting in a delay in tumor progression and prolonged survival in some cancer patients, it failed to eradicate the tumor in most cases, owing partly to the negative effect exerted by the tumor microenvironment on immune response. Thus, in order to develop more efficient and effective cancer vaccines, it is necessary to design new clinical trials combining cancer vaccines with chemotherapy, radiotherapy and drugs which target those factors responsible for immunosuppression of immune cells. This review also discusses relevant patents relating to the use of CEA as a cancer vaccine.
Kudarha, Ritu R; Sawant, Krutika K
Albumin is a versatile protein used as a carrier system for cancer therapeutics. As a carrier it can provide tumor specificity, reduce drug related toxicity, maintain therapeutic concentration of the active moiety like drug, gene, peptide, protein etc. for long period of time and also reduce drug related toxicities. Apart from cancer therapy, it is also utilized in the imaging and multimodal therapy of cancer. This review highlights the important properties, structure and types of albumin based nanocarriers with regards to their use for cancer targeting. It also provides brief discussion on methods of preparation of these nanocarriers and their surface modification. Applications of albumin nanocarriers for cancer therapy, gene delivery, imaging, phototherapy and multimodal therapy have also been discussed. This review also provides brief discussion about albumin based marketed nano formulations and those under clinical trials. Copyright © 2017 Elsevier B.V. All rights reserved.
Zuo, Jiangcheng; Yu, Yalan; Zhu, Man; Jing, Wei; Yu, Mingxia; Chai, Hongyan; Liang, Chunzi; Tu, Jiancheng
Breast cancer is a common cancer in women of worldwide. Cancer cells with stem-like properties played important roles in breast cancer, such as relapse, metastasis and treatment resistance. Micro-RNA-155 (miR-155) is a well-known oncogenic miRNA overexpressed in many human cancers. The expression levels of miR-155 in 38 pairs of cancer tissues and adjacent normal tissues from breast cancer patients were detected using quantitative real-time PCR. The invasive cell line MDA-MB-231 was used to quantify the expression of miR-155 by tumor-sphere forming experiment. Soft agar colony formation assay and tumor xenografts was used to explore whether the inhibition of miR-155 could reduce proliferation of cancer cells in vivo and vitro. In the study, we found miR-155 was upregulated in BC. Soft agar colony formation assay and tumor xenografts showed inhibition of miR-155 could significantly reduce proliferation of cancer cells in vivo and vitro, which confirmed that miR-155 is an effective therapeutic target of breast cancer. Sphere-forming experiment showed that overexpression of miR-155 significantly correlated with stem-like properties. Expressions of ABCG2, CD44 and CD90 were repressed by inhibition of miR-155, but CD24 was promoted. Interestingly, inhibition of miR-155 rendered MDA-MB-231 cells more sensitive to Doxorubicinol, which resulted in an increase of inhibition rate from 20.23% to 68.72%. Expression of miR-155 not only was a therapeutic target but also was associated with cancer stem cell formation and Doxorubicinol sensitivity. Our results underscore the importance of miR-155 as a therapeutic target and combination of Doxorubicinol and miR-155-silencing would be a potential way to cure breast cancer.
Begum, M.; Khurshid, R.; Nagra, S.A.
