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      Classification of current anticancer immunotherapies

      review-article
      1 , 2 , 3 , 4 , 1 , 2 , 3 , 1 , 2 , 3 , 1 , 2 , 3 , 1 , 2 , 3 , 1 , 2 , 3 , 5 , 1 , 2 , 3 , 5 , 1 , 2 , 3 , 5 , 6 , 7 , 8 , 9 , 1 , 2 , 3 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 19 , 25 , 26 , 3 , 27 , 2 , 4 , 28 , 29 , 6 , 30 , 31 , 2 , 4 , 28 , 32 , 8 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 4 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 1 , 2 , 49 , 50 , 51 , 48 , 52 , 53 , 54 , 55 , 56 , 45 , 46 , 57 , 58 , 16 , 57 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 9 , 71 , 72 , 73 , 74 , 75 , 76 , 2 , 4 , 28 , 29 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 6 , 30 , 85 , 86 , 87 , 4 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 46 , 98 , 99 , 100 , 3 , 101 , 102 , 103 , 1 , 2 , 4 , 49 , 104
      Oncotarget
      Impact Journals LLC
      adoptive cell transfer, checkpoint blockers, dendritic cell-based interventions, DNA-based vaccines, immunostimulatory cytokines, peptide-based vaccines, oncolytic viruses, Toll-like receptor agonists

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          Abstract

          During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into “passive” and “active” based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification does not properly reflect the complexity of the drug-host-tumor interaction. Alternatively, anticancer immunotherapeutics can be classified according to their antigen specificity. While some immunotherapies specifically target one (or a few) defined tumor-associated antigen(s), others operate in a relatively non-specific manner and boost natural or therapy-elicited anticancer immune responses of unknown and often broad specificity. Here, we propose a critical, integrated classification of anticancer immunotherapies and discuss the clinical relevance of these approaches.

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          Most cited references432

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          The blockade of immune checkpoints in cancer immunotherapy.

          Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
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            ONCOLYTIC VIROTHERAPY

            Oncolytic virotherapy is an emerging treatment modality which uses replication competent viruses to destroy cancers. Advances in the past two years include preclinical proof of feasibility for a single-shot virotherapy cure, identification of drugs that accelerate intratumoral virus propagation, new strategies to maximize the immunotherapeutic potential of oncolytic virotherapy, and clinical confirmation of a critical viremic thereshold for vascular delivery and intratumoral virus replication. The primary clinical milestone was completion of accrual in a phase III trial of intratumoral herpes simplex virus therapy using talimogene laherparepvec for metastatic melanoma. Challenges for the field are to select ‘winners’ from a burgeoning number of oncolytic platforms and engineered derivatives, to transiently suppress but then unleash the power of the immune system to maximize both virus spread and anticancer immunity, to develop more meaningful preclinical virotherapy models and to manufacture viruses with orders of magnitude higher yields compared to established vaccine manufacturing processes.
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              Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women

