Journal of Immunotoxicology, 2012; 9(3): 231–235 © 2012 Informa Healthcare USA, Inc. ISSN 1547-691X print/ISSN 1547-6901 online DOI: 10.3109/1547691X.2012.686930
ARTICLE INTRO
onference overview: Cancer Immunotherapy and C Immunomonitoring (CITIM): Moving forward Anatoli Malyguine1, Victor Umansky2, Beatrix Kotlan3, Natalia Aptsiauri4, and Michael R. Shurin5 Laboratory of Cell Mediated Immunity, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, USA, 2German Cancer Research Center, Heidelberg, Germany, 3Center of Surgical and Molecular Tumorpathology, National Institute of Oncology, Budapest, Hungary, 4Laboratory of Clinical Analysis and Immunology, University Hospital Virgen de las Nieves, Granada, Spain, and 5Departments of Pathology and Immunology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA 1
Abstract The immune system is a critical element involved in the control of tumor development and progression. While professionals 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 tumor immunosurveillance, but also limit the efficacy of cancer immunotherapy. Meanwhile, the results of recent studies allow the belief that one is on the edge of a real breakthrough in this promising direction in cancer therapy. The 2nd International Conference ‘Cancer Immunotherapy and Immunomonitoring (CITIM)’ was the second 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 Budapest, Hungary, was comprised from 12 plenary sessions, Best Abstract Award session, Poster session, and four Keynote lectures. Outstanding presentations and numerous productive discussions summarized the current place of the field and opened new directions for improving monitoring and therapy for patients with cancer. Keywords: Cancer, immunotherapy, immunomonitoring, tumor immunology
Introduction
its own experimental and clinical experience related to cancer immunotherapy and immunomonitoring. The Conference attracted researchers, clinicians, and biotechnology-related participants from many countries who submitted abstracts, prepared posters, or oral presentations, or participated in various sessions at the meeting. The purpose of the meeting was to serve as a vehicle for interactions between the 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,
The idea of 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 (Frederick, MD) about the uneven expansion of new ideas and the overall progress in the immunological sciences between Western and Eastern European countries. As a result, the 1st International Conference ‘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
Address for Correspondence: Anatoli Malyguine, MD, PhD, Laboratory of Cell Mediated Immunity, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA. Tel: 301-846-1890. Fax: 301-846-6757. E-mail:
[email protected] (Received 16 April 2012; accepted 17 April 2012)
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232 A. Malyguine et al. clinical, laboratory, and medical immunology, and, in particular, the field of cancer immunotherapy and immunomonitoring. After a very successful CITIM meeting in Kiev, the Second International Conference on Cancer Immunotherapy and Immunomonitoring was held on May 2–5, 2011 at the Art’Otel in Budapest, Hungary. The goal of the 2nd CITIM conference was to bring the best world clinicians and scientists to Hungary to participate in plenary sessions, symposia, and educational workshops designed to expose practicing clinicians and researcher from European countries to the newest developments in the field. Lecturers were invited from the US, Israel, Hungary, Germany, France, Italy, Australia, Canada, the UK, and other countries. Special attention was given to novel therapeutic modalities, cancer immunotherapy, stem cells, cancer biomarkers, and immunomonitoring of the immune status of cancer patients. The International and Hungarian Organizing Committees, led by Drs Michael Shurin and Beatrix Kotlan, respectively, organized the Conference. The Conference was sponsored by: • CTL (Cellular Technology Ltd); CTL Europe GmbH, Bonn, Germany; • GTCbio (Global Technology Community), Monrovia, CA, USA; • Nodality Inc. South San Francisco, CA, USA; • Roche (Hungary) Ltd., Budapest, Hungary; • Cancer Immunology and Immunotherapy Journal; • The Journal of Immunotoxicology; • Miltenyi Biotec GmbH, Bergisch Gladbach, Germany; • Epiontis GmbH, Berlin, Germany; • eBioscience, Inc., San Diego, CA, USA; • BioLegend, San Diego, CA, USA; • The Fulbright Program, Hungarian-American Fulbright Commission; and • Ceragem.
