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Melanoma: HELP
Articles from Qatar
Based on 23 articles published since 2008
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These are the 23 published articles about Melanoma that originated from Qatar during 2008-2019.
 
+ Citations + Abstracts
1 Review Assessing Tumor-Infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method from the International Immuno-Oncology Biomarkers Working Group: Part 2: TILs in Melanoma, Gastrointestinal Tract Carcinomas, Non-Small Cell Lung Carcinoma and Mesothelioma, Endometrial and Ovarian Carcinomas, Squamous Cell Carcinoma of the Head and Neck, Genitourinary Carcinomas, and Primary Brain Tumors. 2017

Hendry, Shona / Salgado, Roberto / Gevaert, Thomas / Russell, Prudence A / John, Tom / Thapa, Bibhusal / Christie, Michael / van de Vijver, Koen / Estrada, M V / Gonzalez-Ericsson, Paula I / Sanders, Melinda / Solomon, Benjamin / Solinas, Cinzia / Van den Eynden, Gert G G M / Allory, Yves / Preusser, Matthias / Hainfellner, Johannes / Pruneri, Giancarlo / Vingiani, Andrea / Demaria, Sandra / Symmans, Fraser / Nuciforo, Paolo / Comerma, Laura / Thompson, E A / Lakhani, Sunil / Kim, Seong-Rim / Schnitt, Stuart / Colpaert, Cecile / Sotiriou, Christos / Scherer, Stefan J / Ignatiadis, Michail / Badve, Sunil / Pierce, Robert H / Viale, Giuseppe / Sirtaine, Nicolas / Penault-Llorca, Frederique / Sugie, Tomohagu / Fineberg, Susan / Paik, Soonmyung / Srinivasan, Ashok / Richardson, Andrea / Wang, Yihong / Chmielik, Ewa / Brock, Jane / Johnson, Douglas B / Balko, Justin / Wienert, Stephan / Bossuyt, Veerle / Michiels, Stefan / Ternes, Nils / Burchardi, Nicole / Luen, Stephen J / Savas, Peter / Klauschen, Frederick / Watson, Peter H / Nelson, Brad H / Criscitiello, Carmen / O'Toole, Sandra / Larsimont, Denis / de Wind, Roland / Curigliano, Giuseppe / André, Fabrice / Lacroix-Triki, Magali / van de Vijver, Mark / Rojo, Federico / Floris, Giuseppe / Bedri, Shahinaz / Sparano, Joseph / Rimm, David / Nielsen, Torsten / Kos, Zuzana / Hewitt, Stephen / Singh, Baljit / Farshid, Gelareh / Loibl, Sibylle / Allison, Kimberly H / Tung, Nadine / Adams, Sylvia / Willard-Gallo, Karen / Horlings, Hugo M / Gandhi, Leena / Moreira, Andre / Hirsch, Fred / Dieci, Maria V / Urbanowicz, Maria / Brcic, Iva / Korski, Konstanty / Gaire, Fabien / Koeppen, Hartmut / Lo, Amy / Giltnane, Jennifer / Rebelatto, Marlon C / Steele, Keith E / Zha, Jiping / Emancipator, Kenneth / Juco, Jonathan W / Denkert, Carsten / Reis-Filho, Jorge / Loi, Sherene / Fox, Stephen B. ·Departments of *Pathology §§§Medical Oncology, Peter MacCallum Cancer Centre, Melbourne †The Sir Peter MacCallum Department of Oncology Departments of **Pathology ∥∥Medicine, University of Melbourne ¶¶Department of Anatomical Pathology, Royal Melbourne Hospital, Parkville #Department of Anatomical Pathology, St Vincent's Hospital Melbourne, Fitzroy ††Department of Medical Oncology, Austin Health ‡‡Olivia Newton-John Cancer Research Institute, Heidelberg §§School of Cancer Medicine, La Trobe University, Bundoora §§§§§Centre for Clinical Research and School of Medicine, The University of Queensland ∥∥∥∥∥Pathology Queensland, Royal Brisbane and Women's Hospital, Brisbane §§§§§§§§§§The Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst ∥∥∥∥∥∥∥∥∥∥Australian Clinical Labs, Bella Vista ‡‡‡‡‡‡‡‡‡‡‡‡Directorate of Surgical Pathology, SA Pathology §§§§§§§§§§§§Discipline of Medicine, Adelaide University, Adelaide, Australia ***********Department of Surgical Oncology, Netherlands Cancer Institute †††††††††††††Department of Pathology ##Divisions of Diagnostic Oncology & Molecular Pathology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, The Netherlands ###Université Paris-Est ****INSERM, UMR 955 ††††Département de pathologie, APHP, Hôpital Henri-Mondor, Créteil ∥∥∥∥∥∥∥∥∥Service de Biostatistique et d'Epidémiologie, Gustave Roussy, CESP, Inserm U1018, Université-Paris Sud, Université Paris-Saclay ¶¶¶¶¶¶¶¶¶¶INSERM Unit U981, and Department of Medical Oncology, Gustave Roussy, Villejuif ##########Faculté de Médecine, Université Paris Sud, Kremlin-Bicêtre †††††††Department of Surgical Pathology and Biopathology, Jean Perrin Comprehensive Cancer Centre ‡‡‡‡‡‡‡University of Auvergne UMR1240, Clermont-Ferrand, France ‡‡‡‡Department of Medicine, Clinical Division of Oncology §§§§Institute of Neurology, Comprehensive Cancer Centre Vienna, Medical University of Vienna, Vienna ††††††††††††††Institute of Pathology, Medical University of Graz, Austria ∥∥∥∥European Institute of Oncology ¶¶¶¶School of Medicine ######Department of Pathology, Istituto Europeo di Oncologia, University of Milan, Milan ¶¶¶¶¶¶¶¶¶¶¶¶¶Department of Surgery, Oncology and Gastroenterology, University of Padova #############Medical Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy †††††Molecular Oncology Group, Vall d'Hebron Institute of Oncology, Barcelona †††††††††††Pathology Department, IIS-Fundacion Jimenez Diaz, UAM, Madrid, Spain §Department of Pathology and TCRU, GZA ¶¶¶Department of Pathology, GZA Ziekenhuizen, Antwerp ∥Laboratory of Experimental Urology, Department of Development and Regeneration, KU Leuven ‡‡‡‡‡‡‡‡‡‡‡Department of Pathology, University Hospital Leuven, Leuven, Belgium ¶Department of Pathology, AZ Klina, Brasschaat ††††††Department of Pathology, GZA Ziekenhuizen, Sint-Augustinus, Wilrijk ∥∥∥Molecular Immunology Unit ‡‡‡‡‡‡Department of Medical Oncology, Institut Jules Bordet, Université Libre de Bruxelles ‡Breast Cancer Translational Research Laboratory/Breast International Group, Institut Jules Bordet **************European Organisation for Research and Treatment of Cancer (EORTC) Headquarters *******Department of Pathology, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium §§§§§§§Department of Surgery, Kansai Medical School, Hirakata, Japan #######Severance Biomedical Science Institute and Department of Medical Oncology, Yonsei University College of Medicine, Seoul, South Korea ∥∥∥∥∥∥∥∥Tumor Pathology Department, Maria Sklodowska-Curie Memorial Cancer Center ¶¶¶¶¶¶¶¶Institute of Oncology, Gliwice Branch, Gliwice, Poland ‡‡‡‡‡‡‡‡‡‡‡‡‡‡Pathology and Tissue Analytics, Roche Innovation Centre Munich, Penzberg †††††††††Institute of Pathology, Charité Universitätsmedizin Berlin ‡‡‡‡‡‡‡‡‡VMscope GmbH, Berlin ¶¶¶¶¶¶¶¶¶German Breast Group GmbH, Neu-Isenburg, Germany **********Trev & Joyce Deeley Research Centre, British Columbia Cancer Agency ††††††††††Department of Biochemistry and Microbiology, University of Victoria, Victoria Departments of ‡‡‡‡‡‡‡‡‡‡Medical Genetics #########Pathology and Laboratory Medicine ¶¶¶¶¶¶¶¶¶¶¶Department of Pathology and Laboratory Medicine, Genetic Pathology Evaluation Centre, University of British Columbia, Vancouver, BC ###########Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Canada §§§§§§§§§§§Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Doha, Qatar ‡‡‡‡‡‡‡‡Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center §§§§§§§§Warren Alpert Medical School of Brown University, Providence ¶¶¶¶¶National Surgical Adjuvant Breast and Bowel Project Operations Center/NRG Oncology, Pittsburgh, PA †††Breast Cancer Research Program, Vanderbilt Ingram Cancer Center, Vanderbilt University Departments of ‡‡‡Pathology, Microbiology and Immunology ########Department of Medicine, Vanderbilt University Medical Centre *********Vanderbilt Ingram Cancer Center, Nashville §§§§§§§§§Department of Pathology, Yale University School of Medicine, New Haven ∥∥∥∥∥∥∥∥∥∥∥Department of Oncology, Montefiore Medical Centre, Albert Einstein College of Medicine ∥∥∥∥∥∥∥Montefiore Medical Center ¶¶¶¶¶¶¶The Albert Einstein College of Medicine, Bronx, NY ********Department of Pathology, Brigham and Women's Hospital #####Cancer Research Institute and Department of Pathology, Beth Israel Deaconess Cancer Center ******Harvard Medical School ¶¶¶¶¶¶¶¶¶¶¶¶Division of Hematology-Oncology, Beth Israel Deaconess Medical Center ††††††††Department of Cancer Biology ‡‡‡‡‡‡‡‡‡‡‡‡‡Dana-Farber Cancer Institute, Boston, MA ∥∥∥∥∥∥∥∥∥∥∥∥∥Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO ‡‡‡‡‡Department of Cancer Biology, Mayo Clinic, Jacksonville, FL ∥∥∥∥∥∥Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, IN ¶¶¶¶¶¶Cancer Immunotherapy Trials Network, Central Laboratory and Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA ††††††††††††Department of Pathology, New York University Langone Medical Centre ############New York University Medical School *************Perlmutter Cancer Center §§§§§§§§§§§§§Pulmonary Pathology, New York University Center for Biospecimen Research and Development, New York University ***************Department of Pathology, Memorial Sloan-Kettering Cancer Center ####Departments of Radiation Oncology and Pathology, Weill Cornell Medicine, New York, NY *****Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, TX ∥∥∥∥∥∥∥∥∥∥∥∥Pathology Department, Stanford University Medical Centre, Stanford ∥∥∥∥∥∥∥∥∥∥∥∥∥∥Department of Pathology, Stanford University, Palo Alto ***Department of Pathology, School of Medicine, University of California, San Diego §§§§§§§§§§§§§§Research Pathology, Genentech Inc., South San Francisco, CA *************Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda ¶¶¶¶¶¶¶¶¶¶¶¶¶¶Translational Sciences, MedImmune, Gaithersberg, MD §§§§§§Academic Medical Innovation, Novartis Pharmaceuticals Corporation, East Hanover ##############Translational Medicine, Merck & Co. Inc., Kenilworth, NJ. ·Adv Anat Pathol · Pubmed #28777143.

