Abstract
The immune system is a critical element involved in the control of tumor development and progression. While we have learned how to manipulate the immune system to generate tumor-specific immune responses, cancer immunotherapy has not yet delivered substantial clinical benefits. It has become increasingly clear that tumor-induced abnormalities in the immune system not only hamper natural tumor immune surveillance, but also limit the effect of cancer immunotherapy. If the results of recent studies are of any indication, then we are on the verge of a real breakthrough in our understanding of the immunobiology of tumor-host interactions and of ways to manipulate it. This 1st International Conference on “Cancer Immunotherapy and Immunomonitoring (CITIM)” was the first meeting in Eastern Europe to specifically focus on the issue of immune regulation in the tumor environment, cancer immunotherapy, and immunomonitoring of immunotherapeutic clinical trials. This CITIM Conference held in Kiev, Ukraine, was comprised from eight plenary sessions and two special selected poster presentation sessions. Selected contributions from the participants of the Conference are presented in this issue of the Journal of Immunotoxicology.
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Introduction
The 1st International Conference on “Cancer Immunotherapy and Immunomonitoring” (CITIM) was held in Kiev, Ukraine on May 18–21, 2009. It opened a unique opportunity for the Eastern Europe immunological community to host and interact with leading basic and clinical immunologists from around the world and to introduce its own experimental and clinical experience related to cancer immunotherapy and immunomonitoring. The idea for the CITIM Conference was born in 2008 as a result of multiple discussions between Drs. Michael R. Shurin (Pittsburgh, PA), Victor Umansky (Heidelberg, Germany), and Anatoli Malyguine (SAIC-Frederick, Inc., Frederick, MD) () about the uneven development of new immunological ideas and the overall progress in the immunological sciences between Western and Eastern European countries. Ultimately, Dr. Michael R. Shurin developed the meeting title “Cancer Immunotherapy and Immunomonitoring” (CITIM) and its slogan “Redefining Cancer Therapy”. Dr. Anatoli Malyguine designed the emblem and the Conference brochure. The Internet site for the Conference (www.CancerITIM.org) was developed and managed by Dr. Shurin.
Figure 1. The organizers of the First International Conference “Cancer Immunotherapy and Immunomonitoring” (CITIM-2009). From left to right: Dr. Victor Umansky (Heidelberg, Germany), Dr. Michael R. Shurin (Pittsburgh, PA) and Dr. Anatoli Malyguine (Frederick, MD). Kiev, May 2009.
The Conference attracted almost 200 researchers, clinicians, and biotechnology-related participants from 26 countries who submitted abstracts, prepared posters, or oral presentations, or participated in various sessions at the meeting. The Conference was organized by the International and Ukrainian Organizing Committees led, respectively, by Drs. Michael R. Shurin and Dimitry A. Bazyka. All sessions were held at the “MasterKlass” Corporation Conference Hall in the historical Center of Kiev. The CITIM Conference was sponsored by the Global Technology Company GTCbio, the International Union of Immunological Societies (IUIS), Applied Biosystems, Cellular Technology Limited (Ohio, USA), Springer Science+Business Media, VISICOM (Kiev, Ukraine), the Department of Pathology at the University of Pittsburgh Medical Center, and the Research Institute for Radiation Oncology (Kiev, Ukraine).
The purpose of Cancer Immunotherapy and Immunomonitoring meeting was to foster an exchange of the most recent findings and ideas in tumor immunology and immunotherapy for Ukrainian and Easter European basic and clinical immunologists, clinicians, clinical and post-doctoral fellows, and medical students. This CITIM meeting also provided an environment for stimulating scientific discussions, exchanging ideas, and considering novel clinical diagnostic and therapeutic approaches. By providing Best Abstract and Travel Awards, the CITIM meeting specifically supported creativity and uniqueness in order to inspire a strong basic research portfolio and achieve a rapid translation of insights gleaned from the research laboratories to bedsides worldwide. This CITIM Conference also served as a vessel for interactions between Western scientists and Ukrainian and Easter European scientists with an international array of biomedical scientists and researchers, Primary Care physicians, medical residents and fellows, medical technologists, post-doctoral fellows, medical and graduate students, and anybody who was interested in recent developments in the fields of basic, clinical, laboratory, and medical immunology and, in particular, the field of cancer immunotherapy and immunomonitoring.