Vaccine development is one of the most promising fields in cancer research. After autologous transplantation, due to low tumour burden, patients are more likely to respond immunologically to a cancer vaccine. MUC1 with its adhesive and anti adhesive functions, immunostimulatory and immunosuppressive activities, is therefore a good candidate for breast cancer vaccine. A structure-based insight into the immunogenicity of natural MUC1 glyco forms, of its sub-domains, motifs and post translational modification like glycosylation and myriostoylation may aid the design of tumour vaccines. Primary sequences of human MUC1 were retrieved from the SWISSPROT data bank. Protein pattern search: The primary sequence of Human MUC1 was searched at PROSITE (a dictionary of protein sites and patterns) database. Our study observes that post-translational modifications play an important role in presenting MUC1 as a candidate for breast cancer vaccine. It is found that the phosphorylation and glycosylation of important functional motifs of MUC1 may take part in the production of cytokines that may provide immunization. (author)
Full Text Available DNA-based cancer vaccines represent an attractive strategy for inducing immunity to tumor associated antigens (TAAs in cancer patients. The demonstration that the delivery of a recombinant plasmid encoding epitopes can lead to epitope production, processing, and presentation to CD8+ T-lymphocytes, and the advantage of using a single DNA construct encoding multiple epitopes of one or more TAAs to elicit a broad spectrum of cytotoxic T-lymphocytes has encouraged the development of a variety of strategies aimed at increasing immunogenicity of TAA polyepitope DNA-based vaccines. The polyepitope DNA-based cancer vaccine approach can (a circumvent the variability of peptide presentation by tumor cells, (b allow the introduction in the plasmid construct of multiple immunogenic epitopes including heteroclitic epitope versions, and (c permit to enroll patients with different major histocompatibility complex (MHC haplotypes. This review will discuss the rationale for using the TAA polyepitope DNA-based vaccination strategy and recent results corroborating the usefulness of DNA encoding polyepitope vaccines as a potential tool for cancer therapy.
Sutton, Philip; Robinson, Karen
Helicobacter pylori infections typically commence during childhood and last for life. Freire de Melo and colleagues compared cytokine profiles in the stomachs of H. pylori-infected and H. pylori-uninfected children and adults from Brazil. They suggest that the immune effector response in infected children differs from infected adults, specifically that stomachs of infected children contained elevated regulatory T-cell markers and less IL-17 compared with adults. As vaccine-mediated protection against H. pylori is believed to involve IL-17 and to be inhibited by regulatory T cells, this raises the possibility that individual H. pylorivaccines may have different efficacies in children and adults.
Villena, Rodolfo; Zubieta, Marcela; Hurtado, Carmen; Salgado, Carmen; Silva, Gladys; Fernández, Jazmine; Villarroel, Milena; Fernández, Marisol; Brahm, Javier; O'Ryan, Miguel; Santolaya, María Elena
Immune response against vaccine antigens may be impaired in children with cancer. The aim of this study was to evaluate the seroconversion response against hepatitis B vaccination (HBV) at the time of chemotherapy onset and/or remission in children with cancer. Prospective, two-centre, controlled, non-randomised study conducted on children recently diagnosed with cancer, paired with healthy subjects. Cases received HBV at time 0, 1 and 6 months with DNA recombinant HBV at a dose of 20 and 40 μg if than 10 years of age, respectively, at the time of diagnosis for solids tumours and after the remission in case of haematological tumours. Controls received the same schedule, but at of 10 and 20 μg doses, respectively. HBs antibodies were measured in serum samples obtained at 2, 8 and 12 months post-vaccination. Protective titres were defined as > 10 mIU/ml at 8th month of follow up. A total of 78 children with cancer and 25 healthy controls were analysed at month 8th of follow up. Seroconversion rates in the cancer group reached 26.9%, with no differences by age, gender or type of tumour (P = .13, .29, and .44, respectively). Control group seroconversion was 100% at the 8th month, with P 10 mIU/ml. Vaccination against hepatitis B with three doses of DNA recombinant vaccine at an increased concentration, administrated at the time of onset of chemotherapy and/or remission provided an insufficient immune response in a majority of children with cancer. More immunogenic vaccines should be evaluated in this special population, such as a third generation, with more immunogenic adjuvants, enhanced schedules at 0, 1, 2, 6 month, evaluation of antibody titres at month 8 and 12h to evaluate the need for further booster doses. Copyright © 2015 Sociedad Chilena de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.
Full Text Available Tumor-associated macrophages (TAMs and regulatory T cells (Tregs are significant components of the microenvironment of solid tumors in the majority of cancers. TAMs sequentially develop from monocytes into functional macrophages. In each differentiation stage, TAMs obtain various immunosuppressive functions to maintain the tumor microenvironment (e.g., expression of immune checkpoint molecules, production of Treg-related chemokines and cytokines, production of arginase I. Although the main population of TAMs is immunosuppressive M2 macrophages, TAMs can be modulated into M1-type macrophages in each differential stage, leading to the suppression of tumor growth. Because the administration of certain drugs or stromal factors can stimulate TAMs to produce specific chemokines, leading to the recruitment of various tumor-infiltrating lymphocytes, TAMs can serve as targets for cancer immunotherapy. In this review, we discuss the differentiation, activation, and immunosuppressive function of TAMs, as well as their benefits in cancer immunotherapy.