ABSTRACT: Assessment of the immune response to tumors is growing in importance as the prognostic implications of this response are increasingly recognized, and as immunotherapies are evaluated and implemented in different tumor types. However, many different approaches can be used to assess and describe the immune response, which limits efforts at implementation as a routine clinical biomarker. In part 1 of this review, we have proposed a standardized methodology to assess tumor-infiltrating lymphocytes (TILs) in solid tumors, based on the International Immuno-Oncology Biomarkers Working Group guidelines for invasive breast carcinoma. In part 2 of this review, we discuss the available evidence for the prognostic and predictive value of TILs in common solid tumors, including carcinomas of the lung, gastrointestinal tract, genitourinary system, gynecologic system, and head and neck, as well as primary brain tumors, mesothelioma and melanoma. The particularities and different emphases in TIL assessment in different tumor types are discussed. The standardized methodology we propose can be adapted to different tumor types and may be used as a standard against which other approaches can be compared. Standardization of TIL assessment will help clinicians, researchers and pathologists to conclusively evaluate the utility of this simple biomarker in the current era of immunotherapy.

2 Review Harnessing the immune system for the treatment of melanoma: current status and future prospects. 2016

Guennoun, Andrea / Sidahmed, Heba / Maccalli, Cristina / Seliger, Barbara / Marincola, Francesco M / Bedognetti, Davide. ·a Division of Translational Medicine , Research Branch, Sidra Medical and Research Center , Doha , Qatar. · b Tumor Biology, Immunology and Therapy Section, Division of Translational Medicine , Research Branch, Sidra Medical and Research Center , Doha , Qatar. · c Institute of Medical Immunology , Martin Luther University Halle-Wittenberg , Halle , Germany. · d Office of the Chief Research Officer (CRO) , Research Branch, Sidra Medical and Research Center , Doha , Qatar. ·Expert Rev Clin Immunol · Pubmed #27070898.

ABSTRACT: When malignant melanoma is diagnosed early, surgical resection is the intervention of choice and is often curative, but many patients present with unresectable disease at later stages. Due to its complex etiology paired with well-documented chemoresistance and high metastatic potential, patients with advanced melanoma had a poor prognosis, and the treatment of this disease remained unsatisfactory for many years. Recently, targeted therapy, immune checkpoint inhibition, or combinatory approaches have revolutionized the therapeutic options of melanoma allowing considerable improvement in disease control and survival. In this review we will summarize these novel therapeutic strategies with particular focus on combinatory immunotherapies and further discuss recent data derived from immunogenomic studies and potential options to improve the therapeutic efficacy of immune modulatory approaches.

3 Review Single versus combination immunotherapy drug treatment in melanoma. 2016

Grimaldi, Antonio Maria / Marincola, Francesco M / Ascierto, Paolo Antonio. ·a Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy , Istituto Nazionale Tumori Fondazione G. Pascale , Napoli , Italy. · b Sidra Medical and Research Centre , Doha , Qatar. ·Expert Opin Biol Ther · Pubmed #26642234.

ABSTRACT: INTRODUCTION: The advent of new immunotherapies for the treatment of metastatic melanoma has resulted in various novel combination strategies. Because of their distinct modes of action, different immunotherapies have been investigated in combination with one another, as well as combined with targeted therapies and other treatment modalities. AREAS COVERED: Anti-CTLA-4 and anti-PD-1 treatments enhance antitumor immunity through complementary and non-redundant mechanisms. The combination of the anti-CTLA-4 agent ipilimumab and the anti-PD-1 agent nivolumab has been shown to improve progression-free survival and objective response rate compared with either agent alone as monotherapy in patients with advanced melanoma. However, the combination was associated with significant toxicity, with around one-third of patients discontinuing treatment as a result. The sequential use of nivolumab and ipilimumab was associated with similar outcomes and comparable toxicity to concurrent therapy. Clinical trials assessing various combinations of immunomodulating antibodies are ongoing or planned. Ipilimumab and pembrolizumab have also been investigated in combination with the oncolytic virus, talimogene laherparepvec (T-VEC), with promising results. In addition, immunotherapies have also been combined with chemotherapy, radiotherapy and electrochemotherapy. EXPERT OPINION: Investigation of combination approaches represents the start of a new story that begins with melanoma treatment and expands to embrace other solid and hematological cancers.

4 Review Prognostic and predictive immune gene signatures in breast cancer. 2015

Bedognetti, Davide / Hendrickx, Wouter / Marincola, Francesco M / Miller, Lance D. ·aTumor Biology, Immunology and Therapy Section, Division of Translational Medicine, Research Branch bOffice of the Chief Research Officer (CRO), Research Branch, Sidra Medical and Research Center, Doha, Qatar cDepartment of Cancer Biology, Wake Forest School of Medicine dThe Comprehensive Cancer Center of Wake Forest University, Winston Salem, North Carolina, USA. ·Curr Opin Oncol · Pubmed #26418235.

ABSTRACT: PURPOSE OF REVIEW: Here, we focus on molecular biomarkers derived from transcriptomic studies to summarize the recent advances in our understanding of the mechanisms associated with differential prognosis and treatment outcome in breast cancer. RECENT FINDINGS: Breast cancer is certainly immunogenic; yet it has been historically resistant to immunotherapy. In the past few years, refined immunotherapeutic manipulations have been shown to be effective in a significant proportion of cancer patients. For example, drugs targeting the PD-1 immune checkpoint have been proven to be an effective therapeutic approach in several solid tumors including melanoma and lung cancer. Very recently, the activity of such therapeutics has also been demonstrated in breast cancer patients. Pari passu with the development of novel immune modulators, the transcriptomic analysis of human tumors unveiled unexpected and paradoxical relationships between cancer cells and immune cells. SUMMARY: This review examines our understanding of the molecular pathways associated with intratumoral immune response, which represents a critical step for the implementation of stratification strategies toward the development of personalized immunotherapy of breast cancer.

5 Review 2015: The Year of Anti-PD-1/PD-L1s Against Melanoma and Beyond. 2015

Ascierto, Paolo A / Marincola, Francesco M. ·Istituto Nazionale Tumori, Fondazione "G. Pascale", Napoli, Italy. · Sidra Medical and Research Centre, Doha, Qatar. ·EBioMedicine · Pubmed #26137543.

