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Cancer vaccines have been developed largely as therapeutic approaches targeting specific tumor antigens while sparing the deleterious and generalized immune-suppressive effects of radiation and chemotherapy. "First Generation" cancer vaccines (such as Provenge) are autologous preparations and patient-specific. This approach has shown some success, but like anti-tumor monoclonal antibody products, it is limited by tumor mutations that render the vaccine less effective. "Second Generation" anti-cancer vaccines and immunotherapies aim to correct this deficiency by utilizing universal or heterologous antigens. These vaccines and therapies often require an in vivo rather than an in vitro approach to generate the anti-tumor immune response. This approach aims to utilize the patient's immune system to generate an anti-tumor immune response and destroy the tumor. Through imparting exogenous and activating endogenous anti-tumor mechanisms within the patient to overcome tumor tolerance and generate a robust, sustainable and effective anti-tumor immune response, this response may be able to withstand tumor mutations and overcome tumor mechanisms geared towards the inhibition of an effective anti-tumor response in the patient. This symposium will highlight current approaches in cancer immunotherapy and immunomodulation, and emerging cancer vaccines.
Reception to follow.
This event will also be broadcast as a webinar.
Please note: Transmission of presentations via the webinar is subject to individual consent by the speakers. Therefore, we cannot guarantee that every speaker’s presentation will be broadcast in full via the webinar. To access all speakers’ presentations in full, we invite you to attend the live event in New York City where possible.
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Presented by
This meeting is part of our Translational Medicine Initiative, sponsored by the Josiah Macy Jr. Foundation.
Agenda
* Presentation times are subject to change.
Tuesday May 15, 2012
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12:00 PM
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Registration
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12:30 PM
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Welcome and Introduction
Jennifer Henry, PhD, The New York Academy of Sciences
George Zavoico, PhD, MLV
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12:40 PM
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Dendritic Cell-Targeting Vaccines For Cancer Immunotherapy
Sangkon Oh, PhD, Baylor Institute of Immunology Research
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1:20 PM
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Immunotherapy to Target Cancer Stem Cells
John S. Yu, MD, Cedars-Sinai Medical Center and Immunocellular Therapeutics, Ltd
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2:00 PM
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Modulation of Immune Responses to Cancer
Rachel L. Sabado, PhD, NYU Langone Medical Center
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2:40 PM
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Coffee Break
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3:10 PM
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A Genetic Inference on Cancer Immune Responsiveness
Francesco Marincola, MD, National Institutes of Health
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3:50 PM
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Heat Shock Protein Vaccine for Glioma
Andrew T. Parsa, MD, PhD, University of California, San Francisco
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4:30 PM
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Multikine® Cancer Immunotherapy: Mechanism of Action, Clinical Experience, Phase III Global Study and Possible New Standard of Care
Eyal Talor, PhD, CEL-SCI Corporation
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5:10 PM
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Closing remarks and future directions
Eyal Talor, PhD, CEL-SCI Corporation
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5:15 PM
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Networking Reception
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6:00 PM
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Close
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Speakers
Organizers
Eyal Talor, PhD
CEL-SCI Corporation
Dr. Talor joined CEL-SCI Corporation in October 1993 and is currently CEL-SCI's Chief Scientific Officer. Before coming to CEL-SCI, he was Director of R&D and Clinical Development at CBL, Inc. and Principal Scientist (Project Director, and Clinical Laboratory Director) at SRA Technologies, Inc. Dr. Talor is a clinical immunologist with over 20 years of hands-on management of clinical research and drug development for immunotherapy application; pre-clinical to Phase III. Dr. Talor's expertise includes: biopharmaceutical R&D and biologics product development, GMP manufacturing, quality control, biological assays, analytical methods development and validation, and the design and building of GMP manufacturing and testing facilities. He holds two US patents; 1) Multikine's composition of matter and method of use in cancer, and 2) a platform Peptide technology ('Adapt') for the treatment of autoimmune diseases, asthma, allergy, and transplantation rejection. He also holds one European and one Chinese patent on Multikine. Dr. Talor received his Ph.D. in Microbiology and Immunology from the University of Ottawa, Ontario, Canada, and had post-doctoral training in clinical and cellular immunology at The Johns Hopkins University, Baltimore, Maryland, USA, where he was active Faculty and is now an Adjunct Associate. Dr. Talor has been teaching a post-graduate course in clinical immunology at the Johns Hopkins University Medical Institutions for the past 24 years.