Ho, Mingqian Feng, Mitchell
Glypican-3 (GPC3) is an emerging therapeutic target in hepatocellular carcinoma (HCC), even though the biological function of GPC3 remains elusive. Currently human (MDX-1414 and HN3) and humanized mouse (GC33 and YP7) antibodies that target GPC3 for HCC treatment are under different stages of preclinical or clinical development. Humanized mouse antibody GC33 is being evaluated in a phase II clinical trial. Human antibodies MDX-1414 and HN3 are under different stages of preclinical evaluation....
Cox, J.D.; Bauer, M.
Bronchopulmonary carcinomas have long been considered among the most frustrating problems in radiation oncology. In spite of the reasonably favorable results reported over 30 years ago with conventional X-irradiation of patients with operable carcinoma of the lung, the patients usually referred for radiation therapy with unresectable tumors permit few opportunities for successful treatment and thus lead to a general nihilism about this disease. The potential damage that can occur from radiation therapy to the normal lung can be life-threatening. Such damage was thought, erroneously, to be increased dramatically with even moderately high doses, e.g.; more than 50 Gy in 5 weeks. Therefore, few attempts were made to deliver the same high doses of radiations that would be considered mandatory for epithelial tumors of other locations such as the upper respiratory and digestive tract or the female genital tract. The therapeutic ratio was altered in an unfavorable direction with the use of small numbers of large fractions. Based on the earliest RTOG studies of carcinoma of the lung, the therapeutic ratio is at an acceptable level with 60 Gy in 30 fractions of 2.0 Gy in 6 weeks. It is encouraging that there is no evidence of an increased rate of morbidity in the hyperfractionation trials of the RTOG. The data are too preliminary with regard to therapeutic effect to know if there will truly be an increase in therapeutic ratio. It was evident that 12-24 months of follow-up are necessary before definitive answers are available
Gerer, Kerstin F.; Erdmann, Michael; Hadrup, Sine Reker
antigens is an active form of immunotherapy, which intends to direct the immune system towards tumors which express the respective vaccination antigens. Methods: Cytokine-matured monocyte-derived DCs of healthy donors and MCC patients were electroporated with mRNA encoding the truncLT. To permit major......Background: Merkel cell carcinoma (MCC) is a rare but very aggressive skin tumor that develops after integration of a truncated form of the large T-antigen (truncLT) of the Merkel cell polyomavirus (MCV) into the host's genome. Therapeutic vaccination with dendritic cells (DCs) loaded with tumor......-antigen-specific T-cell responses. Therapeutic vaccination with such transfected DCs could direct the immune system against MCC....
Zo, Jae Ill; Park, Jong Ho; Baek, Hee Jong
The aims of this study were to make the lung cancer clinics in Korea Cancer Center Hospital, and to establish new therapeutic methods of lung cancer for increasing the cure rate and survival rate of patients. Also another purpose of this study was to establish a common treatment method in our hospital. All patients who were operated in Korea Cancer Center Hospital from 1987 due to lung cancer were followed up and evaluated. And we have been studied the effect of postoperative adjuvant therapy in stage 1, 2, 3A non-small cell lung cancer patients from 1989 with the phase three study form. Follow-up examinations were scheduled in these patients and interim analysis was made. Also we have been studied the effect of chemotherapeutic agents in small cell lung cancer patients from 1997 with the phase two study form. We evaluated the results of this study
Genetic engineering of tumor cells to express MHC class and subsequent use of said cells for treatment of established and metastatic tumors has yielded promising results in animal models for treatment of breast cancer...