ABSTRACT: -- No abstract --

6 Clinical Trial Intratumoral interferon-gamma increases chemokine production but fails to increase T cell infiltration of human melanoma metastases. 2016

Mauldin, Ileana S / Wages, Nolan A / Stowman, Anne M / Wang, Ena / Smolkin, Mark E / Olson, Walter C / Deacon, Donna H / Smith, Kelly T / Galeassi, Nadedja V / Chianese-Bullock, Kimberly A / Dengel, Lynn T / Marincola, Francesco M / Petroni, Gina R / Mullins, David W / Slingluff, Craig L. ·Department of Surgery/Division of Surgical Oncology and the Human Immune Therapy Center, Cancer Center, University of Virginia, 1352 Jordan Hall, P.O. Box 801457, Charlottesville, VA, 22908, USA. · Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA. · Research Branch, Sidra Medical and Research Center, Doha, Qatar. · Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA. · Department of Surgery/Division of Surgical Oncology and the Human Immune Therapy Center, Cancer Center, University of Virginia, 1352 Jordan Hall, P.O. Box 801457, Charlottesville, VA, 22908, USA. cls8h@virginia.edu. ·Cancer Immunol Immunother · Pubmed #27522581.

ABSTRACT: INTRODUCTION: Optimal approaches to induce T cell infiltration of tumors are not known. Chemokines CXCL9, CXCL10, and CXCL11 support effector T cell recruitment and may be induced by IFN. This study tests the hypothesis that intratumoral administration of IFNγ will induce CXCL9-11 and will induce T cell recruitment and anti-tumor immune signatures in melanoma metastases. PATIENTS AND METHODS: Nine eligible patients were immunized with a vaccine comprised of 12 class I MHC-restricted melanoma peptides and received IFNγ intratumorally. Effects on the tumor microenvironment were evaluated in sequential tumor biopsies. Adverse events (AEs) were recorded. T cell responses to vaccination were assessed in PBMC by IFNγ ELISPOT assay. Tumor biopsies were evaluated for immune cell infiltration, chemokine protein expression, and gene expression. RESULTS: Vaccination and intratumoral administration of IFNγ were well tolerated. Circulating T cell responses to vaccine were detected in six of nine patients. IFNγ increased production of chemokines CXCL10, CXCL11, and CCL5 in patient tumors. Neither vaccination alone, nor the addition of IFNγ promoted immune cell infiltration or induced anti-tumor immune gene signatures. CONCLUSION: The melanoma vaccine induced circulating T cell responses, but it failed to infiltrate metastases, thus highlighting the need for combination strategies to support T cell infiltration. A single intratumoral injection of IFNγ induced T cell-attracting chemokines; however, it also induced secondary immune regulation that may paradoxically limit immune infiltration and effector functions. Alternate dosing strategies or additional combinatorial treatments may be needed to promote trafficking and retention of tumor-reactive T cells in melanoma metastases.

7 Article Role of epithelial-mesenchymal transition involved molecules in the progression of cutaneous melanoma. 2017

Murtas, Daniela / Maxia, Cristina / Diana, Andrea / Pilloni, Luca / Corda, Claudia / Minerba, Luigi / Tomei, Sara / Piras, Franca / Ferreli, Caterina / Perra, Maria Teresa. ·Department of Biomedical Sciences, Section of Cytomorphology, University of Cagliari, Cittadella Universitaria, S.P. 8, Monserrato, 09042, Cagliari, Italy. murtas@unica.it. · Department of Biomedical Sciences, Section of Cytomorphology, University of Cagliari, Cittadella Universitaria, S.P. 8, Monserrato, 09042, Cagliari, Italy. · Department of Surgical Sciences, Section of Pathological Anatomy, University of Cagliari, Via Ospedale, 09124, Cagliari, Italy. · Department of Medical Sciences and Public Health, University of Cagliari, Via Ospedale, 09124, Cagliari, Italy. · Omics Core and Biorepository, Sidra Medical and Research Center, Doha, Qatar. · Department of Medical Sciences and Public Health, Section of Dermatology, University of Cagliari, Via Ospedale, 09124, Cagliari, Italy. ·Histochem Cell Biol · Pubmed #28828681.

ABSTRACT: Epithelial-mesenchymal transition (EMT) has been suggested to have a driving role in the acquisition of a metastatic potential by melanoma cells. Important hallmarks of EMT include both E-cadherin downregulation and increased expression of N-cadherin. This switch in distinct classes of adhesion molecules leads melanoma cells to lose contact with adjacent keratinocytes and interact instead with stromal fibroblasts and endothelial cells, thus promoting dermal and vascular melanoma invasion. Consequently, tumor cells migrate to distant host tissues and establish metastases. A key regulator in the induction of EMT in melanoma is the Notch1 signaling pathway that, when activated, is prompt to upregulate N-cadherin expression. By means of this strategy, melanoma cells gain enhanced survival, proliferation and invasion properties, driving the tumor toward a more aggressive phenotype. On the basis of these statements, the present study aimed to investigate the possible association between N-cadherin and Notch1 presence in primary cutaneous melanomas and lymph node metastases. Our results from immunohistochemical analysis confirmed a positive correlation between N-cadherin and Notch1 presence in the same tumor samples. Moreover, this study highlighted that a concomitant high expression of N-cadherin and Notch1, both in primary lesions and in lymph node metastases, predicts an adverse clinical outcome in melanoma patients. Therefore, N-cadherin and Notch1 co-presence can be monitored as a predictive factor in early- and advanced-stage melanomas and open additional therapeutic targets for the restraint of melanoma metastasis.

8 Article Protein kinase C inhibitor Gö6976 but not Gö6983 induces the reversion of E- to N-cadherin switch and metastatic phenotype in melanoma: identification of the role of protein kinase D1. 2017

Merzoug-Larabi, Messaouda / Spasojevic, Caroline / Eymard, Marianne / Hugonin, Caroline / Auclair, Christian / Karam, Manale. ·LBPA, ENS Cachan, CNRS, Université Paris-Saclay, Cachan, 94235, France. · Département de Génétique, Institut Curie, Unité de Pharmacogénomique, Paris, 75248, France. · LBPA, ENS Cachan, CNRS, Université Paris-Saclay, Cachan, 94235, France. manale.karam@gmail.com. · Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha, 5825, Qatar. manale.karam@gmail.com. ·BMC Cancer · Pubmed #28056869.

ABSTRACT: BACKGROUND: Melanoma is a highly metastatic type of cancer that is resistant to all standard anticancer therapies and thus has a poor prognosis. Therefore, metastatic melanoma represents a significant clinical problem and requires novel and effective targeted therapies. The protein kinase C (PKC) family comprises multiple isoforms of serine/threonine kinases that possess distinct roles in cancer development and progression. In this study, we determined whether inhibition of PKC could revert a major process required for melanoma progression and metastasis; i.e. the E- to N-cadherin switch. METHODS: The cadherin switch was analyzed in different patient-derived primary tumors and their respective metastatic melanoma cells to determine the appropriate cellular model (aggressive E-cadherin-negative/N-cadherin-positive metastasis-derived melanoma cells). Next, PKC inhibition in two selected metastatic melanoma cell lines, was performed by using either pharmacological inhibitors (Gö6976 and Gö6983) or stable lentiviral shRNA transduction. The expression of E-cadherin and N-cadherin was determined by western blot. The consequences of cadherin switch reversion were analyzed: cell morphology, intercellular interactions, and β-catenin subcellular localization were analyzed by immunofluorescence labeling and confocal microscopy; cyclin D1 expression was analyzed by western blot; cell metastatic potential was determined by anchorage-independent growth assay using methylcellulose as semi-solid medium and cell migration potential by wound healing and transwell assays. RESULTS: Gö6976 but not Gö6983 reversed the E- to N-cadherin switch and as a consequence induced intercellular interactions, profound morphological changes from elongated mesenchymal-like to cuboidal epithelial-like shape, β-catenin translocation from the nucleus to the plasma membrane inhibiting its oncogenic function, and reverting the metastatic potential of the aggressive melanoma cells. Comparison of the target spectrum of these inhibitors indicated that these observations were not the consequence of the inhibition of conventional PKCs (cPKCs), but allowed the identification of a novel serine/threonine kinase, i.e. protein kinase Cμ, also known as protein kinase D1 (PKD1), whose specific inhibition allows the reversion of the metastatic phenotype in aggressive melanoma. CONCLUSION: In conclusion, our study suggests, for the first time, that while cPKCs don't embody a pertinent therapeutic target, inhibition of PKD1 represents a novel attractive approach for the treatment of metastatic melanoma.

9 Article IL2 Variant Circumvents ICOS+ Regulatory T-cell Expansion and Promotes NK Cell Activation. 2016

Sim, Geok Choo / Liu, Chengwen / Wang, Ena / Liu, Hui / Creasy, Caitlin / Dai, Zhimin / Overwijk, Willem W / Roszik, Jason / Marincola, Francesco / Hwu, Patrick / Grimm, Elizabeth / Radvanyi, Laszlo. ·Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. laszlo.radvanyi@emdserono.com gcsim1@yahoo.co.uk. · Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. · Division of Translational Medicine, Sidra Medical and Research Center, Doha, Qatar. · Cell Processing Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland. ·Cancer Immunol Res · Pubmed #27697858.

