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16th International Cancer Immunotherapy Symposium of the Cancer Research Institute
September 15-17, 2008
Millennium Conference Center, New York, NY
DAY ONE
Session I: Cancer Immunoediting and Cancer and Inflammation
- Dr. Robert Schreiber of the Washington University School of Medicine in St. Louis, Missouri, shared new data from his laboratory’s research into signaling molecules called cytokines, which he has learned play a significant role in the phases of cancer immunoediting—elimination, equilibrium, and escape—a process of immune-moderated cancer control and development he first described, along with Dr. Mark Smyth, who also presented at the symposium, and Dr. Lloyd J. Old, one of the symposium organizers. Dr. Schreiber discussed how his research team is exploring the therapeutic potential of learning how to influence the outcome of the immunoediting process by enhancing or inhibiting the expression and/or action of specific cytokines.
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- Dr. Adrian Hayday of King’s College School of Medicine at Guy’s Hospital in London, England, shared new data from his laboratory that sheds light on how specific repertoires of tissue-associated T-lymphocytes form. He described results from his studies of a novel gene he and his team of researchers helped to identify—the Skint-1 gene, a prototypic member of a novel family of immunoglobulin-like genes specifically expressed in skin and thymus epithelium—and how, through animal models and biochemical and molecular techniques, he is seeking to better define the molecular basis and implications of epithelial – T cell crosstalk mediated by Skint and another closely related homologue, Btnl, expressed in epithelial cells found in the gut, one of the most important areas in the body for immunosurveillance.
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- Dr. Mark Smyth of the Peter MacCallum Cancer Centre in East Melbourne, Australia, discussed recent progress his laboratory is making in further exploring the equilibrium and elimination phases of cancer immunoediting. Dr. Smyth, one of the key contributors to our understanding of the processes of immunosurveillance and immunoediting, described how his laboratory has shown in a variety of oncogene- and irradiation-driven mouse models of cancer that perforin—a cytolytic protein found in the granules of CD8 T cells and NK cells that punctures the plasma membranes of target cells and induces apoptosis, or cell death—plays a significant role in the suppression of B-cell malignancies. He also shared his lab’s research into the activity and function of signaling molecules during the equilibrium and elimination phases of cancer development, and revealed evidence of tumor cells in an equilibrium state in his novel mouse model of equilibrium, which he also described.
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- Dr. Glenn Dranoff of the Dana-Farber Cancer Institute in Boston, Massachusetts, described results from early-phase clinical trials of cancer vaccines composed of irradiated tumor cells engineered to secrete granulocyte-macrophage colony stimulating factor (GM-CSF) followed by administration of a humanized blocking antibody against cytotoxic T lymphocyte-associated antigen 4 (anti-CTLA-4 antibody). He discussed results from recent investigations of GM-CSF-deficient mice and the unexpected critical role he discovered this cytokine plays in the homeostasis of FoxP3-expressing regulatory T cells. He also shared data from mouse studies that show that GM-CSF vaccination in combination with inhibitors of milk fat globule EGF-8 (MFG-E8), a stimulator of regulatory T cell activity, could improve the efficacy of cancer vaccines and complement the activity of CTLA-4 antibody blockade.
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- Dr. Wolf Fridman of the Cordeliers Research Centre, INSERM, University Paris Descartes and University Pierre et Marie Curie, Paris, France, discussed his high throughput analyses of the immune response to three in situ human cancers—colorectal, lung, and intra-ocular lymphoma—and how they provide some of the first direct evidence of the impact of immune reactions to the tumors on the clinical outcome of the patient. He described how specific patterns of immune cell infiltration within certain tumors and their milieu is the strongest prognosticator of disease free survival, recurrence, and overall survival above the classical tumor-associated factors, such as age differentiation and lymph node involvement.
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Session II: Immunological Consequences of Current Cancer Therapy
- Dr. Laurence Zitvogel of Institut Gustave Roussy, Villejuif, France, presented her research into how chemotherapies and X rays can stimulate anti-tumor immune responses resulting from immunogenic tumor cell death. These immune responses, she described, may contribute to the overall effectiveness of the chemical or radiation therapy by eliminating cells that escaped initial destruction or by maintaining micrometastases in a state of dormant equilibrium. She discussed her examination of the molecular pathways involved in chemically induced tumor cell death and how this dying process plays a role in the mobilization of dendritic cells and, in turn, tumor-specific T cells.