Beierlein, J M; Anderson, A C
Bacillus anthracis, the causative agent responsible for anthrax infections, poses a significant biodefense threat. There is a high mortality rate associated with untreated anthrax infections; specifically, inhalation anthrax is a particularly virulent form of infection with mortality rates close to 100%, even with aggressive treatment. Currently, a vaccine is not available to the general public and few antibiotics have been approved by the FDA for the treatment of inhalation anthrax. With the threat of natural or engineered bacterial resistance to antibiotics and the limited population for whom the current drugs are approved, there is a clear need for more effective treatments against this deadly infection. A comprehensive review of current research in drug discovery is presented in this article, including efforts to improve the purity and stability of vaccines, design inhibitors targeting the anthrax toxins, and identify inhibitors of novel enzyme targets. High resolution structural information for the anthrax toxins and several essential metabolic enzymes has played a significant role in aiding the structure-based design of potent and selective antibiotics.
Kovjazin, Riva; Volovitz, Ilan; Kundel, Yulia; Rosenbaum, Eli; Medalia, Gal; Horn, Galit; Smorodinsky, Nechama I; Brenner, Baruch; Carmon, Lior
An optimal cancer vaccine should be able to induce highly potent, long-lasting, tumor-specific responses in the majority of the cancer patient population. One approach for achieving this is to use synthetic peptide vaccines derived from widely expressed tumor-associated antigens, that promiscuously bind multiple MHC class I and class II alleles. MUC1-SP-L (ImMucin, VXL100) is a 21mer peptide encoding the complete signal peptide domain of MUC1, a tumor-associated antigen expressed by over 90% of solid and non-solid tumors. MUC1-SP-L was predicted in silico to bind various MHC class I and MHC class II alleles, covering the majority of the Caucasian population. PBLs obtained from 13 naïve donors all proliferated, with a Stimulation Index (SI≥2), to the MUC1-SP-L peptide, producing mixed CD4+ and CD8+ responses. Similar results were manifested by MUC1-SP-L in PBLs derived from 9 of 10 cancer patients with MUC1 positive tumors. CD4+ and CD8+ T cell populations exhibited CD45RO memory markers and secreted IFN-gamma and IL-2 following stimulation with MUC1-SP-L. These T cells also exhibited proliferation to the MUC1-SP-L inner 9mer epitopes and cytotoxicity against tumor cell lines expressing MUC1 and a concordant MHC class I allele. Cytotoxicity to MUC1-expressing human and murine tumors was shown also in T cells obtained from HLA-A2 transgenic mice and BALB/c syngeneic mice immunized with the MUC1-SP-L and GM-CSF. In an immunotherapy model, BALB/c mice inoculated with metastatic MUC1 transfected murine DA3 mammary tumor cells, exhibited significantly prolonged survival following vaccination with MUC1-SP-L. Our results indicate superior immunological and anti-tumor properties of MUC1-SP-L compared to previously published MUC1-derived epitopes. Copyright © 2011 Elsevier Ltd. All rights reserved.
Maharajan, Mari Kannan; Rajiah, Kingston; Num, Kelly Sze Fang; Yong, Ng Jin
The primary objective of this study was to assess the knowledge of medical students and determine variation between different cultural groups. A secondary aim was to find out the willingness to pay for cervical cancer vaccination and the relationships between knowledge and attitudes towards Human Papillomavirus vaccination. A cross-sectional survey was conducted in a private medical university between June 2014 and November 2014 using a convenient sampling method. A total of 305 respondents were recruited and interviewed with standard questionnaires for assessment of knowledge, attitudes and practice towards human papilloma virus and their willingness to pay for HPV vaccination. Knowledge regarding human papilloma virus, human papilloma virus vaccination, cervical cancer screening and cervical cancer risk factors was good. Across the sample, a majority (90%) of the pupils demonstrated a high degree of knowledge about cervical cancer and its vaccination. There were no significant differences between ethnicity and the participants' overall knowledge of HPV infection, Pap smear and cervical cancer vaccination. Some 88% of participants answered that HPV vaccine can prevent cervical cancer, while 81.5% of medical students said they would recommend HPV vaccination to the public although fewer expressed an intention to receive vaccination for themselves.