ABSTRACT: Clinical responses to high-dose IL2 therapy are limited due to selective expansion of CD4

10 Article Topical treatment of melanoma metastases with imiquimod, plus administration of a cancer vaccine, promotes immune signatures in the metastases. 2016

Mauldin, Ileana S / Wages, Nolan A / Stowman, Anne M / Wang, Ena / Olson, Walter C / Deacon, Donna H / Smith, Kelly T / Galeassi, Nadedja / Teague, Jessica E / Smolkin, Mark E / Chianese-Bullock, Kimberly A / Clark, Rachael A / Petroni, Gina R / Marincola, Francesco M / Mullins, David W / Slingluff, Craig L. ·Division of Surgical Oncology, Department of Surgery, Human Immune Therapy Center, Cancer Center, University of Virginia, 1352 Jordan Hall, P.O. Box 801457, Charlottesville, VA, 22908, USA. · Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA. · Research Branch, Sidra Medical and Research Center, Doha, Qatar. · Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. · Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, USA. · Department of Microbiology and Immunology, Norris-Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA. · Division of Surgical Oncology, Department of Surgery, Human Immune Therapy Center, Cancer Center, University of Virginia, 1352 Jordan Hall, P.O. Box 801457, Charlottesville, VA, 22908, USA. cls8h@virginia.edu. ·Cancer Immunol Immunother · Pubmed #27522582.

ABSTRACT: INTRODUCTION: Infiltration of cancers by T cells is associated with improved patient survival and response to immune therapies; however, optimal approaches to induce T cell infiltration of tumors are not known. This study was designed to assess whether topical treatment of melanoma metastases with the TLR7 agonist imiquimod plus administration of a multipeptide cancer vaccine will improve immune cell infiltration of melanoma metastases. PATIENTS AND METHODS: Eligible patients were immunized with a vaccine comprised of 12 melanoma peptides and a tetanus toxoid-derived helper peptide, and imiquimod was applied topically to metastatic tumors daily. Adverse events were recorded, and effects on the tumor microenvironment were evaluated from sequential tumor biopsies. T cell responses were assessed by IFNγ ELIspot assay and T cell tetramer staining. Patient tumors were evaluated for immune cell infiltration, cytokine and chemokine production, and gene expression. RESULTS AND CONCLUSIONS: Four eligible patients were enrolled, and administration of imiquimod and vaccination were well tolerated. Circulating T cell responses to the vaccine was detected by ex vivo ELIspot assay in 3 of 4 patients. Treatment of metastases with imiquimod induced immune cell infiltration and favorable gene signatures in the patients with circulating T cell responses. This study supports further study of topical imiquimod combined with vaccines or other immune therapies for the treatment of melanoma.

11 Article Mitochondrial Membrane Potential Identifies Cells with Enhanced Stemness for Cellular Therapy. 2016

Sukumar, Madhusudhanan / Liu, Jie / Mehta, Gautam U / Patel, Shashank J / Roychoudhuri, Rahul / Crompton, Joseph G / Klebanoff, Christopher A / Ji, Yun / Li, Peng / Yu, Zhiya / Whitehill, Greg D / Clever, David / Eil, Robert L / Palmer, Douglas C / Mitra, Suman / Rao, Mahadev / Keyvanfar, Keyvan / Schrump, David S / Wang, Ena / Marincola, Francesco M / Gattinoni, Luca / Leonard, Warren J / Muranski, Pawel / Finkel, Toren / Restifo, Nicholas P. ·Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. Electronic address: sukumarm2@mail.nih.gov. · Center for Molecular Medicine, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. · Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. · Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA; NIH-Georgetown University Graduate Partnership Program, Georgetown University Medical School, Washington, DC 20057, USA. · Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA; Clinical Investigator Development Program, NCI, NIH, Bethesda, MD 20892, USA. · Experimental Transplantation and Immunology Branch, NCI, NIH, Bethesda, MD 20892, USA. · Laboratory of Molecular Immunology and the Immunology Center, NHLBI, NIH, Bethesda, MD 20892, USA. · Hematology Branch, NHLBI, NIH, Bethesda, MD 20892, USA. · Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA; Medical Scientist Training Program, The Ohio State University College of Medicine, Columbus, OH 43210, USA. · Thoracic and GI Oncology Branch, NCI, NIH, Bethesda, MD 20892, USA. · Sidra Medical and Research Center, Doha, Qatar. · Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. Electronic address: restifo@nih.gov. ·Cell Metab · Pubmed #26674251.

ABSTRACT: Long-term survival and antitumor immunity of adoptively transferred CD8(+) T cells is dependent on their metabolic fitness, but approaches to isolate therapeutic T cells based on metabolic features are not well established. Here we utilized a lipophilic cationic dye tetramethylrhodamine methyl ester (TMRM) to identify and isolate metabolically robust T cells based on their mitochondrial membrane potential (ΔΨm). Comprehensive metabolomic and gene expression profiling demonstrated global features of improved metabolic fitness in low-ΔΨm-sorted CD8(+) T cells. Transfer of these low-ΔΨm T cells was associated with superior long-term in vivo persistence and an enhanced capacity to eradicate established tumors compared with high-ΔΨm cells. Use of ΔΨm-based sorting to enrich for cells with superior metabolic features was observed in CD8(+), CD4(+) T cell subsets, and long-term hematopoietic stem cells. This metabolism-based approach to cell selection may be broadly applicable to therapies involving the transfer of HSC or lymphocytes for the treatment of viral-associated illnesses and cancer.

12 Article Cish actively silences TCR signaling in CD8+ T cells to maintain tumor tolerance. 2015

Palmer, Douglas C / Guittard, Geoffrey C / Franco, Zulmarie / Crompton, Joseph G / Eil, Robert L / Patel, Shashank J / Ji, Yun / Van Panhuys, Nicholas / Klebanoff, Christopher A / Sukumar, Madhusudhanan / Clever, David / Chichura, Anna / Roychoudhuri, Rahul / Varma, Rajat / Wang, Ena / Gattinoni, Luca / Marincola, Francesco M / Balagopalan, Lakshmi / Samelson, Lawrence E / Restifo, Nicholas P. ·National Cancer Institute, Bethesda, MD 20892 palmerd@mail.nih.gov restifo@nih.gov. · National Cancer Institute, Bethesda, MD 20892. · National Institute of Allergy and Infectious Disease, Bethesda, MD 20892. · National Cancer Institute, Bethesda, MD 20892 Medical Scientist Training Program, The Ohio State University College of Medicine, Columbus, OH 43210. · Sidra Medical and Research Center, Doha, Qatar. ·J Exp Med · Pubmed #26527801.

ABSTRACT: Improving the functional avidity of effector T cells is critical in overcoming inhibitory factors within the tumor microenvironment and eliciting tumor regression. We have found that Cish, a member of the suppressor of cytokine signaling (SOCS) family, is induced by TCR stimulation in CD8(+) T cells and inhibits their functional avidity against tumors. Genetic deletion of Cish in CD8(+) T cells enhances their expansion, functional avidity, and cytokine polyfunctionality, resulting in pronounced and durable regression of established tumors. Although Cish is commonly thought to block STAT5 activation, we found that the primary molecular basis of Cish suppression is through inhibition of TCR signaling. Cish physically interacts with the TCR intermediate PLC-γ1, targeting it for proteasomal degradation after TCR stimulation. These findings establish a novel targetable interaction that regulates the functional avidity of tumor-specific CD8(+) T cells and can be manipulated to improve adoptive cancer immunotherapy.

13 Article What's new in melanoma? Combination! 2015

Ascierto, Paolo A / Marincola, Francesco M / Atkins, Michael B. ·Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale", Via Mariano Semmola, 80131, Naples, Italy. paolo.ascierto@gmail.com. · Sidra Medical and Research Centre, Doha, Qatar. fmarincola@sidra.org. · Oncology and Medicine, Georgetown-Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, 3970 Reservoir Rd NW, Washington, DC, 20057, USA. mba41@georgetown.edu. ·J Transl Med · Pubmed #26141621.