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 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. Recently, Sipuleucel-T vaccine (Provenge™, Dendreon Corporation, Seattle, WA) was approved for the treatment of men with castration-resistant metastatic prostate cancer as the first therapeutic cancer vaccine in humans. In addition, the human monoclonal antibody Ipilimumab (Yervoy, Bristol-Myers Squibb, Princeton, NJ) was approved this year for the treatment of advanced melanoma as a second-line therapy. This raised high
expectations among scientists and the general public that immunotherapy would provide a further breakthrough in cancer treatment; however, to date, these expectations have not yet fully materialized. 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 we expect any progress in this area. This area of research attracts attention of a large number of investigators and clinicians. Their work resulted in discovery of a significant number of possible mechanisms of immune non-responsiveness associated with tumor microenvironment. They include, among others: T-cell tolerance; immune suppression caused by regulatory T-cells; myeloid-derived suppressor cells (MDSC); tolerogenic or regulatory dendritic cells (DC) and plasmacytoid DC; regulatory macrophages and B-cells; and specific sub-sets of neutrophils, mast cells, and fibroblasts. Tumor cells, the surrounding stromal cells, and a number of tumor-infiltrating cell populations inhibit natural killer (NK) cell, T-cell, macrophage, and DC function by producing a variety of soluble factors and enzymes, including transforming growth factor (TGF)-β, interleukins (IL)-10, -8, and -13, indoleamine2,3-dioxygenase (IDO), inducible nitrous oxide synthase (iNOS), prostagladin E2 (PGE2), arginase-1 (ARG1), and many other immunomodulating factors. Loss of tumor HLA Class I molecules and low expression of tumorassociated antigens are among other important factors responsible for immune escape and cancer resistance to immunotherapy. There are now a number of molecular pathways implicated in the defective or dis-balanced 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 natural for 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 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 will be a critical element in the success of any potential cancer immunotherapy. The 2nd International Conference ‘Cancer Immunotherapy and Immunomonitoring’, held in Budapest, Hungary, was the second meeting in Eastern Europe to specifically focus on the issue of immune regulation in the tumor milieu, innovative Journal of Immunotoxicology
CITIM conference overview 233 cancer immunotherapy, and immune-monitoring 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. The organizers brought the world best clinicians and scientists to Eastern Europe to participate in plenary sessions and symposia designed to expose basic and clinical immunologists from Eastern European countries to the newest developments in these fields.
Table 1. Topics at the 2nd International Conference on Cancer Immunotherapy and Immuno-monitoring (CITIM-2011). Topics 1. Immunity and the malignant process 2. Regulatory and effector mechanisms in the tumor environment 3. Tumor microenvironment and cancer immunotherapy 4. New insights in cancer immunotherapy 5. Improving cancer immunotherapy: New targets, vaccines, and models 6. Immunotherapeutic approached to pediatric malignancies 7. New aspects of immune regulation 8. Cancer immunotherapy: Lessons and perspectives 9. Cancer immunotherapy: Regulatory and effector cell interactions 10. Cancer immunotherapy: New approaches 11. Novel cancer vaccines in clinical trials 12. Novel cancer vaccines and immunomonitoring in clinical trials
Conference overview The CITIM-2011 Conference covered multiple topics related to modern cancer immune-therapy and immunomonitoring (Table 1). The relatively small size of the CITIM conference cultivated an atmosphere of collegiality and allowed ample opportunity for informal discussions (Figure 1). This format provided an extraordinary opportunity for young investigators to interact with established reputable scientists and maximized the benefits garnered from the conference. At this conference the successes and failures of ongoing and recently completed clinical trials, as well as recent discoveries in basic and pre-clinical research, cellular and molecular mechanisms of immune abnormalities associated with antigen presenting cells, including DC, MDSC, interactions between immune cells and the tumor microenvironment, regulatory T-cells, and many other topics were discussed. Overall, the CITIM-2011 Conference was comprised of 12 plenary sessions (Table 1), Best Abstract Award session, and Poster session. The conference started with opening remarks by Drs Michael Shurin (US), Victor Umansky (Germany), Francesco Marincola (US) and Beatrix Kotlan (Hungary). Dr Dmitry Gabrilovich (H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, US) then presented the Keynote lecture ‘Myeloid suppressor cells in cancer: From biology to immune-therapy’. This was followed by the first plenary session comprised of four talks that were each followed by short discussions. These talks included presentations by Drs Ron Apte (Beer Sheva, Israel; ‘Involvement of the IL-1 family molecules in the malignant process: Basic mechanisms and clinical
Figure 1. Participants of the Second International Conference on Cancer Immunotherapy and Immunomonitoring (CITIM), May 2–5, 2011, Budapest, Hungary. © 2012 Informa Healthcare USA, Inc.
