title: Immune checkpoint inhibitors: therapeutic advances in melanoma.
abstract: In recent years, new strategies for treating melanoma have been introduced, improving the outlook for this challenging disease. One of the most important advances has been the development of immunotherapy. The better understanding of the role of the immunological system in tumor control has paved the way for strategies to enhance the immune response against cancer cells. Monoclonal antibodies (mAbs) against the immune checkpoints cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1) and its ligand (PD-L1) have demonstrated high activity in melanoma and other tumors. Ipilimumab, an anti CTLA-4 antibody, was the first drug of this class that was approved. Although the response rate with ipilimumab is low (less than 20% of patients have objective responses), 20% of patients have long survival, with similar results in the first and second line settings. Nivolumab and pembrolizumab, both anti PD-1 inhibitors, have been approved for the treatment of melanoma, with response rates of 40% and a demonstrated survival advantage in phase III trials. This has marked a new era in the treatment of metastatic melanoma and much research is now ongoing with other drugs targeting checkpoint inhibitors. In addition, the agonist of activating molecules on T cells and their combinations are being investigated. Herein we review the clinical development of checkpoint inhibitors and their approval for treatment of metastatic melanoma.
authors.affiliation: 1 Servicio de Oncología Médica, Hospital General Universitario Gregorio Marañon, Madrid, Spain ; 2 Spanish Melanoma Group (GEM); 3 Servicio Oncología Médica, Hospital General Universitario Santa Lucía, Cartagena, Spain ; 4 Servicio de Oncología Médica, Universitario Ramon y Cajal, Madrid, Spain ; 5 Servicio de Oncología Médica, Hospital General Universitario de Valencia, Valencia, Spain ; 6 Translational Cancer Research Unit, Instituto Oncológico Dr Rosell, Quirón Dexeus University Hospital, Barcelona, Spain ; 7 Servicio de Oncología Médica, Clínica Universitaria de Navarra, Pamplona, Spain.
authors.forename: Ivan
authors.initials: I
authors.lastname: Márquez-Rodas
authors.affiliation: 1 Servicio de Oncología Médica, Hospital General Universitario Gregorio Marañon, Madrid, Spain ; 2 Spanish Melanoma Group (GEM); 3 Servicio Oncología Médica, Hospital General Universitario Santa Lucía, Cartagena, Spain ; 4 Servicio de Oncología Médica, Universitario Ramon y Cajal, Madrid, Spain ; 5 Servicio de Oncología Médica, Hospital General Universitario de Valencia, Valencia, Spain ; 6 Translational Cancer Research Unit, Instituto Oncológico Dr Rosell, Quirón Dexeus University Hospital, Barcelona, Spain ; 7 Servicio de Oncología Médica, Clínica Universitaria de Navarra, Pamplona, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Cerezuela
authors.affiliation: 1 Servicio de Oncología Médica, Hospital General Universitario Gregorio Marañon, Madrid, Spain ; 2 Spanish Melanoma Group (GEM); 3 Servicio Oncología Médica, Hospital General Universitario Santa Lucía, Cartagena, Spain ; 4 Servicio de Oncología Médica, Universitario Ramon y Cajal, Madrid, Spain ; 5 Servicio de Oncología Médica, Hospital General Universitario de Valencia, Valencia, Spain ; 6 Translational Cancer Research Unit, Instituto Oncológico Dr Rosell, Quirón Dexeus University Hospital, Barcelona, Spain ; 7 Servicio de Oncología Médica, Clínica Universitaria de Navarra, Pamplona, Spain.
authors.forename: Ainara
authors.initials: A
authors.lastname: Soria
authors.affiliation: 1 Servicio de Oncología Médica, Hospital General Universitario Gregorio Marañon, Madrid, Spain ; 2 Spanish Melanoma Group (GEM); 3 Servicio Oncología Médica, Hospital General Universitario Santa Lucía, Cartagena, Spain ; 4 Servicio de Oncología Médica, Universitario Ramon y Cajal, Madrid, Spain ; 5 Servicio de Oncología Médica, Hospital General Universitario de Valencia, Valencia, Spain ; 6 Translational Cancer Research Unit, Instituto Oncológico Dr Rosell, Quirón Dexeus University Hospital, Barcelona, Spain ; 7 Servicio de Oncología Médica, Clínica Universitaria de Navarra, Pamplona, Spain.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Berrocal
authors.affiliation: 1 Servicio de Oncología Médica, Hospital General Universitario Gregorio Marañon, Madrid, Spain ; 2 Spanish Melanoma Group (GEM); 3 Servicio Oncología Médica, Hospital General Universitario Santa Lucía, Cartagena, Spain ; 4 Servicio de Oncología Médica, Universitario Ramon y Cajal, Madrid, Spain ; 5 Servicio de Oncología Médica, Hospital General Universitario de Valencia, Valencia, Spain ; 6 Translational Cancer Research Unit, Instituto Oncológico Dr Rosell, Quirón Dexeus University Hospital, Barcelona, Spain ; 7 Servicio de Oncología Médica, Clínica Universitaria de Navarra, Pamplona, Spain.
authors.forename: Aldo
authors.initials: A
authors.lastname: Riso
authors.affiliation: 1 Servicio de Oncología Médica, Hospital General Universitario Gregorio Marañon, Madrid, Spain ; 2 Spanish Melanoma Group (GEM); 3 Servicio Oncología Médica, Hospital General Universitario Santa Lucía, Cartagena, Spain ; 4 Servicio de Oncología Médica, Universitario Ramon y Cajal, Madrid, Spain ; 5 Servicio de Oncología Médica, Hospital General Universitario de Valencia, Valencia, Spain ; 6 Translational Cancer Research Unit, Instituto Oncológico Dr Rosell, Quirón Dexeus University Hospital, Barcelona, Spain ; 7 Servicio de Oncología Médica, Clínica Universitaria de Navarra, Pamplona, Spain.
authors.forename: María
authors.initials: M
authors.lastname: González-Cao
authors.affiliation: 1 Servicio de Oncología Médica, Hospital General Universitario Gregorio Marañon, Madrid, Spain ; 2 Spanish Melanoma Group (GEM); 3 Servicio Oncología Médica, Hospital General Universitario Santa Lucía, Cartagena, Spain ; 4 Servicio de Oncología Médica, Universitario Ramon y Cajal, Madrid, Spain ; 5 Servicio de Oncología Médica, Hospital General Universitario de Valencia, Valencia, Spain ; 6 Translational Cancer Research Unit, Instituto Oncológico Dr Rosell, Quirón Dexeus University Hospital, Barcelona, Spain ; 7 Servicio de Oncología Médica, Clínica Universitaria de Navarra, Pamplona, Spain.
authors.forename: Salvador
authors.initials: S
authors.lastname: Martín-Algarra
keywords: Checkpoint inhibitors; immunotherapy; melanoma; programmed cell death protein 1 (PD-1)