ABSTRACT: Melanoma was again a focus of attention at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting, in particular the use of combination treatment strategies involving immunotherapies and/or targeted agents. New data on targeted therapies confirmed previous findings, with combined BRAF inhibitor (vemurafenib) plus MEK inhibitor (cobimetinib) improving progression-free survival (PFS) compared to vemurafenib monotherapy in patients with BRAFV600 mutation-positive tumors (CoBRIM trial). Positive results were also seen with combined dabrafenib and trametinib in patients with BRAF V600E/K metastatic melanoma and encorafenib plus binimetinib in BRAFV600-mutant cutaneous melanoma. Even more interesting news centered on the use of combination immunotherapy, in particular the randomized, double-blind CheckMate 067 study in which median PFS with nivolumab plus ipilimumab was 11.5 months, compared to 2.9 months with ipilimumab alone (HR 0.42) and 6.9 months with nivolumab alone (HR 0.57). Of interest, in patients with ≥5% PD-L1 expression, median PFS was 14 months with the combination or with nivolumab alone compared with 3.9 months in the ipilimumab group, while in the PD-L1 negative cohort, the combination remained superior to both monotherapies. Given that combination therapy was accompanied by a high occurrence of side-effects, this raises the suggestion that combination therapy might be reserved for PD-L1 negative patients only, with PD-L1 positive patients achieving the same benefit from nivolumab monotherapy. However, overall survival data are awaited and the equivalence of single agent to the combination remains unconvincing. Interesting data were also reported on the combination of T-VEC (talimogene laherparepvec) with ipilimumab, and the anti-PD-1 agent MEDI4736 (durvolumab) combined with dabrafenib plus trametinib. Emerging data also suggested that predictive markers based on immunoprofiling and mismatch repair deficiency may be of clinical use. In conclusion, the use of combination approaches to treat patients with melanoma, as well as other cancers, is no longer a just a wish for the future but is today a clinical reality with a rapidly growing evidence-base. Moreover, the most exciting consideration is that this is far from the end of the story, but rather a fantastic introduction.

14 Article Ran signaling in melanoma: implications for the development of alternative therapeutic strategies. 2015

Caputo, Emilia / Wang, Ena / Valentino, Anna / Crispi, Stefania / De Giorgi, Valeria / Fico, Annalisa / Ficili, Bartolomea / Capone, Mariaelena / Anniciello, AnnaMaria / Cavalcanti, Ernesta / Botti, Gerardo / Mozzillo, Nicola / Ascierto, Paolo A / Marincola, Francesco M / Travali, Salvatore. ·Institute of Genetics and Biophysics -I.G.B. A. Buzzati-Traverso- CNR, Naples I-80131, Italy; Dipartimento di Scienze Biomediche, Università degli Studi di Catania, Catania I-95124, Italy. Electronic address: emilia.caputo@igb.cnr.it. · Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine (DTM), Clinical Center (CC), Center for Human Immunology (CHI), National Institutes of Health (NIH), Bethesda, MD, United States; Sidra Medical and Research Center, Doha, Qatar. · Institute of Genetics and Biophysics -I.G.B. A. Buzzati-Traverso- CNR, Naples I-80131, Italy. · Institute of Genetics and Biophysics -I.G.B. A. Buzzati-Traverso- CNR, Naples I-80131, Italy; Institute of Biosciences and BioResources-IBB, CNR, Naples I-8013, Italy. · Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine (DTM), Clinical Center (CC), Center for Human Immunology (CHI), National Institutes of Health (NIH), Bethesda, MD, United States. · Dipartimento di Scienze Biomediche, Università degli Studi di Catania, Catania I-95124, Italy. · Istituto Nazionale Tumori Fondazione G. Pascale, Naples I-80131, Italy. ·Cancer Lett · Pubmed #25444926.

ABSTRACT: We performed a comparative study between two human metastatic melanoma cell lines (A375 and 526), and melanocytes (FOM78) by gene expression profiling and pathway analysis, using Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA) software. Genes involved in Ran signaling were significantly over-represented (p ≤ 0.001) and up-regulated in melanoma cells. A melanoma-associated molecular pathway was identified, where Ran, Aurora Kinase A (AurkA) and TERT were up-regulated, while c-myc and PTEN were down-regulated. A consistent high Ran and AurkA gene expression was detected in about 48% and 53%, respectively, of 113 tissue samples from metastatic melanoma patients. AurkA down-regulation was observed in melanoma cells, by Ran knockdown, suggesting AurkA protein is a Ran downstream target. Furthermore, AurkA inhibition, by exposure of melanoma cells to MLN8054, a specific AurKA inhibitor, induced apoptosis in both melanoma cell lines and molecular alterations in the IPA-identified molecular pathway. These alterations differed between cell lines, with an up-regulation of c-myc protein level observed in 526 cells and a slight reduction seen in A375 cells. Moreover, Ran silencing did not affect the A375 invasive capability, while it was enhanced in 526 cells, suggesting that Ran knockdown, by AurkA down-regulation, resulted in a Ran-independent enhanced melanoma cell invasion. Finally, AurK A inhibition induced a PTEN up-regulation and its action was independent of B-RAF mutational status. These findings provide insights relevant for the development of novel therapeutic strategies as well as for a better understanding of mechanisms underlying therapy resistance in melanoma.

15 Article Akt inhibition enhances expansion of potent tumor-specific lymphocytes with memory cell characteristics. 2015

Crompton, Joseph G / Sukumar, Madhusudhanan / Roychoudhuri, Rahul / Clever, David / Gros, Alena / Eil, Robert L / Tran, Eric / Hanada, Ken-Ichi / Yu, Zhiya / Palmer, Douglas C / Kerkar, Sid P / Michalek, Ryan D / Upham, Trevor / Leonardi, Anthony / Acquavella, Nicolas / Wang, Ena / Marincola, Francesco M / Gattinoni, Luca / Muranski, Pawel / Sundrud, Mark S / Klebanoff, Christopher A / Rosenberg, Steven A / Fearon, Douglas T / Restifo, Nicholas P. ·National Cancer Institute (NCI), NIH, Bethesda, Maryland. Department of Surgery, University of California Los Angeles, Los Angeles, California. Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom. joe.crompton@nih.gov sukumarm2@mail.nih.gov restifo@nih.gov. · National Cancer Institute (NCI), NIH, Bethesda, Maryland. joe.crompton@nih.gov sukumarm2@mail.nih.gov restifo@nih.gov. · National Cancer Institute (NCI), NIH, Bethesda, Maryland. · National Cancer Institute (NCI), NIH, Bethesda, Maryland. Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom. · Metabolon Incorporated, Durham, North Carolina. · Sidra Medical and Research Centre, Doha, Qatar. · Department of Cancer Biology, The Scripps Research Institute, Jupiter, Florida. · National Cancer Institute (NCI), NIH, Bethesda, Maryland. Clinical Investigator Development Program, NCI, NIH, Bethesda, Maryland. · Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom. ·Cancer Res · Pubmed #25432172.

ABSTRACT: Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) results in complete regression of advanced cancer in some patients, but the efficacy of this potentially curative therapy may be limited by poor persistence of TIL after adoptive transfer. Pharmacologic inhibition of the serine/threonine kinase Akt has recently been shown to promote immunologic memory in virus-specific murine models, but whether this approach enhances features of memory (e.g., long-term persistence) in TIL that are characteristically exhausted and senescent is not established. Here, we show that pharmacologic inhibition of Akt enables expansion of TIL with the transcriptional, metabolic, and functional properties characteristic of memory T cells. Consequently, Akt inhibition results in enhanced persistence of TIL after adoptive transfer into an immunodeficient animal model and augments antitumor immunity of CD8 T cells in a mouse model of cell-based immunotherapy. Pharmacologic inhibition of Akt represents a novel immunometabolomic approach to enhance the persistence of antitumor T cells and improve the efficacy of cell-based immunotherapy for metastatic cancer.

16 Article Type I cytokines synergize with oncogene inhibition to induce tumor growth arrest. 2015

Acquavella, Nicolas / Clever, David / Yu, Zhiya / Roelke-Parker, Melody / Palmer, Douglas C / Xi, Liqiang / Pflicke, Holger / Ji, Yun / Gros, Alena / Hanada, Ken-Ichi / Goldlust, Ian S / Mehta, Gautam U / Klebanoff, Christopher A / Crompton, Joseph G / Sukumar, Madhusudhanan / Morrow, James J / Franco, Zulmarie / Gattinoni, Luca / Liu, Hui / Wang, Ena / Marincola, Francesco / Stroncek, David F / Lee, Chyi-Chia R / Raffeld, Mark / Bosenberg, Marcus W / Roychoudhuri, Rahul / Restifo, Nicholas P. ·Surgery Branch, Center for Cancer Research, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland. restifo@nih.gov nacquavella@miami.edu cleverdc@mail.nih.gov. · Surgery Branch, Center for Cancer Research, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland. · Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland. · Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland. · Division of Preclinical Innovation, U.S. National Institutes of Health Chemical Genomics Center, National Center for Advancing Translational Sciences, Rockville, Maryland. Cancer Research United Kingdom Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, United Kingdom. · Surgery Branch, Center for Cancer Research, National Cancer Institute (NCI), US National Institutes of Health (NIH), Bethesda, Maryland. Cancer Research United Kingdom Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, United Kingdom. · Department of Pathology, Case Western Reserve University, Cleveland, Ohio. Department of Genetics & Genome Sciences Case Western Reserve University, Cleveland, Ohio. · Sidra Medical and Research Center, Doha, Qatar. · Department of Transfusion Medicine, Cell Processing Section, National Institutes of Health (NIH), Bethesda, Maryland. · Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut. ·Cancer Immunol Res · Pubmed #25358764.