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- Dr. Hy Levitsky of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine in Baltimore, Maryland, shared data from studies of patients who have received autologous hematopoietic stem-cell transplants toward immune reconstitution following myelo- and lymphoablative chemotherapy and/or systemic radiation. Specifically, he described the frequency and function of naïve and effector T cells and regulatory T cells during immune reconstitution, their interrelationship during the early post-transplant period, and the factors that influence the repopulation of effector T cells and regulatory T cells during this period. He also discussed data that suggest an explanation for the reversal of tolerance leading to tumor rejection in transplant recipients and could suggest ways to strengthen adoptive T-cell therapies.
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- Dr. Jeffrey Ravetch of The Rockefeller University in New York, New York, shared data from his studies of novel animal models he has developed for the in vivo evaluation of modified IgG-based anti-tumor therapeutics, whose Fc domains have been rationally engineered for optimized Fc receptor engagement. He discussed the clinical significance of supportive data accumulated from patient populations that demonstrate a strong correlation between clinical response and alleles of activating Fc receptors.
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- Dr. Padmanee Sharma of the University of Texas M.D. Anderson Cancer Center in Houston, Texas, presented data from clinical trials of anti-CTLA-4 antibody, including data from the first trial of this antibody in the pre-surgical setting in patients with localized disease, providing novel data on immunological activity at the tumor site, and discussed strategies for developing prognostic biological markers to identify patients who will benefit from this therapy.
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DAY TWO
Session III: Cross Presentation and Tumor Stroma
- Dr. Michael Bevan of the University of Washington School of Medicine in Seattle, Washington, presented data that describes the “exogenous pathway” for antigen presentation, whereby antigen from outside the antigen-presenting cells are presented by class I molecules to stimulate the response of cytotoxic T lymphocytes (CTL). This is in contrast to the well-described endogenous pathway of antigen presentation. Dr. Bevan also presented information on professional antigen presenting cells most likely to be involved in taking exogenous antigen from tumor cells for stimulation of CTL.
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- Dr. Pramod Srivastava of the University of Connecticut Center for Immunotherapy of Cancer and Infectious Diseases in Farmington, Connecticut, presented data from his laboratory’s recent studies of the mechanisms of cross presentation of antigen, a key process in cancer-specific immunotherapy, and described information that unifies conflicting reports on how antigenic peptides are generated by either antigen-expressing cells or antigen-presenting cells.
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- Dr. Günter Hämmerling of the German Cancer Research Center, DKFZ Heidelberg, in Heidelberg, Germany, discussed his research into the importance of the tumor vasculature to the ultimate outcome of cancer immunotherapies. Specifically, Dr. Hämmerling presented data that show how aberrant tumor endothelium forms a barrier against infiltration by tumor-specific lymphocytes, thus preventing them from destroying the tumor cells. He discussed the therapeutic potential of strategies that seek to normalize aberrant tumor vasculature to make the tumors more susceptible to T-cell infiltration.
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- Dr. George Coukos of the University of Pennsylvania Medical Center in Philadelphia, Pennsylvania, described his research into the role of tumor endothelium in the prevention of infiltration by T cells during cancer immunotherapy. Specifically, based on studies that compared the endothelia of human ovarian cancer tumors in patients with and without infiltrating T cells, he has developed a strategy that has been shown in mice to be effective at disrupting the anti-immune protection of tumor endothelium, resulting in improved tumor-specific responses to immunotherapy. He showed that his research is ready for translation into clinical studies of combinatorial therapies in humans.
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- Dr. Ellen Puré of The Wistar Institute in Philadelphia, Pennsylvania, and the Ludwig Institute for Cancer Research in New York, New York, described research her laboratory is conducting on FAP, a stromal cell protease that is expressed almost entirely only in malignant tumors and which has been associated in animal studies with tumorigenesis and poor cancer prognosis. Dr. Puré shared her findings into the mechanisms of FAP-associated tumor progression, and offered strategies for developing anti-cancer therapies based on our new understanding of these mechanisms.