George Zavoico, PhD
MLV
George B. Zavoico, PhD, is Managing Director, Research, and a Senior Equity Research Analyst at MLV, a boutique investment bank and institutional broker-dealer based in New York. He has over 6 years of experience as a life sciences analyst writing research on publicly traded equities. Prior to MLV, he was an equity analyst with Westport Capital Markets and Cantor Fitzgerald. Prior to working as an analyst, Dr Zavoico established his own consulting company serving the biotech and pharmaceutical industries by providing competitive intelligence and marketing research, due diligence services, and guidance in regulatory affairs. He also wrote extensively on healthcare and the biotech and pharmaceutical industries for periodicals targeting the general public and industry executives. Dr Zavoico began his career as a Senior Research Scientist at Bristol-Myers Squibb Co., moving on to management positions at Alexion Pharmaceuticals, Inc. and T Cell Sciences, Inc. (now Celldex Therapeutics, Inc.). He has a BS in Biology from St. Lawrence University and PhD in Physiology from the University of Virginia and has held post-doctoral positions at the University of Connecticut Health Sciences Center and Brigham and Women's Hospital and Harvard Medical School.
Jennifer Henry, PhD
The New York Academy of Sciences
Speakers
Francesco Marincola, MD
National Institutes of Health
Dr. Marincola is Chief of the Infectious Disease and Immunogenetics Section in the Department of Transfusion Medicine at the Clinical Center of the National Institutes of Heath in Bethesda, Maryland. He is also associate-Director of the Trans-NIH Center for Human Immunology and Director of the FOCIS Center for Excellence at NIH. Dr. Marincola received his MD, summa cum laude from the University of Milan, and his surgery training at Stanford University where he also completed a postdoctoral fellowship in surgical research. He joined the Surgical Oncology Branch of the National Cancer Institute, NIH, in 1990.
Dr. Marincola is a NIH tenured senior investigator, Adjunct Professor, Peking Union Medical College, Beijing, China, Adjunct Professor, First Military Medical University, Tonghe, Guangzhou – China, and President Elect of the Society for the Immunotherapy of cancer (Previously: International Society for Biological Therapy of Cancer) and President elect of the International Society for Translational Medicine. Dr. Marincola serves at the Editor-in-Chief, Journal of Translational Medicine; US Senior Editor of Immunotherapy, Associate Editor for The Journal of Immunotherapy, Tumori, and Clinical Cancer Research; Section Editor for Expert Opinion in Biological Therapy; Editorial Board, Cancer Immunology & Immunotherapy, The Journal of Experimental and Clinical Cancer Research.
Dr. Marincola is an author of over 450 peer reviewed research articles and over 100 abstracts. He has been invited to speak at over 200 national and international meetings. Dr. Marincola is the second most cited scientist in melanoma during the last ten years.
Sangkon Oh
Institute of Immunology Research
SangKon Oh, Ph.D. received PhD in Viral Immunology at Johns Hopkins University (2000) and trained at NCI, NIH. Dr. Oh joined BIIR as an Assistant Investigator in 2005. In September 2010, he was promoted to Associate Investigator. He is also affiliated with Baylor University at Waco, TX, as an Associate Professor. Dr. Oh's research has focused on the characterization of human dendritic cell subsets and their distinct functions in directing T and B cell responses. As a part of his researches, Dr. Oh has been playing a key role in the study of "Harnessing Human DC Subsets for Immunity (NIH: U19 program)" for developing DC targeting vaccines. In particular, Dr. Oh's laboratory has uncovered novel immunological functions of DC surface lectins, including Dectin-1 and DC-asialoglycoprotein receptor, in controlling host immune responses toward either immunity or tolerance. Dr. Oh's study will help us understand the fundamental roles of DCs in controlling host immune responses toward either immunity or tolerance.