ABSTRACT: Both targeted inhibition of oncogenic driver mutations and immune-based therapies show efficacy in treatment of patients with metastatic cancer, but responses can be either short lived or incompletely effective. Oncogene inhibition can augment the efficacy of immune-based therapy, but mechanisms by which these two interventions might cooperate are incompletely resolved. Using a novel transplantable BRAF(V600E)-mutant murine melanoma model (SB-3123), we explored potential mechanisms of synergy between the selective BRAF(V600E) inhibitor vemurafenib and adoptive cell transfer (ACT)-based immunotherapy. We found that vemurafenib cooperated with ACT to delay melanoma progression without significantly affecting tumor infiltration or effector function of endogenous or adoptively transferred CD8(+) T cells, as previously observed. Instead, we found that the T-cell cytokines IFNγ and TNFα synergized with vemurafenib to induce cell-cycle arrest of tumor cells in vitro. This combinatorial effect was recapitulated in human melanoma-derived cell lines and was restricted to cancers bearing a BRAF(V600E) mutation. Molecular profiling of treated SB-3123 indicated that the provision of vemurafenib promoted the sensitization of SB-3123 to the antiproliferative effects of T-cell effector cytokines. The unexpected finding that immune cytokines synergize with oncogene inhibitors to induce growth arrest has major implications for understanding cancer biology at the intersection of oncogenic and immune signaling and provides a basis for design of combinatorial therapeutic approaches for patients with metastatic cancer.

17 Article The immune-related role of BRAF in melanoma. 2015

Tomei, Sara / Bedognetti, Davide / De Giorgi, Valeria / Sommariva, Michele / Civini, Sara / Reinboth, Jennifer / Al Hashmi, Muna / Ascierto, Maria Libera / Liu, Qiuzhen / Ayotte, Ben D / Worschech, Andrea / Uccellini, Lorenzo / Ascierto, Paolo A / Stroncek, David / Palmieri, Giuseppe / Chouchane, Lotfi / Wang, Ena / Marincola, Francesco M. ·Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and Trans-NIH Center for Human Immunology (CHI), National Institutes of Health, Bethesda, MD 20892, USA; Department of Genetic Medicine, Weill Cornell Medical College in Qatar, PO Box 24144, Doha, Qatar; Sidra Medical and Research Center, P.O. Box 26999, Doha, Qatar. Electronic address: stomei@sidra.org. · Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and Trans-NIH Center for Human Immunology (CHI), National Institutes of Health, Bethesda, MD 20892, USA; Sidra Medical and Research Center, P.O. Box 26999, Doha, Qatar. · Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and Trans-NIH Center for Human Immunology (CHI), National Institutes of Health, Bethesda, MD 20892, USA. · Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and Trans-NIH Center for Human Immunology (CHI), National Institutes of Health, Bethesda, MD 20892, USA; Department of Biomedical Sciences for Health, Università degli Studi di Milano, Milan, Italy. · Cell Processing Section, Department of Transfusion Medicine, Clinical Center and Trans-NIH Center for Human Immunology (CHI), National Institutes of Health, Bethesda, MD 20892, USA. · Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and Trans-NIH Center for Human Immunology (CHI), National Institutes of Health, Bethesda, MD 20892, USA; Department of Biochemistry, Biocenter, University of Wuerzburg, Wuerzburg 97074, Germany; Genelux Corporation, San Diego Science Center, San Diego 92109, USA. · Sidra Medical and Research Center, P.O. Box 26999, Doha, Qatar. · Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and Trans-NIH Center for Human Immunology (CHI), National Institutes of Health, Bethesda, MD 20892, USA; Center of Excellence for Biomedical Research (CEBR), University of Genoa, Italy. · Department of Biology, Northern Michigan University, Marquette, MI, USA. · Department of Genetic Medicine, Weill Cornell Medical College in Qatar, PO Box 24144, Doha, Qatar. · Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and Trans-NIH Center for Human Immunology (CHI), National Institutes of Health, Bethesda, MD 20892, USA; Institute of Infectious and Tropical Diseases, University of Milan, L. Sacco Hospital, Milan, Italy. · Istituto Nazionale Tumori Fondazione "G. Pascale", Via G. Semmola, Naples, Italy. · Institute of Biomolecular Chemistry, National Research Council, Sassari, Italy. ·Mol Oncol · Pubmed #25174651.

ABSTRACT: BACKGROUND: The existence of a dichotomy between immunologically active and quiescent tumor phenotypes has been recently recognized in several types of cancer. The activation of a Th1 type of immune signature has been shown to confer better prognosis and likelihood to respond to immunotherapy. However, whether such dichotomy depends on the genetic make-up of individual cancers is not known yet. BRAF and NRAS mutations are commonly acquired during melanoma progression. Here we explored the role of BRAF and NRAS mutations in influencing the immune phenotype based on a classification previously identified by our group. METHODS: One-hundred-thirteen melanoma metastases underwent microarray analysis and BRAF and NRAS genotyping. Allele-specific PCR was also performed in order to exclude low-frequency mutations. RESULTS: Comparison between BRAF and NRAS mutant versus wild type samples identified mostly constituents or regulators of MAPK and related pathways. When testing gene lists discriminative of BRAF, NRAS and MAPK alterations, we found that 112 BRAF-specific transcripts were able to distinguish the two immune-related phenotypes already described in melanoma, with the poor phenotype associated mostly with BRAF mutation. Noteworthy, such association was stronger in samples displaying low BRAF mRNA expression. However, when testing NRAS mutations, we were not able to find the same association. CONCLUSION: This study suggests that BRAF mutation-related specific transcripts associate with a poor phenotype in melanoma and provide a nest for further investigation.

18 Article Activation and propagation of tumor-infiltrating lymphocytes on clinical-grade designer artificial antigen-presenting cells for adoptive immunotherapy of melanoma. 2014

Forget, Marie-Andrée / Malu, Shruti / Liu, Hui / Toth, Christopher / Maiti, Sourindra / Kale, Charuta / Haymaker, Cara / Bernatchez, Chantale / Huls, Helen / Wang, Ena / Marincola, Francesco M / Hwu, Patrick / Cooper, Laurence J N / Radvanyi, Laszlo G. ·*Department of Melanoma Medical Oncology †Division of Pediatrics, MD Anderson Cancer Center, Houston, TX ‡Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center and trans-NIH Center for Human Immunology, National Institutes of Health, Bethesda, MD ∥Lion Biotechnologies, Woodland Hills, CA §Sidra Medical and Research Hospital, Doha, Qatar. ·J Immunother · Pubmed #25304728.

ABSTRACT: PURPOSE: Adoptive cell therapy with autologous tumor-infiltrating lymphocytes (TIL) is a therapy for metastatic melanoma with response rates of up to 50%. However, the generation of the TIL transfer product is challenging, requiring pooled allogeneic normal donor peripheral blood mononuclear cells (PBMC) used in vitro as "feeders" to support a rapid-expansion protocol. Here, we optimized a platform to propagate TIL to a clinical scale using K562 cells genetically modified to express costimulatory molecules such as CD86, CD137-ligand, and membrane-bound IL-15 to function as artificial antigen-presenting cells (aAPC) as an alternative to using PBMC feeders. EXPERIMENTAL DESIGN: We used aAPC or γ-irradiated PBMC feeders to propagate TIL and measured rates of expansion. The activation and differentiation state was evaluated by flow cytometry and differential gene expression analyses. Clonal diversity was assessed on the basis of the pattern of T-cell receptor usage. T-cell effector function was measured by evaluation of cytotoxic granule content and killing of target cells. RESULTS: The aAPC propagated TIL at numbers equivalent to that found with PBMC feeders, whereas increasing the frequency of CD8 T-cell expansion with a comparable effector-memory phenotype. mRNA profiling revealed an upregulation of genes in the Wnt and stem-cell pathways with the aAPC. The aAPC platform did not skew clonal diversity, and CD8 T cells showed comparable antitumor function as those expanded with PBMC feeders. CONCLUSIONS: TIL can be rapidly expanded with aAPC to clinical scale generating T cells with similar phenotypic and effector profiles as with PBMC feeders. These data support the clinical application of aAPC to manufacture TIL for the treatment of melanoma.

19 Article Direct T cell-tumour interaction triggers TH1 phenotype activation through the modification of the mesenchymal stromal cells transcriptional programme. 2014

Jin, P / Civini, S / Zhao, Y / De Giorgi, V / Ren, J / Sabatino, M / Jin, J / Wang, H / Bedognetti, D / Marincola, F / Stroncek, D. ·Cell Processing Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA. · Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA. · 1] Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA [2] Sidra Medical and Research Centre, Doha, Qatar. ·Br J Cancer · Pubmed #24809778.