Cekanova, Maria; Rathore, Kusum
Cancer is the term used to describe over 100 diseases that share several common hallmarks. Despite prevention, early detection, and novel therapies, cancer is still the second leading cause of death in the USA. Successful bench-to-bedside translation of basic scientific findings about cancer into therapeutic interventions for patients depends on the selection of appropriate animal experimental models. Cancer research uses animal and human cancer cell lines in vitro to study biochemical pathways in these cancer cells. In this review, we summarize the important animal models of cancer with focus on their advantages and limitations. Mouse cancer models are well known, and are frequently used for cancer research. Rodent models have revolutionized our ability to study gene and protein functions in vivo and to better understand their molecular pathways and mechanisms. Xenograft and chemically or genetically induced mouse cancers are the most commonly used rodent cancer models. Companion animals with spontaneous neoplasms are still an underexploited tool for making rapid advances in human and veterinary cancer therapies by testing new drugs and delivery systems that have shown promise in vitro and in vivo in mouse models. Companion animals have a relatively high incidence of cancers, with biological behavior, response to therapy, and response to cytotoxic agents similar to those in humans. Shorter overall lifespan and more rapid disease progression are factors contributing to the advantages of a companion animal model. In addition, the current focus is on discovering molecular targets for new therapeutic drugs to improve survival and quality of life in cancer patients. PMID:25342884
P., Popova, T., De laMotte Rouge, T., Fourchotte, V., Gentien, D., Hupé, P., Becette, V., Houdayer, C., Roman - Roman , S., et al. (2015). Histo...Breast Cancer ResearchConsortium atWistar (R. Zhang).H. Zhu is an OCRF Ann Schreiber Mentored Investigator (372953). B.G. Bitler is sup- ported by an
existent in some provinces. However, Lubumbashi onset of cervical cancer of the uterus was observed earlier for respondents (30-45 years at 52.5%) and this seems to be linked to several risk factors including poor socio-economic ...
Thorsen, Stine Buch; Obad, Susanna; Jensen, Niels Frank
MicroRNAs (miRNAs) have been uncovered as important posttranscriptional regulators of nearly every biological process in the cell. Furthermore, mounting evidence implies that miRNAs play key roles in the pathogenesis of cancer and that many miRNAs can function either as oncogenes or tumor...
Piperigkou, Zoi; Manou, Dimitra; Karamanou, Konstantina; Theocharis, Achilleas D
Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that are capable of degrading numerous extracellular matrix (ECM) components thus participating in physiological and pathological processes. Apart from the remodeling of ECM, they affect cell-cell and cell-matrix interactions and are implicated in the development and progression of various diseases such as cancer. Numerous studies have demonstrated that MMPs evoke epithelial to mesenchymal transition (EMT) of cancer cells and affect their signaling, adhesion, migration and invasion to promote cancer cell aggressiveness. Various studies have suggested MMPs as suitable targets for treatment of malignancies, and several MMP inhibitors (MMPIs) have been developed. Although initial trials have failed to establish MMPIs as anticancer agents due to lack of specificity and side effects, new MMPIs have been developed with improved action that are currently being investigated. Furthermore, novel strategies that target MMPs for improving drug delivery and regulating their activity in tumors are presented. This review summarizes the implication of MMPs in cancer progression and discusses the advancements in their targeting.
Cormier, L; Créhange, G
The management of localized prostate cancer has been marked over these last years by the importance of Active Surveillance for low risk forms. Indeed, the long follow-up and the quality of the results are now sufficient to offer this option even in relatively young people. However, the question is still under investigation concerning intermediate risk of prostate cancer. Patients' selection and follow-up management are of very high importance. Another major evolution is the robotic assistance for radical prostatectomy. Even if the level of evidence is still low, the global utilization all over the world of robotic assistance is a major fact of these last years mostly explained by the difficulty to correctly perform manual laparoscopic surgical procedure. Lastly, the focal therapy of prostate cancer is a new concept. The development of this approach is authorized by the improvement of the quality of prostate MRI and the accuracy of prostate biopsy. Presently, the focal treatment has to be performed in clinical trials or maybe with the help of national database validated by all the actors concerned by the treatment of prostate cancer. Copyright © 2017 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.