Andrew T. Parsa, MD, PhD
University of California, San Francisco
Dr. Parsa is professor and vice chairman of the department of neurological surgery at the University of California San Francisco. He is a practicing neurosurgeon specializing in adult brain and spinal cord tumors. Dr. Parsa has extensive research interests including the development of a brain tumor vaccine, and has led a national effort to treat glioblastoma patients with an autologous heat shock protein based vaccine. His research has been continuously funded by the NIH since 2002, and he has published in high impact journals including Nature Medicine, Oncogene and Cancer Research. He is the first recipient of the Reza and Georgianna Khatib Endowed Chair in Skull Base Tumor Surgery, awarded in 2007 at UCSF.
Rachel L. Sabado, PhD
NYU Langone Medical Center
Rachel Lubong Sabado received her B.S. in Microbiology from the University of California San Diego. She received her PhD in Biological Sciences from the New York University School of Medicine. Her past work involved understanding HIV and Dendritic cell (DC) interactions including pathways utilized by DCs to activate HIV-specific T cell responses, priming naïve T cell responses, and the early effects of HIV infection on DC subset numbers and function in vivo. Her current research interests include using DCs and TLR agonists as adjuvants for modulating immune responses against cancer and HIV.
Eyal Talor, PhD
CEL-SCI Corporation
John S. Yu, MD
Cedars-Sinai Medical Center and Immunocellular Therapeutics, Ltd.
Dr. Yu earned his bachelor's degree in French literature and biological sciences from Stanford University and spent a year at the Sorbonne in Paris studying French literature. He also pursued a fellowship in immunology at the Institut Pasteur in Paris, France. He earned his medical degree from Harvard Medical School and master of science degree from the Harvard University Department of Genetics. He completed his neurosurgical residency at Massachusetts General Hospital in Boston. Dr. Yu is the Director of Surgical Neuro-Oncology and Professor of Neurosurgery at Cedars-Sinai Medical Center. Along with a clinical focus on the surgical treatment of malignant and benign brain tumors, he is conducting research in immune and stem cell therapies for brain tumors. He founded Immunocellular therapeutics in 2006.
Abstracts
Multikine® Cancer Immunotherapy: Mechanism of Action, Clinical Experience, Phase III Global Study and Possible New Standard of Care
Eyal Talor, PhD, CEL-SCI Corporation
Head and Neck cancer is a disease with an unmet medical need for which there has been little increase in median overall survival in over 4 decades despite general advances in overall cancer treatment and therapy. The value of combining chemotherapy with radiotherapy following surgery for head and neck cancer patients has been confirmed (Bernier J, et al 2004, NEJM, and Cooper JS, et al, 2004, NEJM). However, despite this progress, further improvements in therapy are needed to increase anti-tumor responses and ameliorate the debilitating side effects of chemotherapy and radiation. Multikine* - Leukocyte Interleukin, Injection (LI) is a complex biologic, investigational immunotherapy that is intended as neoadjuvant/adjuvant treatment/therapy of previously untreated patients with locally advanced primary, squamous cell carcinoma of the head and neck. Multikine (LI) is administered percutaneously (½ daily dose peritumorally and ½ daily dose perilymphatically) aimed at eliciting an anti-tumor immune response. Multikine (LI) Immunotherapy is the first of a new class of cancer immunotherapy drugs; the first First-Line Immunotherapy (Timar, et al 2005 JCO). A global pivotal open-label, randomized, controlled, Phase III study of Multikine (LI) in patients with advanced primary squamous cell carcinoma of the oral cavity and soft/palate (H&N cancer) is currently being conducted in 8 countries (including the USA) at 36 clinical centers. The primary end point for the study is overall survival; secondary end points include progression free survival, local regional control, and quality of life. * Multikine is the trademark that CEL-SCI has registered for this investigational therapy, and this proprietary name is subject to FDA review in connection with its future anticipated regulatory submission for approval. Further research is required, and early-phase clinical trial results must be confirmed in the well-controlled, Phase III clinical trial of this investigational therapy that is currently in progress.