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Session IV: Modulators of Immune Escape
- Dr. James Allison of the Ludwig Center for Cancer Immunotherapy at Memorial Sloan-Kettering Cancer Center in New York, New York, described his laboratory’s latest research into the mechanisms of immune checkpoint blockade in the treatment of cancer, and showed data from mouse and human studies that support the further investigation of immune checkpoint blockade therapy alone and in combination with other anti-cancer therapies.
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- Dr. Vincenzo Bronte of the Istituto Oncologico Veneto and Venetian Institute for Molecular Medicine in Padova, Italy, shared data from his studies of myeloid-derived suppressor cells (MDSCs) and their role in protecting tumors from immune destruction and in promoting tumor stroma and neovasculature formation. He discussed strategies for altering or suppressing MDSC function during cancer immunotherapy; he also described how MDSCs can have a beneficial impact in the treatment of autoimmune diseases like diabetes.
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- Dr. Michail Sitkovsky of the New England Inflammation and Tissue Protection Institute, Northeastern University in Boston, Massachusetts, reported his latest data from studies into the anti-hypoxia-adenosinergic cancer immunotherapy strategy, which attempts to disrupt the tissue-protecting, negative feed-back immunosuppressive mechanism normally associated with excessive tissue damage but which Dr. Sitkovsky and others have shown is also found in cancerous tissue. He described recent genetic in vivo work that demonstrated that weakening or eliminating the hypoxia-adenosinergic signaling could prevent inhibition of cancer vaccine-induced anti-tumor T cells, and shared data from preclinical studies that suggest the addition of synthetic antagonists these signaling receptors could improve current cancer immunotherapies.
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- Dr. Arlene Sharpe of the Harvard Medical School and Brigham and Women’s Hospital in Boston, Massachusetts, described her work on one of the newer T-cell co-inhibitory receptors, PD-1 and its ligands, and showed data from her recent studies demonstrating specific, multiple checkpoints for PD-1 associated regulation of peripheral T-cell tolerance. She also described the role of PD-1 in viral infection and cancer formation, and provided evidence to support the continued study of PD-1 and its ligands as potential therapeutic targets in the treatment of infectious disease, cancer, and autoimmune disorders.
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DAY THREE
Session V: Adoptive Immunotherapy
- Dr. Carl June of the Abramson Cancer Center at the University of Pennsylvania in Philadelphia, Pennsylvania, described his investigation of lentiviral engineered T cells bearing chimeric receptors that incorporate a “tumor resistance genotype” and strategies to augment their anti-tumor efficacy in the adoptive transfer setting. Specifically, he showed preclinical data from humanized mouse models bearing tumor xenografts that demonstrate the engineered T cells with chimeric receptors should function more effectively than previous trials of adoptive immunotherapy for cancer that have used cytotoxic T lymphocytes, which he hypothesizes fail due to poor trafficking to tumor sites and insufficient effector functions to self antigens. He also described a complementary strategy using artificial antigen presenting cells (aAPC) his laboratory engineered to reprogram T cells, resulting in improved anti-tumor efficacy, and provided data to support the targeting of a surface membrane glycoprotein for the immunotherapy of mesothelioma, ovarian, and pancreatic tumors.
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- Dr. Michel Sadelain of Memorial Sloan-Kettering Cancer Center in New York, New York, discussed his recent report of a novel strategy to improve adoptive T-cell therapy by offsetting the costimulatory deficit that characterizes the tumor microenvironment, one of the factors comprising the “immunosuppressive milieu” that protects tumors from immune destruction. He shared data from his studies of T cells that he has genetically engineered to deliver activating costimulatory signals and are able to stimulate T-cell proliferation in the absence of costimulatory signals from antigen presenting cells. Dr. Sadelain showed how his engineered T cells were very effective at clearing viral infection and rejecting tumor burden in mouse models of cytomegalovirus infection and metastatic prostate cancer.
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- Dr. Cassian Yee of the Fred Hutchinson Cancer Research Center and University of Washington in Seattle, Washington, described his recently published studies in the adoptive transfer of antigen-specific CD4+ T cells in the treatment of patients with metastatic melanoma, and discussed the possible role the CD4+ T cells play in desirable “antigen spreading,” or targeting of tumor-specific antigens other than those selected by Dr. Yee’s team. Dr. Yee also discussed the patient responses, including one complete response and two responses that suggest a dose-dependent effect, and the effect of CD4+ T cell transfer on the CD8+ T-cell response.