              The Lancet, 374(9686), 301-314
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                December 2014
                18 December 2014
                : 5
                : 24
                : 12472-12508
                Affiliations
                1 Equipe 11 labellisée pas la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France
                2 INSERM, U1138, Paris, France
                3 Gustave Roussy Cancer Campus, Villejuif, France
                4 Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France
                5 Faculté de Medicine, Université Paris Sud/Paris XI, Le Kremlin-Bicêtre, France
                6 Sotio a.c., Prague, Czech Republic
                7 Pole d'innovation thérapeutique en oncologie, Institut de Recherches Internationales Servier, Suresnes, France
                8 Cell Death Research and Therapy (CDRT) Laboratory, Dept. of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium
                9 The Shraga Segal Dept. of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
                10 Group of Immune receptors of the Innate and Adaptive System, Institut d'Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
                11 INSERM, U1102, Saint Herblain, France
                12 Institut de Cancérologie de l'Ouest, Saint Herblain, France
                13 Translational Immunology Division, German Cancer Research Center, Heidelberg, Germany
                14 Equipe 11, Centre Léon Bérard (CLR), Lyon, France
                15 Centre de Recherche en Cancérologie de Lyon (CRCL), Lyon, France
                16 Dept. of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
                17 INSERM, U1160, Paris, France
                18 Groupe Hospitalier Saint Louis-Lariboisière - F. Vidal, Paris, France
                19 Unit of Immunotherapy of Human Tumors, Dept. of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy
                20 Molecular Biotechnology Center, Dept. of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
                21 Cancer Immunology, Inflammation and Tolerance Program, Georgia Regents University Cancer Center, Augusta, GA, USA
                22 MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
                23 Institute of Cancer & Genetics, School of Medicine, Cardiff University, Cardiff, UK
                24 Velindre Cancer Centre, Cardiff, UK
                25 Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
                26 Sect. of Hematology and Immunobiology, Yale Cancer Center, Yale University, New Haven, CT, USA
                27 Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA
                28 Université Pierre et Marie Curie/Paris VI, Paris, France
                29 Equipe 13, Centre de Recherche des Cordeliers, Paris, France
                30 Dept. of Immunology, 2nd Faculty of Medicine and University Hospital Motol, Charles University, Prague, Czech Republic
                31 Dept. of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
                32 Laboratory of Integrative Cancer Immunology, Centre de Recherche des Cordeliers, Paris, France
                33 INSERM, UMR866, Dijon, France
                34 Centre Georges François Leclerc, Dijon, France
                35 Université de Bourgogne, Dijon, France
                36 Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA
                37 Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
                38 Dept. of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, USA
                39 Sect. of Hematology/Oncology, Immunology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
                40 Glaxo Smith Kline, Cancer Immunotherapy Consortium, Collegeville, PA, USA
                41 INSERM, U1016, Paris, France
                42 CNRS, UMR8104, Paris, France
                43 Hôpital Cochin, AP-HP, Paris, France
                44 National Center for Tumor Diseases, University Medical Center Heidelberg, Heidelberg, Germany
                45 Dept. of Surgery, University of Pittsburgh, Pittsburgh, PA, USA
                46 University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA, USA
                47 Dept. of Immunology and Infectious Diseases and Microbiology, University of Pittsburgh, Pittsburgh, PA, USA
                48 Dept. of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden
                49 Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France
                50 Dept. of Oncology, Karolinska Institute Hospital, Stockholm, Sweden
                51 University of Pittsburgh Cancer Institute Laboratory, Pittsburgh, PA, USA
                52 National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
                53 Academic Unit of Inflammation and Tumour Targeting, Dept. of Oncology, University of Sheffield Medical School, Sheffield, UK
                54 INSERM, UMR1043, Toulouse, France
                55 CNRS, UMR5282, Toulouse, France
                56 Laboratoire d'Immunologie, CHU Toulouse, Université Toulouse II, Toulouse, France
                57 Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Institute, Rozzano, Italy
                58 Dept. of Biochemistry, University of Lausanne, Epalinges, Switzerland
                59 Dept. of Medical Biotechnologies and Translational Medicine, University of Milan, Rozzano, Italy
                60 Dept. of Immunology, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, Spain
                61 Dept. of Oncology, Clínica Universidad de Navarra, Pamplona, Spain
                62 ISA Therapeutics, Leiden, The Netherlands
                63 Dept. of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
                64 Research Dept. of Surgical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
                65 Istituto Giannina Gaslini, Genova, Italy
                66 Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, NY, USA
                67 Dept. of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA
                68 The Jackson Laboratory for Genomics Medicine, Farmington, CT, USA
                69 Div. of Hematology/Oncology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
                70 The James Buchanan Brady Urological Institute, The Johns Hopkins Medical Institutions, Baltimore, MD, USA
                71 Lankenau Institute for Medical Research, Wynnewood, PA, USA
                72 Dept. of Pathology, Anatomy and Cell Biology, Sidney Kimmel Medical College, Philadelphia, PA, USA
                73 Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
                74 Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Buenos Aires, Argentina
                75 National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, USA
                76 Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA
                77 Dept. of Pathology, The Cancer Research Center, The University of Chicago, Chicago, IL, USA
                78 Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Halle, Germany
                79 Dept. of Immuno-GeneTherapy, Mie University Graduate School of Medicine, Tsu, Japan
                80 Instituto de Medicina Molecular, Universidade de Lisboa, Lisboa, Portugal
                81 Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
                82 School of Medicine, University of Queensland, Herston, Queensland, Australia
                83 Dept. of Oncology, University of Lausanne, Lausanne, Switzerland
                84 Ludwig Cancer Research Center, Lausanne, Switzerland
                85 Dept. of Immunology, University of Connecticut School of Medicine, Farmington, CT, USA
                86 Carole and Ray Neag Comprehensive Cancer Center, Farmington, CT, USA
                87 Laboratory of Transplantation Immunology, Dept. of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
                88 INSERM, U970, Paris, France
                89 Paris-Cardiovascular Research Center (PARCC), Paris, France
                90 Service d'Immunologie Biologique, Hôpital Européen Georges Pompidou (HEGP), AP-HP, Paris, France
                91 Dept. of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands
                92 Ludwig Institute for Cancer Research, Brussels, Belgium
                93 de Duve Institute, Brussels, Belgium
                94 Université Catholique de Louvain, Brussels, Belgium
                95 Dept. of Molecular Medicine and Immunology, Mayo Clinic College of Medicine, Rochester, MN, USA
                96 Institute of Medical Microbiology, Immunology and Hygiene, Technical University Munich, Munich, Germany
                97 Donald A. Adam Comprehensive Melanoma Research Center, Moffitt Cancer Center, Tampa, FL, USA
                98 University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
                99 Dept. of Medicine and Ludwig Center, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA
                100 Weill Cornell Medical College, New York, NY, USA
                101 INSERM, U1015, Villejuif, France
                102 Centre d'Investigation Clinique Biothérapie 507 (CICBT507), Gustave Roussy Cancer Campus, Villejuif, France
                103 University of Michigan, School of Medicine, Ann Arbor, MI, USA
                104 Pôle de Biologie, Hôpital Européen Georges Pompidou (HEGP), AP-HP, Paris, France
                Author notes
                Correspondence to: Lorenzo Galluzzi, deadoc@ 123456vodafone.it
                Article
                10.18632/oncotarget.2998
                4350348
                25537519
                19f0b64e-2be9-409a-ad4e-ae23e48b83ae
                Copyright: © 2014 Galluzzi et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 2 November 2014
                : 15 December 2014
                Categories
                Review

                Oncology & Radiotherapy
                adoptive cell transfer,checkpoint blockers,dendritic cell-based interventions,dna-based vaccines,immunostimulatory cytokines,peptide-based vaccines,oncolytic viruses,toll-like receptor agonists

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