A genetic inference on cancer immune responsiveness
Francesco Marincola, MD, National Institutes of Health
A cancer immune signature implicating good prognosis and responsiveness to immunotherapy was described that is observed also in other aspects of immune-mediated, tissue-specific destruction (TSD). Its determinism remains, however, elusive. On one side it appears that the genetic background of the host’s bears significantly on immune responsiveness, on the other it appears that tumor can behave differently within the same genetic background (as in the case of mixed responses). This apparent paradox can only be explained by a multi-factorial model of cancer immune responsiveness. It should be emphasized that host and cancer genetics are largely overlapping since cancer cells carry the majority of the host’s genetics. Thus, inherited genetic factors may affect the biology of cancer cells besides that of normal cells. It could be postulated that some patients carry a genetic background that make them resistant to immunotherapy by effecting either the biology of the immune response, the biology of the cancer cells or both. On the other hand, “an immune-responsive genotype” may still be limited by the genetics of the tumors: in other words, although the patient may be predisposed to cancer rejection the tumor lacks additional properties necessary for its recognition by the immune response. In this model, a favorable genetic background of the host is necessary but not sufficient for tumor rejection as the possession of a shotgun is necessary to shoot a duck but at the same time a skill in shooting is required. A good example is provided by the analysis of patients with IRF-5 polymorphism; the “immune resistant phenotype” appears to almost exclusively preclude cancer rejection during adoptive therapy with tumor infiltrating lymphocytes; however, “the immune responsive phenotype” can be segregated into two categories; one enriched in patients responding to therapy and the other of non-responding. Although, other host’s genetic factors could be responsible for this sub-classification, it is also possible that, given a favorable genetic background, the genetics of the tumor may become the determining factor. We recognize that this classification of factors that may influence immune responsiveness may be too rigid. In reality, immune responsiveness may depend upon a continuum determined by the interaction of a multitude of factors that for simplicity can be separated into broad categories depending upon the host’s genetic background, somatic mutations, and external factors such as intensity and effectiveness of treatment, general condition of the patient and a multitude of other hidden co-factors. In the presentation at the NY Academy of Sciences we will present our strategy to dissect the question of cancer immune responsiveness by study dynamically the behavior of human cancers under natural conditions on in response to therapy.
Dendritic Cell-Targeting Vaccines For Cancer Immunotherapy
Sangkon Oh, Institute of Immunology Research
Adaptively transferred T cells can reject established tumor in patients, demonstrating that immune system can be harnessed for cancer therapy. Thus, active immunotherapy with vaccines has the potential to induce tumor-specific effector and memory T cells that can control tumor outgrowth long term. This is also supported by the recent phase III clinical trials of cancer vaccines showing survival benefit to patients.
Nonetheless, clinical efficacy of current vaccine models is still limited. This could be due to the facts that 1) the potency of therapeutic immunity elicited by current vaccine models may not be sufficient to overcome tumor growth and 2) tumors evade the immune system by means of regulatory T cells (Tregs). To this end, we need to design new immunotherapeutic strategies that can efficiently prime and boost host immunity to cancer and also help overcome Tregs to allow the breakdown of immunosuppressive tumor microenvironment. Based on our current knowledge in tumor immunology, this could be achieved by designing novel combination therapies targeting those two major components.
Dendritic cells (DCs) are the major immune inducers/regulators. Thus, critical to improved vaccine design will be the concept of an efficient delivery of tumor antigens to DCs as well as a proper activation of DC to generate potent immunity against growing tumors. In this context, Baylor Institute for Immunology Research (BIIR) has developed a platform technology for targeting antigens directly to human in vivo DCs. These DC-targeting vaccines are composed of recombinant monoclonal antibodies (mAbs) specific for individual DC surface receptors engineered to be covalently linked to cancer antigens.
