Future perspectives in melanoma research : Meeting report from the "Melanoma Bridge". Napoli, December 1st-4th 2015

The sixth "Melanoma Bridge Meeting" took place in Naples, Italy, December 1st-4th, 2015. The four sessions at this meeting were focused on: (1) molecular and immune advances; (2) combination therapies; (3) news in immunotherapy; and 4) tumor microenvironment and biomarkers. Recent advances in tumor biology and immunology has led to the development of new targeted and immunotherapeutic agents that prolong progression-free survival (PFS) and overall survival (OS) of cancer patients. Immunotherapies in particular have emerged as highly successful approaches to treat patients with cancer including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), bladder cancer, and Hodgkin's disease. Specifically, many clinical successes have been using checkpoint receptor blockade, including T cell inhibitory receptors such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death-1 (PD-1) and its ligand PD-L1. Despite demonstrated successes, responses to immunotherapy interventions occur only in a minority of patients. Attempts are being made to improve responses to immunotherapy by developing biomarkers. Optimizing biomarkers for immunotherapy could help properly select patients for treatment and help to monitor response, progression and resistance that are critical challenges for the immuno-oncology (IO) field. Importantly, biomarkers could help to design rational combination therapies. In addition, biomarkers may help to define mechanism of action of different agents, dose selection and to sequence drug combinations. However, biomarkers and assays development to guide cancer immunotherapy is highly challenging for several reasons: (i) multiplicity of immunotherapy agents with different mechanisms of action including immunotherapies that target activating and inhibitory T cell receptors (e.g., CTLA-4, PD-1, etc.); adoptive T cell therapies that include tissue infiltrating lymphocytes (TILs), chimeric antigen receptors (CARs), and T cell receptor (TCR) modified T cells; (ii) tumor heterogeneity including changes in antigenic profiles over time and location in individual patient; and (iii) a variety of immune-suppressive mechanisms in the tumor microenvironment (TME) including T regulatory cells (Treg), myeloid derived suppressor cells (MDSC) and immunosuppressive cytokines. In addition, complex interaction of tumor-immune system further increases the level of difficulties in the process of biomarkers development and their validation for clinical use. Recent clinical trial results have highlighted the potential for combination therapies that include immunomodulating agents such as anti-PD-1 and anti-CTLA-4. Agents targeting other immune inhibitory (e.g., Tim-3) or immune stimulating (e.g., CD137) receptors on T cells and other approaches such as adoptive cell transfer are tested for clinical efficacy in melanoma as well. These agents are also being tested in combination with targeted therapies to improve upon shorter-term responses thus far seen with targeted therapy. Various locoregional interventions that demonstrate promising results in treatment of advanced melanoma are also integrated with immunotherapy agents and the combinations with cytotoxic chemotherapy and inhibitors of angiogenesis are changing the evolving landscape of therapeutic options and are being evaluated to prevent or delay resistance and to further improve survival rates for melanoma patients' population. This meeting's specific focus was on advances in immunotherapy and combination therapy for melanoma. The importance of understanding of melanoma genomic background for development of novel therapies and biomarkers for clinical application to predict the treatment response was an integral part of the meeting. The overall emphasis on biomarkers supports novel concepts toward integrating biomarkers into personalized-medicine approach for treatment of patients with melanoma across the entire spectrum of disease stage. Translation of the knowledge gained from the biology of tumor microenvironment across different tumors represents a bridge to impact on prognosis and response to therapy in melanoma. We also discussed the requirements for pre-analytical and analytical as well as clinical validation process as applied to biomarkers for cancer immunotherapy. The concept of the fit-for-purpose marker validation has been introduced to address the challenges and strategies for analytical and clinical validation design for specific assays.

Journal of translational medicine. 2016 Nov 15*** epublish ***

Paolo A Ascierto, Sanjiv Agarwala, Gerardo Botti, Alessandra Cesano, Gennaro Ciliberto, Michael A Davies, Sandra Demaria, Reinhard Dummer, Alexander M Eggermont, Soldano Ferrone, Yang Xin Fu, Thomas F Gajewski, Claus Garbe, Veronica Huber, Samir Khleif, Michael Krauthammer, Roger S Lo, Giuseppe Masucci, Giuseppe Palmieri, Michael Postow, Igor Puzanov, Ann Silk, Stefani Spranger, David F Stroncek, Ahmad Tarhini, Janis M Taube, Alessandro Testori, Ena Wang, Jennifer A Wargo, Cassian Yee, Hassane Zarour, Laurence Zitvogel, Bernard A Fox, Nicola Mozzillo, Francesco M Marincola, Magdalena Thurin

IRCCS Istituto Nazionale Tumori, Fondazione "G. Pascale", Naples, Italy. ., Department of Oncology and Hematology, St. Luke's University Hospital and Temple University, Bethlehem, PA, USA., IRCCS Istituto Nazionale Tumori, Fondazione "G. Pascale", Naples, Italy., Nanostring Inc., 500 Fairview Avenue N, Seattle, WA, 98109, USA., Division of Cancer Medicine, Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Departments of Radiation Oncology and Pathology, Weill Cornell Medical College, New York, NY, USA., Skin Cancer Unit, Department of Dermatology, University Hospital Zürich, 8091, Zurich, Switzerland., Gustave Roussy Cancer Campus Grand Paris, Villejuif, France., Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA., Departments of Medicine and of Pathology, Immunology and Cancer Program, The University of Chicago Medicine, Chicago, IL, USA., Department of Dermatology, Center for Dermato Oncology, University of Tübingen, Tübingen, Germany., Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Georgia Regents University Cancer Center, Georgia Regents University, Augusta, GA, USA., Yale University School of Medicine, New Haven, CT, USA., Departments of Medicine and Molecular and Medical Pharmacology, David Geffen School of Medicine and Jonsson Comprehensive Cancer Center at the University of California Los Angeles (UCLA), Los Angeles, CA, USA., Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden., Unit of Cancer Genetics, Institute of Biomolecular Chemistry, National Research Council, Sassari, Italy., Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA., Department of Medicine, Early Phase Clinical Trials Program, Roswell Park Cancer Institute, New York, NY, USA., University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA., University of Chicago, Chicago, IL, USA., Cell Processing Section, Department of Transfusion Medicine, Clinical Center, NIH, Bethesda, MD, USA., Departments of Medicine, Immunology and Dermatology, University of Pittsburgh, Pittsburgh, PA, USA., Department of Dermatology, Johns Hopkins University SOM, Baltimore, MD, USA., Istituto Europeo di Oncologia, Milan, Italy., Division of Translational Medicine, Sidra Medical and Research Center, Doha, Qatar., Genomic Medicine and Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Gustave Roussy Cancer Center, U1015 INSERM, Villejuif, France., Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Cancer Center, Providence Portland Medical Center, Portland, OR, USA., Cancer Diagnosis Program, National Cancer Institute, NIH, Bethesda, MD, USA. .