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Session VI: Biomarkers and Novel Clinical Parameters in Immunotherapeutic Clinical Trials
- Dr. David Berman of Bristol-Myers Squibb in Princeton, New Jersey, reported data from a randomized, double-blind, placebo-controlled, multi-center, phase II clinical study (CA184-007) of ipilimumab (anti-CTLA-4 antibody) + placebo or prophylactic budesonide, an oral steroid with minimal systemic exposure hypothesized to reduce gastrointestinal immune-related adverse effects (GI irAEs) in patients with unresectable stage III or IV melanoma. Objectives of the biomarker analysis were to assess the effect of ipilimumab on peripheral T-cell populations during the induction phase (i.e., to week 12), and to evaluate potential biomarkers of irAEs, particularly GI.
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- Dr. Sacha Gnjatic of the Ludwig Center for Cancer Research at Memorial Sloan-Kettering Cancer Center in New York, New York, shared data from protein analyses of a comparison of sera from pancreatic and ovarian cancer patients to sera from healthy donors. Dr. Gnjatic described how he used a protein array capable of determining specific reactivity of serum or plasma samples against very large sets of antigens, a process called seromics, to identify a series of immunogenic tumor-specific antigens that could form potential targets for immunotherapies like cancer vaccines, and could also serve as biomarker signatures for cancer diagnosis and prognosis.
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- Dr. Kirsten Hege of Cell Genesys, Inc., in South San Francisco, California, shared data from recent and ongoing clinical trials of GVAX immunotherapy for prostate cancer, a platform composed of two allogeniec prostate carcinoma cells lines that have been modified to secrete granulocyte-macrophage colony stimulating factor (GM-CSF). Dr. Hege described progress made in her efforts to determine patient, disease, and immune response biomarkers in prostate cancer patients, and also described developments in application of the GVAX platform to patients with acute myelogenous leukemia.
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- Dr. Jedd Wolchok of Memorial Sloan-Kettering Cancer Center in New York, New York, showed response and survival data from two phase II clinical trials of ipilimumab (anti-CTLA-4 antibody) that reveal that modified World Health Organization (mWHO) criteria may not fully capture ipilimumab’s clinical benefit. Specifically, Dr. Wolchok showed that mWHO-defined criteria for progressive disease (PD) may not always be a surrogate for drug failure in ipilimumab-treated melanoma patients, as patient response to the immunotherapy requires more time than is allowed by these criteria, which are based on data from chemical and radiological therapies. Dr. Wolchok offered alternative and novel response criteria that may better characterize the clinical activity of ipilimumab and other immunotherapies.
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- Dr. Cécile Gouttefangeas of the University of Tübingen in Tübingen, Germany, described the efforts of the CIMT Immunoguiding Program (CIP) to develop validated, harmonized assays that guarantee robust and reproducible results from immune monitoring of antigen-specific T cell activity during immunotherapeutic clinical trials. She reported success CIP has had in increasing the performance and reducing the inter-center variability of assays among program participants, and shared news of the program’s ongoing progress and future plans toward harmonization of other assays, including HLA-tetramer staining, IFN-gamma ELISPOT, and intra-cellular cytokine staining.
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- Dr. Frederic Lehmann of GlaxoSmithKline (GSK) Biologicals in Rixensart, Belgium, showed data from a phase II study of the MAGE-A3 Antigen-Specific Cancer Immunotherapeutic (ASCI) in patients with progressive, unresectable stage III or stage IV metastatic melanoma, in which gene expression profiling of tumor biopsies prior to immunization was used to identify biomarkers predictive of the observed clinical activity of the MAGE-A3 ASCI. Dr. Lehmann reported that GSK researchers have identified a new and more accurate genetic classifier associated with improved immune response prior to immunization, and showed how this new classifier can be used to select patients with a higher likelihood of clinical response to treatment with the ASCI.
Abstract >> Play Audio (Pt 1) >> Play Audio (Pt 2) >> Download Audio Pt. 1 (.mp3) >> Download Audio Pt. 2 (.mp3) >>
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