234 A. Malyguine et al. implications’), Philipp Beckhove (Heidelberg, Germany; ‘Regulation of T-cell responses in cancer’), Sattva Neelapu (Houston, TX; ‘Immune checkpoints in lymphoma’), and Francesco Marincola (Bethesda, MD; ‘Melanoma as a model to understand the pathophysiology of rejection’). Keynote lectures in the following days included those by Drs Isaac Witz (Tel Aviv, Israel; ‘Metastasis and the metastatic microenvironment—the case of neuroblastoma and mel-noma’), Malcolm Brenner (Houston, TX; ‘Developing Gene modified T-cells as effective agents for cancer treatment’), and William Murphy (Sacramento, CA; ‘Bystander memory T-cell activation after immunotherapy: How much do we need antigen-specific responses in cancer?’). Several very informative and challenging lectures addressed the important area of the regulatory and effector mechanisms in the tumor environment. These included presentations by Drs Alessandra Cesano (San Francisco, CA; ‘Insight into autoimmune and malignant diseases via Single Cell Network Profiling’), Elena Voronov (Beer Sheva, Israel; ‘Differential role of IL-1α and β in inflammation and cancer’), Suzanne Ostrand-Rosenberg (Baltimore, MD; ‘Immune suppression in the tumor microenvironment’), Luca Vannucci (Prague, Czech Republic; ‘Stroma-proinflammatory elements cross-talk can functionally shape tissue structures influencing the tumor microenvironment’), and Olga Aprelikova (Bethesda, MD; ‘MicroRNA regulation in cancer-associated fibroblasts’). Tumor microenvironment and cancer immunotherapy were discussed in lectures given by Drs Arthur Hurwitz (Frederick, MD; ‘Identifying immunosuppressive targets in prostate cancer to enhance T-cell responses’), Theresa Whiteside (Pittsburgh, PA; ‘Disarming suppressor cells to improve cancer immunotherapy’), Licia Rivoltini (Milan, Italy; ‘Targeting tumor-related immunosuppression in cancer patients’), Michal Baniyash (Jerusalem, Israel; ‘Chronic inflammation-induced immunosuppression: Underlying mechanisms and clinical implications for cancer therapy’), and Éva Rajnavölgyi (Debrecen, Hungary; ‘Dendritic cell sub-sets as targets of anti-tumor immunotherapies’). A number of sessions were dedicated to modern cancer immunotherapy, and different aspects of this topic were discussed in depth by Drs Federico Garrido (Granada, Spain; ‘“Hard” and “Soft” lesions underlying HLA Class I alterations in cancer cells: Implications for cancer immune escape and immunotherapy’), Zoltán Szekanecz (Debrecen, Hungary; ‘Common targets of anti-cancer and anti-inflammatory therapy’), Anahid Jewett (Los Angeles, CA; ‘Natural killer cells preferentially target cancer stem cells: Role of monocytes in protection against NK cell mediated lysis of cancer stem cells’), Paolo Ascierto (Naples, Italy; ‘Immunomodulating antibodies in treatment of melanoma patients: What’s new?’), Angel Porgador (Beer Sheva, Israel; ‘Cancer-associated nuclear factors as ligands to NK receptors’), Eitan Yefenof (Jerusalem, Israel; ‘The molecular rationale of steroid based therapy’), Perthor Straten (Herlev, Denmark; ‘CD8 T-cells in cancer: Killers, supporters, and suppressors’),
Jonathan Weiss (Frederick, MD; ‘Re-structuring tumor/tissue microenvironments by IL-12-dependent interventions’), Jozsef Timar (Budapest, Hungary; ‘Identification and clinical validation of an IFN-resistance gene signature of human melanoma’), Nechama Haran-Ghera (Rehovot, Israel; ‘Chemoimmunotherapy reduces the progression of multiple myeloma: Implication for maintenance therapy’), Michael Shurin (Pittsburgh, PA; ‘Targeting immune regulators in the tumor microenvironment’), Udo S. Gaipl (Erlanger, Germany; ‘Ex vivo- and in vivo-induced dead tumor cells as modulators of anti-tumor responses’), Ramon Kaneno (Botucatu, Brazil; ‘Development of dendritic cell vaccines for colon cancer’), Barbara Seliger (Halle, Germany; ‘Novel insights into the modulation of MHC Class I antigen processing molecules in tumors’), Hideho Okada (Pittsburgh, PA; ‘Promotion of type-1 response for effective brain tumor immunotherapy’), Gurkamal S. Chatta (Pittsburgh, PA; ‘Prostate cancer vaccines’), Thomas Sayers (Frederick, MD; ‘Combining molecular targeting and immunotherapy in cancer’), Mepur H. Ravindranath (Los Angeles, CA; ‘Autologous melanoma vaccines’), Tibor Hajto and Angelika Kirsch (Budapest, Hungary; ‘Immunomodulatory therapy with mistletoe lectins and mistletoe extracts: Pre-clinical and clinical data’), Graham Pawelec (Tübingem, Germany; ‘Immune signatures in long-term melanoma survivors’), Claude Leclerc (Paris, France; ‘Comparative repertoire analysis of tumor-infiltrating effector and regulatory CD4+ T-cells’), Viktor Umansky (Heidelberg, Germany; ‘Overcoming