Full Text Available Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs have been widely used in non-small cell lung cancer (NSCLC patients, it is still controversial about how to combine EGFR-TKI with chemotherapy and other targeted drugs. We have made a summary on the current therapeutic models of EGFR-TKI combined with chemotherapy/bevacizumab in this review and aimed to find the optimal therapeutic strategy for NSCLC patients with EGFR mutation.
Djurhuus, Sissal Sigmundsdòttir; Brasso, Klaus; Berg, Kasper Drimer
Therapeutic vaccines is a novel approach in castration-resistant prostate cancer treatment Castration-resistant prostate cancer (CRPC) is defined as tumour progression despite castrate levels of serum testosterone. During the past decade a number of new therapies, including chemotherapy and novel...... endocrine agents have been approved for CRPC treatment. The continued need for new effective drugs in CRPC has led to development of a novel therapeutic approach in CRPC treatment. Therapeutic vaccines activate the immune system to kill prostate cancer cells. This review describes recent pivotal phase 2...... and 3 trials of CRPC vaccines and discusses the impact on future CRPC management....
Recently, volumetric-modulated arc therapy (VMAT) has demonstrated the ability to deliver radiation dose precisely and accurately with a shorter delivery time compared to conventional intensity-modulated fixed-field treatment (IMRT). We applied the hypothesis of VMAT technique at our hospital to determine the superior dose coverage for planning target volume (PTV) with adequate sparing of organs-at-risk (OARs). The delivery time and monitor units (MUs) is reduced in comparison with conventional fixed-field IMRT. Rapid Arc (RA) plans had a pre-treatment quality assurance and results were summarised in terms of the Gamma Agreement Index (GAI) scoring criteria of 3% and 3 mm thresholds. A total of 771 patients were treated between July 2011 and August 2013 of which head and neck cancer were 385, prostate cancer 53, brain tumours 112, cervical and endometrial cancer 77, breast cancer 38, rectal and bladder cancer 56, special technique using SBRT 45 (Liver and Lung) and Cranio-spinal irradiation 5 patients using RA single (177 control points) and double arcs (354 control points). The Average treatment time was 4.8 ±0.2 minutes (220 seconds of beam-on). The number of MU per fraction of 2.0 Gy was 522.5 ± 133.62. VMAT can be a valuable clinical tool that can deliver the prescribed dose efficiently in 1.5-3 minutes (single or double arcs) with high target homogeneity and adequate sparing of organs at risk. It would allow to reduce patient lying time on couch and over all beam on time from 4 hours to one hour. The toxicity (Tracheal fistula) observed in two patients of Carcinoma Lung receiving SRT high lights the need for peer review. (author)
Maria Graziella eCatalano
Full Text Available At present no successful treatment is available for advanced thyroid cancer, which comprises poorly differentiated, anaplastic, and metastatic or recurrent differentiated thyroid cancer not responding to radioiodine. In the last few years, biologically targeted therapies for advanced thyroid carcinomas have been proposed on the basis of the recognition of key oncogenic mutations. Although the results of several phase II trials look promising, none of the patients treated had a complete response, and only a minority of them had a partial response, suggesting that the treatment is, at best, effective in stabilizing patients with progressive disease. Epigenetic refers to the study of heritable changes in gene expression that occur without any alteration in the primary DNA sequence. The epigenetic processes establish and maintain the global and local chroma¬tin states that determine gene expression. Epigenetic abnormalities are present in almost all cancers and, together with genetic changes, drive tumour progression. Various genes involved in the control of cell proliferation and invasion (p16INK4A, RASSF1A,PTEN, Rap1GAP, TIMP3, DAPK, RARβ2, E-cadherin, and CITED1 as well as genes specific of thyroid differentiation (Na+/I- symport, TSH receptor, pendrin, SL5A8, and TTF-1 present aberrant methylation in thyroid cancer.This review deals with the most frequent epigenetic alterations in thyroid cancer and focuses on epigenetic therapy, whose goal is to target the chromatin in rapidly dividing tumour cells and potentially restore normal cell functions. Experimental data and clinical trials, especially using deacetylase inhibitors and demethylating agents, are discussed.
... will not work well for all pets. Your veterinarian will determine a vaccination schedule most appropriate for ... programs, but in some instances may help your veterinarian determine if your pet has a reasonable expectation ...