title: Immune-related adverse events with immune checkpoint blockade: a comprehensive review.
abstract: Cancer immunotherapy is coming of age; it has prompted a paradigm shift in oncology, in which therapeutic agents are used to target immune cells rather than cancer cells. The first generation of new immunotherapies corresponds to antagonistic antibodies that block specific immune checkpoint molecules cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein (PD-1) and its ligand PD-L1. Targeting these checkpoints in patients living with cancer had led to long-lasting tumour responses. By unbalancing the immune system, these new immunotherapies also generate dysimmune toxicities, called immune-related adverse events (IRAEs) that mainly involve the gut, skin, endocrine glands, liver, and lung but can potentially affect any tissue. In view of their undisputed clinical efficacy, anti-CTLA-4 and anti-PD-1 antibodies are entering in the routine oncological practice, and the number of patients exposed to these drugs will increase dramatically in the near future. Although steroids can be used to treat these IRAEs, the associated immunosuppression may compromise the antitumour response. Oncologists must be ready to detect and manage these new types of adverse events. This review focuses on the mechanisms of IRAE generation, putative relationship between dysimmune toxicity and antitumour efficacy, as a basis for management guidelines.
authors.affiliation: Department of Medicine Oncology, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France; Drug Development Department, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France; Internal Medicine and Clinical Immunology Department, Assistance Publique-Hôpitaux de Paris, Hôpital Universitaire Bicêtre, F-94275 Le Kremlin Bicêtre, France. Electronic address: jean-marie.michot@gustaveroussy.fr.
authors.forename: J M
authors.initials: JM
authors.lastname: Michot
authors.affiliation: Department of Medicine Oncology, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France.
authors.forename: C
authors.initials: C
authors.lastname: Bigenwald
authors.affiliation: Drug Development Department, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France.
authors.forename: S
authors.initials: S
authors.lastname: Champiat
authors.affiliation: Gastroenterology Department, Assistance Publique-Hôpitaux de Paris, Hôpital Universitaire Bicêtre, F-94275 Le Kremlin Bicêtre, France; Université Paris Sud 11, F-94275 Le Kremlin-Bicêtre, France.
authors.forename: M
authors.initials: M
authors.lastname: Collins
authors.affiliation: Gastroenterology Department, Assistance Publique-Hôpitaux de Paris, Hôpital Universitaire Bicêtre, F-94275 Le Kremlin Bicêtre, France; Université Paris Sud 11, F-94275 Le Kremlin-Bicêtre, France.
authors.forename: F
authors.initials: F
authors.lastname: Carbonnel
authors.affiliation: Drug Development Department, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France.
authors.forename: S
authors.initials: S
authors.lastname: Postel-Vinay
authors.affiliation: Department of Medicine Oncology, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France.
authors.forename: A
authors.initials: A
authors.lastname: Berdelou
authors.affiliation: Drug Development Department, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France.
authors.forename: A
authors.initials: A
authors.lastname: Varga
authors.affiliation: Drug Development Department, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France.
authors.forename: R
authors.initials: R
authors.lastname: Bahleda
authors.affiliation: Drug Development Department, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France.
authors.forename: A
authors.initials: A
authors.lastname: Hollebecque
authors.affiliation: Drug Development Department, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France.
authors.forename: C
authors.initials: C
authors.lastname: Massard
authors.affiliation: Department of Medicine Oncology, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France; Drug Development Department, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France.
authors.forename: A
authors.initials: A
authors.lastname: Fuerea
authors.affiliation: Department of Medicine Oncology, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France; Drug Development Department, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France.
authors.forename: V
authors.initials: V
authors.lastname: Ribrag
authors.affiliation: Drug Development Department, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France.
authors.forename: A
authors.initials: A
authors.lastname: Gazzah
authors.affiliation: Drug Development Department, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France.
authors.forename: J P
authors.initials: JP
authors.lastname: Armand
authors.affiliation: Drug Development Department, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France.
authors.forename: N
authors.initials: N
authors.lastname: Amellal
authors.affiliation: Drug Development Department, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France.
authors.forename: E
authors.initials: E
authors.lastname: Angevin
authors.affiliation: Internal Medicine and Clinical Immunology Department, Assistance Publique-Hôpitaux de Paris, Hôpital Universitaire Bicêtre, F-94275 Le Kremlin Bicêtre, France; Université Paris Sud 11, F-94275 Le Kremlin-Bicêtre, France; CEA, DSV/iMETI, Division of Immunovirology, IDMIT, F-92265 Fontenay-aux-Roses, France; INSERM, U1184, Center for Immunology of Viral Infections and Autoimmune Diseases, F-94276 Le Kremlin-Bicêtre, France.
authors.forename: N
authors.initials: N
authors.lastname: Noel
authors.affiliation: Department of Medicine Oncology, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France; Drug Development Department, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France; Internal Medicine and Clinical Immunology Department, Assistance Publique-Hôpitaux de Paris, Hôpital Universitaire Bicêtre, F-94275 Le Kremlin Bicêtre, France.
authors.forename: C
authors.initials: C
authors.lastname: Boutros
authors.affiliation: Department of Medicine Oncology, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France; Drug Development Department, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France; Internal Medicine and Clinical Immunology Department, Assistance Publique-Hôpitaux de Paris, Hôpital Universitaire Bicêtre, F-94275 Le Kremlin Bicêtre, France.
authors.forename: C
authors.initials: C
authors.lastname: Mateus
authors.affiliation: Department of Medicine Oncology, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France; Drug Development Department, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France; Internal Medicine and Clinical Immunology Department, Assistance Publique-Hôpitaux de Paris, Hôpital Universitaire Bicêtre, F-94275 Le Kremlin Bicêtre, France.
authors.forename: C
authors.initials: C
authors.lastname: Robert
authors.affiliation: Drug Development Department, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France.
authors.forename: J C
authors.initials: JC
authors.lastname: Soria
authors.affiliation: Drug Development Department, Gustave Roussy Comprehensive Cancer Center, F-94805 Villejuif, France.
authors.forename: A
authors.initials: A
authors.lastname: Marabelle
authors.affiliation: Internal Medicine and Clinical Immunology Department, Assistance Publique-Hôpitaux de Paris, Hôpital Universitaire Bicêtre, F-94275 Le Kremlin Bicêtre, France; Université Paris Sud 11, F-94275 Le Kremlin-Bicêtre, France; CEA, DSV/iMETI, Division of Immunovirology, IDMIT, F-92265 Fontenay-aux-Roses, France; INSERM, U1184, Center for Immunology of Viral Infections and Autoimmune Diseases, F-94276 Le Kremlin-Bicêtre, France.
authors.forename: O
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authors.lastname: Lambotte
mesh_terms: D000069594:Abatacept / Q000009:adverse effects; D000818:Animals; D000906:Antibodies / Q000009:adverse effects*; D000970:Antineoplastic Agents / Q000009:adverse effects*; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D064420:Drug-Related Side Effects and Adverse Reactions / Q000175:diagnosis / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy / Q000009:adverse effects* / Q000379:methods; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D012307:Risk Factors; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D000069594:Abatacept
keywords: Anti-PD-1 antibody; Cytotoxic T-lymphocyte-associated antigen 4; Immune checkpoint blockade; Immune-related adverse events; Tumour neoantigen