ABSTRACT: BACKGROUND: Mesenchymal stromal cells (MSCs) are heterogeneous cells with immunoregulatory and wound-healing properties. In cancer, they are known to be an essential part of the tumour microenvironment. However, their role in tumour growth and rejection remains unclear. To investigate this, we co-cultured human MSCs, tumour infiltrating lymphocytes (TIL), and melanoma cells to investigate the role of MSCs in the tumour environment. METHODS: Mesenchymal stromal cells were co-cultured with melanoma antigen-specific TIL that were stimulated either with HLA-A*0201(+) melanoma cells or with a corresponding clone that had lost HLA-A*0201 expression. RESULTS: Activated TIL induced profound pro-inflammatory gene expression signature in MSCs. Analysis of culture supernatant found that MSCs secreted pro-inflammatory cytokines, including TH1 cytokines that have been previously associated with immune-mediated antitumor responses. In addition, immunohistochemical analysis on selected markers revealed that the same activated MSCs secreted both the TH1 cytokine (interleukin-12) and indoleamine 2,3 dioxygenase (IDO), a classical immunosuppressive factor. CONCLUSIONS: This study reflected that the plasticity of MSCs is highly dependent upon microenvironment conditions. Tumour-activated TIL induced TH1 phenotype change in MSCs that is qualitatively similar to the previously described immunologic constant of rejection signature observed during immune-mediated, tissue-specific destruction. This response may be responsible for the in loco amplification of antigen-specific anti-cancer immune response.

20 Article Longitudinal study of recurrent metastatic melanoma cell lines underscores the individuality of cancer biology. 2014

Pos, Zoltan / Spivey, Tara L / Liu, Hui / Sommariva, Michele / Chen, Jinguo / Wunderlich, John R / Parisi, Giulia / Tomei, Sara / Ayotte, Ben D / Stroncek, David F / Malek, Joel A / Robbins, Paul F / Rivoltini, Licia / Maio, Michele / Chouchane, Lotfi / Wang, Ena / Marincola, Francesco M. ·Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA; Hungarian Academy of Sciences-Semmelweis University "Lendület" Experimental and Translational Immunomics Research Group, Budapest, Hungary; Department of Genetics, Cell, and Immunobiology, Semmelweis University, Budapest, Hungary. · Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA; Clinical Research Training Program (CRTP), National Institutes of Health, Bethesda, Maryland, USA; Department of General Surgery, Rush University Medical Center, Chicago, Illinois, USA. · Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA. · Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA; Department of Biomedical Sciences for Health, Universita' degli Studi di Milano, Milan, Italy. · Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. · Cancer Bioimmunotherapy Unit, Centro di Riferimento Oncologico, Aviano, Italy. · Department of Genetic Medicine, Weill Cornell Medical College in Qatar, Education City, Doha, Qatar. · Department of Biology, Northern Michigan University, Marquette, Michigan, USA. · Cell Processing Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA. · Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. · Weill Cornell Medical College in Qatar, Education City, Doha, Qatar. · Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA; Research Branch, Sidra Medical and Research Centre, Doha, Qatar. Electronic address: fmarincola@sidra.org. ·J Invest Dermatol · Pubmed #24270663.

ABSTRACT: Recurrent metastatic melanoma provides a unique opportunity to analyze disease evolution in metastatic cancer. Here, we followed up eight patients with an unusually prolonged history of metastatic melanoma, who developed a total of 26 recurrences over several years. Cell lines derived from each metastasis were analyzed by comparative genomic hybridization and global transcript analysis. We observed that conserved, patient-specific characteristics remain stable in recurrent metastatic melanoma even after years and several recurrences. Differences among individual patients exceeded within-patient lesion variability, both at the DNA copy number (P<0.001) and RNA gene expression level (P<0.001). Conserved patient-specific traits included expression of several cancer/testis antigens and the c-kit proto-oncogene throughout multiple recurrences. Interestingly, subsequent recurrences of different patients did not display consistent or convergent changes toward a more aggressive disease phenotype. Finally, sequential recurrences of the same patient did not descend progressively from each other, as irreversible mutations such as homozygous deletions were frequently not inherited from previous metastases. This study suggests that the late evolution of metastatic melanoma, which markedly turns an indolent disease into a lethal phase, is prone to preserve case-specific traits over multiple recurrences and occurs through a series of random events that do not follow a consistent stepwise process.

21 Unspecified Future perspectives in melanoma research : Meeting report from the "Melanoma Bridge". Napoli, December 1st-4th 2015. 2016

Ascierto, Paolo A / Agarwala, Sanjiv / Botti, Gerardo / Cesano, Alessandra / Ciliberto, Gennaro / Davies, Michael A / Demaria, Sandra / Dummer, Reinhard / Eggermont, Alexander M / Ferrone, Soldano / Fu, Yang Xin / Gajewski, Thomas F / Garbe, Claus / Huber, Veronica / Khleif, Samir / Krauthammer, Michael / Lo, Roger S / Masucci, Giuseppe / Palmieri, Giuseppe / Postow, Michael / Puzanov, Igor / Silk, Ann / Spranger, Stefani / Stroncek, David F / Tarhini, Ahmad / Taube, Janis M / Testori, Alessandro / Wang, Ena / Wargo, Jennifer A / Yee, Cassian / Zarour, Hassane / Zitvogel, Laurence / Fox, Bernard A / Mozzillo, Nicola / Marincola, Francesco M / Thurin, Magdalena. ·IRCCS Istituto Nazionale Tumori, Fondazione "G. Pascale", Naples, Italy. paolo.ascierto@gmail.com. · Unit of Medical Oncology and Innovative Therapy, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale", Via Mariano Semmola, 80131, Naples, Italy. paolo.ascierto@gmail.com. · 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. · University Paris XI, Kremlin Bicêtre, France. · Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Cancer Center, Providence Portland Medical Center, Portland, OR, USA. · Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR, USA. · Cancer Diagnosis Program, National Cancer Institute, NIH, Bethesda, MD, USA. thurinm@mail.nih.gov. ·J Transl Med · Pubmed #27846884.

ABSTRACT: 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.

22 Unspecified Immunoscore and Immunoprofiling in cancer: an update from the melanoma and immunotherapy bridge 2015. 2016

Galon, J / Fox, B A / Bifulco, C B / Masucci, G / Rau, T / Botti, G / Marincola, F M / Ciliberto, G / Pages, F / Ascierto, P A / Capone, M. ·Laboratory of Integrative Cancer Immunology, INSERM UMRS1138 Cordeliers Research Center, University Pierre et Marie Curie, Paris 6, 15 Rue de l'Ecole de Medecine, 75006, Paris, France. · University Paris Descartes, 45 Rue Saints Pères, 75006, Paris, France. · Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Cancer Center, Providence Portland Medical Center, Portland, OR, 97213, USA. · Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, OR, 97239, USA. · Department of Pathology, Providence Portland Medical Center, Portland, OR, 97213, USA. · Department of Oncology-Pathology, The Karolinska Hospital, Stockholm, Sweden. · Institute of Pathology, University of Bern, Bern, Switzerland. · Unit of Pathology, IRCCS, Istituto Nazionale Tumori, Fondazione "G. Pascale", Naples, Italy. · Sidra Medical and Research Center, Doha, Qatar. · IRCCS, Istituto Nazionale Tumori, Fondazione "G. Pascale",Scentific Directorate, Naples, Italy. · Laboratory of Integrative Cancer Immunology, INSERM UMRS1138, Cordeliers Research Center, 15 Rue de l'Ecole de Medecine, 75006, Paris, France. · Centre de Recherche des Cordeliers, University Pierre et Marie Curie, Paris 6, 15 Rue de l'Ecole de Medecine, 75006, Paris, France. · Immunomonitoring Platform, Laboratory of Immunology, Georges Pompidou European Hospital, 20-40 Rue Leblanc, 75015, Paris, France. · Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy, Istituto Nazionale Tumori, Fondazione "G. Pascale", Naples, Italy. · Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy, Istituto Nazionale Tumori, Fondazione "G. Pascale", Naples, Italy. marilenacapone@gmail.com. ·J Transl Med · Pubmed #27650038.

ABSTRACT: The fifth "Melanoma Bridge Meeting" took place in Naples, December 1-5th, 2015. The main topics discussed at this meeting were: Molecular and Immuno advances, Immunotherapies and Combination Therapies, Tumor Microenvironment and Biomarkers and Immunoscore. The natural history of cancer involves interactions between the tumor and the immune system of the host. The immune infiltration at the tumor site may be indicative of host response. Significant correlations were shown between the levels of immune cell infiltration in tumors and patient's clinical outcome. Moreover, incredible progress comes from the discovery of mutation-encoded tumor neoantigens. In fact, as tumors grow, they acquire mutations that are able to influence the response of patients to immune checkpoint inhibitors. It has been demonstrated that sensitivity to PD-1 and CTLA-4 blockade in patients with advanced NSCLC and melanoma was enhanced in tumors enriched for clonal neoantigens. The road ahead is still very long, but the knowledge of the mechanisms of immune escape, the study of tumor neo-antigens as well as of tumor microenvironment and the development of new immunotherapy strategies, will make cancer a more and more treatable disease.