Our study revealed that the quantity and quality of antigen-specific cellular responses can be controlled by not only DC subsets, but also the particular receptors targeted by vaccines. Of multiple DC surface receptors tested, targeting antigens (viral and tumor) to DCs via CD40 resulted in potent CD4+ and particularly CD8+ T cell responses that are critical for tumor immunity. Although treatment of DCs with anti-CD40 mAb (12E12) enhanced tumor antigen-loaded DC-induced Th1 type T cell responses, anti-CD40-antigen fusion proteins are far more efficient at eliciting tumor antigen-specific T cell responses. The immunogenicity of anti-CD40-based vaccines is currently tested in both non-human primate and Humouse models. To suppress the pathways of tumor-induced Treg responses, we will co-administer anti-OX40 antibody. Taken together, we envision that anti-CD40-based vaccines along with anti-OX40 antibody will bring improved clinical benefit to patients.
Heat Shock Protein Vaccine for Glioma
Andrew T. Parsa, MD, PhD, University of California, San Francisco
Vaccination immunotherapies offer the promise of long-term tumor control, and preclinical trials have found promising results. Active immunotherapy uses the adaptive immune response to specifically kill tumor cells. Tumor-specific antigens are processed by antigen-presenting cells and recognized by specific effector lymphocytes. However, basic vaccination strategies with tumor lysates have been unsuccessful in inducing antiglioma immunity in clinical trials. Gliomas are known to modulate the activity of antigen-presenting cells to reduce antitumor immune activity. Recently, tumor-derived heat shock proteins have been found to more effectively activate the immune response. Widely expressed, heat shock proteins are thought to present protein peptide fragments in a format conducive to processing by antigen-presenting cells. As a part of the protein synthesis machinery, peptides complexed with heat shock proteins are effectively representative of antigens expressed by the cell; these peptides convey the specificity of this vaccination strategy. The heat shock protein-peptide vaccine is one of many promising immunotherapeutic strategies being evaluated in clinical trials. These can be broadly classified as active, passive and adoptive, each with advantages and disadvantages. Recently competed and ongoing studies evaluating heat shock protein-peptide vaccines for glioblastoma patients will be discussed.
Modulation of Immune Responses to Cancer
Rachel L. Sabado, PhD, NYU Langone Medical Center
Several approaches have been taken to enhance immunity against tumors in humans. These strategies target either the adaptive immune responses, i.e T cells and B cells, or enhance the activity of antigen presenting cells (APC) such as dendritic cells (DC). Although clinical trials confirm that highly enriched DC vaccines can immunize, they have failed to consistently translate immunogenicity into effective tumor regression in melanoma. Our approach has been to enhance the activity of DCs both in vivo and ex vivo using Toll-like receptor (TLR) agonists. Preliminary data from completed and ongoing clinical trials supporting the safety and immunogenicity of TLR agonists as adjuvants to NY-ESO-1 in stage III melanoma will be presented. Additionally, data from a clinical trial using peptide pulsed DCs injected to patients with stage III melanoma will be presented. Finally, approaches to further optimize the DC-based vaccines will be discussed.
Immunotherapy to target cancer stem cells
John S. Yu, MD, Cedars-Sinai Medical Center and Immunocellular Therapeutics, Ltd.
Glioblastoma multiforme (GBM), is the most common and aggressive form of primary brain tumors. The standard of care for GBM, including surgery followed by radiotherapy and chemotherapy with temozolomide, is associated with a median overall survival of 14.6 months. The identification of brain cancer stem cells has led to a great opportunity to exploit the stem cell mechanisms to inhibit brain tumor initiation, progression, and invasion. Brain cancer stem cells—also called tumor initiating cells or tumor propagating cells—share features with normal neural stem cells but do not necessarily originate from stem cells. Although most cancers have only a small fraction of cancer stem cells, these tumor cells have been shown in laboratory studies to contribute to therapeutic resistance, formation of new blood vessels to supply the tumor and tumor invasion. Recent observations of the laboratory have demonstrated that these cancer stem cells are chemoresistant and may be the major reason for the recurrence of these deadly tumors. The lab has a major emphasis in the development of immunologic strategies to target cancer stem cells.
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