tumor-induced immunosuppression in ret transgenic mouse melanoma model’), Galina Shurin (Pittsburgh, PA; ‘Regulatory dendritic cells in cancer’), Beatrix Kotlan (Budapest, Hungary; ‘Tumor antigen recognition by B-cells in melanoma’), Natalia Aptsiauri (Granada, Spain; ‘Immune escape and resistance to immunotherapy of tumor cells with the β2m gene alterations in recurrent melanoma metastases’), Alexandra Sevko (Heidelberg, Germany; ‘Absence of anti-tumor effect of low-dose cyclophosphamide in ret-transgenic mice due to the accumulation of myeloid-derived suppressor cells’, S. M. Mansour Haeryfar (London, Canada; ‘Rapamycin differentially modulates anti-cancer and alloreactive CD8+ T-cell responses generated in the same host’), Eva Klein (Stockholm, Sweden; ‘Lymphokines can modify the expression of EBV-encoded proteins in B-lymphocytes’), Laszlo Radvanyi (Houston, TX; ‘Melanoma, T-regulatory cells, ICOS and IL-2 therapy: What’s the connection?’), Georgi Guruli (Richmond, VA; ‘The effect of endothelin axis on the function of murine dendritic cells’), and Adit Ben-Baruch (Tel Aviv, Israel; ‘The inflammatory network of cytokines and chemokines in breast cancer: Effects on epithelial-to-mesenchymal transition and beyond’). A plenary session on immunotherapeutic approaches to pediatric malignancies included talks by Drs Gianpietro Dotti (Houston, TX; ‘CAR-modified T-cells for immunotherapy: Enhancement of persistence and trafficking’, Leonid Metelitsa (Houston, TX; ‘Localization Journal of Immunotoxicology
CITIM conference overview 235 and function of NKT cells in neuroblastoma’), John Anderson (London, UK; ‘Human γδ T-cells in cancer immunotherapy; Killing and cross-presenting functions’), and Laurence Cooper (Houston, TX; ‘First-inhuman application of transposon/transposase system to generate T-cells to target malignant B cells’). The Best Abstract Awards speakers included Drs RyuIchiro Hata (Yokosuka, Japan; ‘Production of transgenic mice resistant to cancer cell growth and metastasis’), Galina Kaseko (Eveleigh, Australia; ‘An efficient method of immortalizing rare tumor-infiltrating B-lymphocytes for identification of natural tumor-specific antibody repertoire’), Flavio Salazar-Onfray (Santiago, Chile; ‘Immunological and clinical outcomes of a new DC-based vaccine’), Gerty Schreibelt (Nijmegen, the Netherlands; ‘Vaccination of melanoma patients with monocyte-derived dendritic cells matured with commonly used prophylactic vaccines’), and Fabrizio Mattei (Rome, Italy; ‘IRF-8 controls melanoma progression by regulating cancer and immune cell cross-talk within the tumor microenvironment’). The last session of the Conference covered different aspects of immunological monitoring of cancer clinical trials. Several interesting lectures included those given by Drs Ulrich Hoffmüller (Berlin, Germany; ‘Immunomonitoring using Epigenetic qPCR Assays’), Luigi Buonaguro (Naples, Italy; ‘Ex vivo analysis of idiotypic vaccine for HCV-related lympho-proliferative disorders’), Paul Lehmann (Shaker Heights, IL; ‘Reasons for discrepancy in T-cell monitoring data and clinical outcome: Epitope spreading, T-cell avidity, and effector class’), and Anatoli Malyguine (Frederick, MD; ‘Monitoring CTL activity in cancer vaccine clinical trials’). In concluding remarks, Drs Anatoli Malyguine and Thomas Sayers (both Frederick, 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 the 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; • Integrating the immunological research and educational activities; • Disseminating information and encouraging international collaborations; • Identifying ways to improve the quality of immunological research and clinical care; • Encouraging and providing training and continuous medical and biomedical education; and • Promoting novel preventive, diagnostic, and therapeutic modalities and good patient care. Additional details about the past and future CITIM conferences, CITIM organization, mission, programs, and participants can be found at the CITIM website: www.CancerITIM.org.
Acknowledgments An article based upon original research presented at the 2nd International Conference on Cancer Immunotherapy and Immunomonitoring (CITIM), Budapest, Hungary, May 2011. 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. 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 US Government. NIH Grant RO1 CA84270 (MRS) as well as by the Dr Mildred Scheel Foundation for Cancer Research Grant 108992 (VU) also funded this project. Lastly, the authors would also like to acknowledge the support from the Harry J. Lloyd Charitable Trust for this project.
Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
© 2012 Informa Healthcare USA, Inc.