23 Unspecified Future perspectives in melanoma research: meeting report from the "Melanoma Bridge": Napoli, December 3rd-6th 2014. 2015

Ascierto, Paolo A / Atkins, Michael / Bifulco, Carlo / Botti, Gerardo / Cochran, Alistair / Davies, Michael / Demaria, Sandra / Dummer, Reinhard / Ferrone, Soldano / Formenti, Silvia / Gajewski, Thomas F / Garbe, Claus / Khleif, Samir / Kiessling, Rolf / Lo, Roger / Lorigan, Paul / Arthur, Grant Mc / Masucci, Giuseppe / Melero, Ignacio / Mihm, Martin / Palmieri, Giuseppe / Parmiani, Giorgio / Puzanov, Igor / Romero, Pedro / Schilling, Bastian / Seliger, Barbara / Stroncek, David / Taube, Janis / Tomei, Sara / Zarour, Hassane M / Testori, Alessandro / Wang, Ena / Galon, Jérôme / Ciliberto, Gennaro / Mozzillo, Nicola / Marincola, Francesco M / Thurin, Magdalena. ·Istituto Nazionale Tumori, Fondazione "G. Pascale", Naples, Italy. paolo.ascierto@gmail.com. · Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC, USA. mba41@georgetown.edu. · Translational Molecular Pathology, Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR, USA. carlo.bifulco@providence.org. · Istituto Nazionale Tumori, Fondazione "G. Pascale", Naples, Italy. gbotti1@alice.it. · Departments of Pathology and Laboratory Medicine and Surgery, David Geffen School of Medicine at University of California Los Angeles (UCLA), John Wayne Cancer Institute, Santa Monica, CA, USA. ACochran@mednet.ucla.edu. · Department of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. mdavies@mdanderson.org. · Departments of Radiation Oncology and Pathology, Weill Cornell Medical College, New York, NY, USA. szd3005@med.cornell.edu. · Skin Cancer Unit, Department of Dermatology, University Hospital Zürich, 8091, Zurich, Switzerland. reinhard.dummer@usz.ch. · Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. sferrone@mgh.harvard.edu. · Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA. formenti@med.cornell.edu. · Departments of Medicine and of Pathology, Immunology and Cancer Program, The University of Chicago Medicine, Chicago, IL, USA. tgajewsk@medicine.bsd.uchicago.edu. · Department of Dermatology, Center for Dermato Oncology, University of Tübingen, Tübingen, Germany. claus.garbe@med.uni-tuebingen.de. · Georgia Regents University Cancer Center, Georgia Regents University, Augusta, GA, USA. skhleif@georgiahealth.com. · Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden. rolf.kiessling@ki.se. · 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. rlo@mednet.ucla.edu. · University of Manchester/Christie NHS Foundation Trust, Manchester, UK. paul.lorigan@christie.nhs.uk. · Peter MacCallum Cancer Centre and University of Melbourne, Victoria, Australia. grant.mcarthur@petermac.org. · Department of Oncology-Pathology, The Karolinska Hospital, Stockholm, Sweden. giuseppe.masucci@ki.se. · Centro de Investigación Médica Aplicada, and Clinica Universidad de Navarra, Pamplona, Navarra, Spain. imelero@unav.es. · Department of Dermatology, Harvard Medical School, Boston, MA, USA. mmihm@mgh.harvard.edu. · Unit of Cancer Genetics, Institute of Biomolecular Chemistry, National Research Council, Sassari, Italy. gpalmieri@yahoo.com. · Division of Molecular Oncology, Unit of Bio-Immunotherapy of Solid Tumors, San Raffaele Institute, Milan, Italy. parmiani.giorgio@hsr.it. · Vanderbilt University Medical Center, Nashville, TN, USA. igor.puzanov@vanderbilt.edu. · Ludwig Cancer Research Center, University of Lausanne, Lausanne, Switzerland. pedro.romero@unil.ch. · Department of Dermatology, University Hospital, West German Cancer Center, University Duisburg-Essen, Essen, Germany. bastian.schilling@uk-essen.de. · German Cancer Consortium (DKTK), Essen, Germany. bastian.schilling@uk-essen.de. · Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Halle, Germany. barbara.seliger@uk-halle.de. · Cell Processing Section, Department of Transfusion Medicine, Clinical Center, NIH, Bethesda, MD, USA. dstroncek@cc.nih.gov. · Department of Dermatology, Johns Hopkins University SOM, Baltimore, MD, USA. jtaube1@jhmi.edu. · Division of Translational Medicine, Sidra Medical and Research Center, Doha, Qatar. stomei@sidra.org. · Departments of Medicine, Immunology and Dermatology, University of Pittsburgh, Pittsburgh, PA, USA. zarourhm@upmc.edu. · Istituto Europeo di Oncologia, Milan, Italy. alessandro.testori@ieo.it. · Division of Translational Medicine, Sidra Medical and Research Centre, Doha, Qatar. ewang@sidra.org. · INSERM, UMRS1138, Laboratory of Integrative Cancer Immunology, Université Paris Descartes, Sorbonne Paris Cité, Centre de Recherche des Cordeliers, Paris, France. jerome.galon@crc.jussieu.fr. · Istituto Nazionale Tumori, Fondazione "G. Pascale", Naples, Italy. gennaro54.ciliberto@gmail.com. · Istituto Nazionale Tumori, Fondazione "G. Pascale", Naples, Italy. nimozzi@tin.it. · Sidra Medical and Research Centre, Doha, Qatar. fmarincola@sidra.org. · Cancer Diagnosis Program, National Cancer Institute, NIH, Bethesda, MD, USA. thurinm@mail.nih.gov. ·J Transl Med · Pubmed #26619946.

ABSTRACT: The fourth "Melanoma Bridge Meeting" took place in Naples, December 3-6th, 2014. The four topics discussed at this meeting were: Molecular and Immunological Advances, Combination Therapies, News in Immunotherapy, and Tumor Microenvironment and Biomarkers. Until recently systemic therapy for metastatic melanoma patients was ineffective, but recent advances in tumor biology and immunology have led to the development of new targeted and immunotherapeutic agents that prolong progression-free survival (PFS) and overall survival (OS). New therapies, such as mitogen-activated protein kinase (MAPK) pathway inhibitors as well as other signaling pathway inhibitors, are being tested in patients with metastatic melanoma either as monotherapy or in combination, and all have yielded promising results. These include inhibitors of receptor tyrosine kinases (BRAF, MEK, and VEGFR), the phosphatidylinositol 3 kinase (PI3K) pathway [PI3K, AKT, mammalian target of rapamycin (mTOR)], activators of apoptotic pathway, and the cell cycle inhibitors (CDK4/6). Various locoregional interventions including radiotherapy and surgery are still valid approaches in treatment of advanced melanoma that can be integrated with novel therapies. Intrinsic, adaptive and acquired resistance occur with targeted therapy such as BRAF inhibitors, where most responses are short-lived. Given that the reactivation of the MAPK pathway through several distinct mechanisms is responsible for the majority of acquired resistance, it is logical to combine BRAF inhibitors with inhibitors of targets downstream in the MAPK pathway. For example, combination of BRAF/MEK inhibitors (e.g., dabrafenib/trametinib) have been demonstrated to improve survival compared to monotherapy. Application of novel technologies such sequencing have proven useful as a tool for identification of MAPK pathway-alternative resistance mechanism and designing other combinatorial therapies such as those between BRAF and AKT inhibitors. Improved survival rates have also been observed with immune-targeted therapy for patients with metastatic melanoma. Immune-modulating antibodies came to the forefront with anti-CTLA-4, programmed cell death-1 (PD-1) and PD-1 ligand 1 (PD-L1) pathway blocking antibodies that result in durable responses in a subset of melanoma patients. Agents targeting other immune inhibitory (e.g., Tim-3) or immune stimulating (e.g., CD137) receptors and other approaches such as adoptive cell transfer demonstrate clinical benefit in patients with melanoma as well. These agents are being studied in combination with targeted therapies in attempt to produce longer-term responses than those more typically seen with targeted therapy. Other 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 this patient population. This meeting's specific focus was on advances in combination of targeted therapy and immunotherapy. Both combination targeted therapy approaches and different immunotherapies were discussed. Similarly to the previous meetings, the importance of biomarkers for clinical application as markers for diagnosis, prognosis and prediction of treatment response was an integral part of the meeting. The overall emphasis on biomarkers supports novel concepts toward integrating biomarkers into contemporary clinical management 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.