Cancer immunotherapy and immunomonitoring
The last decades have been characterized by substantial progress in our understanding of the role of the immune system during tumor progression. There are now a large number of examples (in humans and animals) of how the immune system is able to recognize tumor-associated antigens and eliminate or control tumor cells. As a result, Investigators have learned how to manipulate the immune system to generate tumor-specific immune responses. This raised high expectations among scientists and the general public that immunotherapy would provide a breakthrough in cancer treatment; however, to date, these expectations have not yet fully materialized. Cancer immunotherapy has not yet delivered substantial clinical benefits and it has become increasingly clear that tumor-induced abnormalities in the immune system not only hamper natural tumor immune surveillance, but also limit the efficacy of cancer immunotherapy. Thus, it is critically important to understand the mechanisms of tumor-induced immune suppression and polarization if there is to be any progress in this area. If the results of recent studies are of any indication, then we are on the verge of a real breakthrough in our understanding of the biology of tumor-induced immune abnormalities/immune dysfunction.
This area of research attracts attention of a large number of investigators and clinicians. Their work resulted in discover of a significant number of possible mechanisms proposed to explain tumor-associated immune non- responsiveness. They include, among others: T-cell tolerance; immune suppression caused by regulatory T-cells; myeloid-derived suppressor cells; tolerogenic or suppressor dendritic cells; plasmacytoid dendritic cells; tumor stroma-derived factors; and, soluble cytokines such as transforming growth factor (TGF)-β, interleukin (IL)-10, IL-8, and many others response-modifying proteins. There are now a number of molecular pathways implicated in the defective or unbalanced immune functions observed in a host with cancer. These pathways may represent attractive targets for therapeutic interventions. However, the existence of a variety of different mechanisms has created rather perplexing situations. Some of the proposed mechanisms are in direct contradiction to each other and, for some, biological relevance is not clear. It is obvious that tumor- associated immune dysfunction is a complex process and an existence of many alternative theories is a natural process of any rapidly- developing field. The time has come now to start putting together the pieces of this amazing puzzle. This is important not only for obtaining a better understanding the basic biology of tumor escape from the immune system control but, most importantly, for the development of effective molecular therapeutics to correct the defects in the immune system. An effective immune modulation/ correction therapy will be a critical element in the success of any potential cancer immunotherapy.
The 1st International Conference “Cancer Immunotherapy and Immunomonitoring” in Kiev, Ukraine, was the first meeting in Eastern Europe to specifically focus on the issue of immune regulation in the tumor milieu, innovative cancer immunotherapy, and immunomonitoring of immunotherapeutic clinical trials for cancer patients. In the past, these topics have been discussed in related meetings in other parts of the world, and were largely unreachable for those who live/lived in countries that were within the former Soviet Union or under its influence. In the CITIM, the organizers brought the best world clinicians and scientists to Eastern Europe to participate in plenary sessions and symposia designed to expose basic and clinical immunologists from all parts of Ukraine, former Soviet states, and European countries to the newest developments in these fields. To provide the widest spectrum of voices and experiences, speakers were invited from the United States, Israel, Germany, France, Italy, Spain, Australia, and several other countries.
Conference overview
The CITIM Conference covered multiple topics related to modern cancer immunotherapy and immunomonitoring (). The relatively small size of the CITIM conference cultivated an atmosphere of collegiality and allowed ample opportunity for informal discussions. This format provided an extraordinary opportunity for young investigators to interact with established reputable scientists and maximized the benefits garnered from the conference.
Table 1. Topics of the 1st International Conference “Cancer Immunotherapy and Immunomonitoring” (CITIM-2009).
At this conference, the successes and failures of ongoing and recently completed clinical trials, as well as recent discoveries in basic and preclinical research, cellular and molecular mechanisms of immune abnormalities associated with antigen-presenting cells, (including dendritic cells), immature myeloid suppressive cells, interactions between immune cells and the tumor microenvironment, regulatory T-cells, and many other topics were discussed. The evening sessions were focused on discussions of selected presentations from young scientists and provided them with an exclusive opportunity to discuss their results and ideas with leading experts in the field. Overall, the CITIM Conference was comprised of eight plenary sessions () and two special selected poster presentation sessions —in which six travel awards were presented.
