title: New toxicity profile for novel immunotherapy agents: focus on immune-checkpoint inhibitors.
abstract: BACKGROUND
  Tumor development results from a cancer-induced immunosuppression (immune-editing). Immunotherapy has revolutionized the treatment paradigm for many malignancies, putting clinicians before novel toxicities, of immune-mediated etiology (immune-related adverse events).
  
  
  METHODS
  Immune-mediated toxicity depends on both innate and adaptive immunity mechanisms. Healthy tissue damage depends on an aspecific T-cell hyperactivation response causing cross-reaction with normal tissues, which leads to an overproduction of CD4 T-helper cell cytokines and an abnormal migration of cytolytic CD8 T-cells. By stimulating a diffuse T-cell repertoire expansion, immune-checkpoint inhibitors counteract tumor growth but reduce the self-tolerance, damaging healthy organs. In this review, we summarize the toxicity profile of the novel immune-checkpoint inhibitors and their clinical implications, we are convinced that a deep understanding and a prompt resolution of the paradigmatic toxicities of these drugs will result in clinical benefits to patients and an enhanced antitumor effect.
  
  
  CONCLUSIONS
  A focus on immunotoxicity is important in the education of clinicians and will improve patient safety. There is a willingness to tailor specific immune-therapies to each cancer patient, and to stimulate researchers through understanding of the physiopathogenesis, using the hypothesis that immune-mediated toxicities can be used as predictors of response or a prognostic sign of survival, thereby guiding therapeutic decisions.
authors.affiliation: a Medical Oncology , Azienda Ospedaliera Universitaria Integrata, University of Verona , Verona 37124 , Italy.
authors.forename: C
authors.initials: C
authors.lastname: Ciccarese
authors.affiliation: b SSD Oncologia medica Tumori Testa e Collo , Fondazione IRCCS - Istituto Nazionale dei Tumori , Milano 20133 , Italy.
authors.forename: S
authors.initials: S
authors.lastname: Alfieri
authors.affiliation: c Clinica di Oncologia Medica, AOU "Ospedali Riuniti" , Polytechnic University of the Marche Region , Ancona 60126 , Italy.
authors.forename: M
authors.initials: M
authors.lastname: Santoni
authors.affiliation: d Department of Medical Oncology , Campus Bio-Medico University , Oncologia Medica, Rome , Italy.
authors.forename: D
authors.initials: D
authors.lastname: Santini
authors.affiliation: e Department of Pathology and Diagnostic , Azienda Ospedaliera Universitaria Integrata, University of Verona , Verona 37124 , Italy.
authors.forename: M
authors.initials: M
authors.lastname: Brunelli
authors.affiliation: b SSD Oncologia medica Tumori Testa e Collo , Fondazione IRCCS - Istituto Nazionale dei Tumori , Milano 20133 , Italy.
authors.forename: C
authors.initials: C
authors.lastname: Bergamini
authors.affiliation: b SSD Oncologia medica Tumori Testa e Collo , Fondazione IRCCS - Istituto Nazionale dei Tumori , Milano 20133 , Italy.
authors.forename: L
authors.initials: L
authors.lastname: Licitra
authors.affiliation: f Section of Pathological Anatomy, School of Medicine, AOU Ospedali Riuniti , Polytechnic University of the Marche Region , Ancona 60126 , Italy.
authors.forename: R
authors.initials: R
authors.lastname: Montironi
authors.affiliation: a Medical Oncology , Azienda Ospedaliera Universitaria Integrata, University of Verona , Verona 37124 , Italy.
authors.forename: G
authors.initials: G
authors.lastname: Tortora
authors.affiliation: a Medical Oncology , Azienda Ospedaliera Universitaria Integrata, University of Verona , Verona 37124 , Italy.
authors.forename: F
authors.initials: F
authors.lastname: Massari
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology; D000818:Animals; D016207:Cytokines / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D007167:Immunotherapy / Q000009:adverse effects / Q000379:methods*; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D011379:Prognosis; D011971:Receptors, Immunologic / Q000276:immunology*; D015996:Survival Rate; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D016207:Cytokines; D011971:Receptors, Immunologic
keywords: adverse events; immune-checkpoint inhibitors; immunotherapy; safety profile; toxicity