The conference started with opening remarks by Drs. Victor Umansky (Germany) and Volodymyr G. Bebeshko (Ukraine). Dr. Robert Wiltrout, Director of Center for Cancer Research, NCI/NIH, Bethesda, MD, then presented the Keynote lecture on “Immunotherapy of Kidney Cancer by IL-12 based Cytokine Combinations: Mouse to Man”. This was followed by the first plenary session comprised of three talks that were each followed by short discussions.
Of special interest in the following days were “Breakthroughs in CITIM” presentations by Dr. Francesco Marincola (Bethesda, MD; “Vaccines, Immunotherapy and the Immunological Constant of Rejection”) and Dr. Gunther Haemmerling (Heidelberg, Germany; “Overcoming the Tumor Endothelial Barrier for Immunotherapy of Cancer”).
Several very informative and challenging lectures addressed the important area of the involvement of immunity in malignant process and the role of the tumor microenvironment in anti-tumor immunity. These included presentations by Drs. Wolf Hervé Fridman (Paris, France; “In Situ Immune Responses in Human Cancer”), Ron Apte (Beer Sheva, Israel; “IL-1-Mediated Inflammation Versus Immunity in the Malignant Process”), Dimitry Bazyka (Kiev, Ukraine; “Radiation-Induced Cancer: From Molecular Events to Immunomodulation”), Hyam Levitsky (Baltimore, MD; “Quantitative Imaging of Dendritic Cells that Capture and Deliver Tumor-Antigen to Lymph Nodes Following Magnetovaccination”), Catherine Fridman (Paris, France; “New Strategies Used by Human Tumors for Progression and Immune Escape”), Angel Porgador (Beer-Sheva, Israel; “Cancerous Pattern Recognition by Natural Killer Cells”), Volodymyr Bebeshko (Kiev, Ukraine; “The Role of the Bone Marrow Environment in Development and Treatment of Leukemia”), Tom Sayers (Frederick, MD; “Sensitizing Tumor Cells to Immune Responses In Vivo”), Federico Garrido (Granada, Spain; “The Role of Tumor HLA Class I Expression in Cancer Immunotherapy”), Luca Vannucci (Prague, Czech Republic; “Colorectal Carcinoma: Importance of Colonic Immune Environment for Systemic Anti-cancer Response”), Paul Neeson (Melbourne, Australia; “Ex Vivo Transduction and Expansion of Gene-Modified CD8+ T-Cells Generates Cells with an Effector Memory-Like Phenotype and Functional Status”), Eitan Yefenof (Jerusalem, Israel; “Sensitizing Malignant Cells to Glucocorticoid-Induced Apoptosis by PK Inhibitors”), Elena Voronov (Beer Sheva, Israel; “Microenvironmental IL-1 Dictates Tumor Progression and Angiogenesis”), and Udo S. Gaipl (Erlangen, Germany; “The Immunogenicity of Dead Tumor Cells Can be Increased by the Phoshphatidylserine Ligand Annexin V: Implications for Multimodal Cancer Therapies”).
Pre-clinical models of cancer immunotherapy and their prognostic and therapeutic significance were discussed in lectures given by Drs. Viktor Umansky (Heidelberg, Germany; “Transgenic Mouse Tumor Models as a Tool for Development of New Immunotherapies”, Andy Hurwitz (Frederick, MD; “Murine Models to Study T-Cell Responses to Cancer Antigens”), Galina V. Shurin (Pittsburgh, PA; “Phosphatidylserine-Based Ointment for Topical Immunotherapy of Skin Cancer”), Valentin P. Shichkin (Kiev, Ukraine; “Mouse B-Cell Lymphoma as a Model of Brain Tumor: Cross-talk With TCR Clonotypic T-Helper Cells”), and Alexandra Sevko (Kiev, Ukraine; “Combined Low-Dose Cyclophosphomide and TRP-2 Treatment in Mouse Model of Spontaneous Melanoma”).
Several sessions were dedicated to modern cancer immunotherapy, and different aspects of this topic were discussed in depth by Drs. Michael Papamichail (Athens, Greece; “Cellular Therapy Versus Vaccination in Cancer Treatment”), Licia Rivoltini (Milan, Italy; “Can Anti-Tumor Vaccine be More Effective in Early Disease?”), Gurkamal S. Chatta (Pittsburgh, PA; “Vaccines for Prostate Cancer”), Oleg Eremin (Lincoln, UK; “Anti-Cancer Vaccination in Patients with Advanced Malignancy: The Lincolnshire Experience”), Lea Eisenbach (Rehovot, Israel; “Failure of Immunotherapy: Antigen Silencing or Lymphocyte Dysfunction”), Noah Isakov (Beer-Sheva, Israel; “Involvement of PICOT (PKC-Interacting Cousin of Thioredoxin) in Tumor Cell Growth Regulation”), Ronald Gress (Bethesda, MD; “IL-7 and Immunotherapy”, John Morris (Bethesda, MD; “Transforming Growth Factor-β: A Target for Cancer Immunotherapy”), Dmitry Kazansky (Moscow, Russia; “Unconventional Type of APC in Immune Recognition of Allogeneic Tumor Cells”), Vadim Fraifeld (Beer-Sheva, Israel; “The Immune Regulators at the Crossroad of Aging, Longevity and Cancer Networks”), Ilya Korsunskiy (Moscow, Russia; “Severity of GVHD in Leukemia Patients Correlates with the Number of Regulatory CD4+CD25+Foxp3+ T-Cells”), Anatolii Chumak (Kiev, Ukraine; “Persisting Infections in Oncologic and Non-Tumor Pathology”), Claude Leclerc (Paris, France; “Treatment of Large Established Tumors by Combined Immunotherapy Targeting Adaptive and Regulatory Responses”), Qing Yi (Houston, TX; “Immunomodulators for Therapy of Multiple Myeloma”), Michael R. Shurin (Pittsburgh, PA; “Combination of Non-Cytotoxic Chemomodulation and Dendritic Cell Vaccines for Cancer Treatment”, Svetlana Sidorenko (Kiev, Ukraine) “CD150 — A Novel Target for Cancer Immunotherapy”), and Natalia Aptsiauri (Granada, Spain; “Restoration of Tumor HLA Class I Expression for Improving Cancer Immunotherapy”).
The last session of the Conference covered different aspects of immunological monitoring of cancer clinical trials. Several interesting lectures included those given by Drs. Claire Horlock (London, UK; “The Use of HLA Class I or Class II Mono-Specific Antigen-Presenting Cells in the Optimization of ELISPOT and Other Immunoassays”), Jon K. Sherlock (San Francisco, CA; “Gene Expression and Non-Coding RNA Quantitation in Cancer: Biomarker Determination, Disease Stratification and Prediction”), Paul V. Lehmann (Shaker Heights, OH; “ELISPOT Assays for Delineation of T-Cell Effector Classes and Activation States”), Alina Romanenko (Kiev, Ukraine; “Urinary Bladder Carcinogenesis After the Chernobyl Accident in Ukraine”), Bartek Zuber (Nacka, Sweden; “Immunomonitoring Using the ELISpot and FluoroSpot Assays”; and Anatoli Malyguine (Frederick, MD) “Immunological Monitoring of Cancer Vaccine Clinical Trials: What to Measure, How and Why?”).
In his concluding remarks, Dr. Francesco Marincola (Bethesda, MD) gave a brief overview of the Conference and underlined its scientific, clinical and educational importance, as well as the high quality and collaborative nature.
Summary
The field of tumor immunology is one of scientifically, economically, and socially important significance due to increasing role it plays in cancer therapy. Although cancer immunotherapy has not yet delivered substantial clinical benefits, the results of recent studies allow us to believe that we are on the edge of a real breakthrough in this promising direction in cancer therapy.
The CITIM Conference clearly demonstrated that by supporting open communication between scientists and clinicians and sharing ideas, hypotheses and plans we could definitely accelerate the progress in immunological research and eventually change and often save cancer patients’ life. We truly believe that “REDEFINING CANCER THERAPY” can be achieved by:
Promoting basic and clinical research in tumor immunology;
Disseminating information and encouraging international collaborations in immunology;
Integrating the immunological research and educational activities;
Encouraging and providing training and continuous medical and biomedical education; and,
Promoting novel preventive, diagnostic, immunotherapeutic and immunomonitoring modalities in all countries.
Acknowledgments
This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E (to A.M.) and NIH grant CA84270 (to M.R.S.). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.
Declaration of interest: The authors report no conflict of interest. The authors alone are responsible for the content and writing of the paper.