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Genomic correlates of response to CTLA-4 blockade in metastatic melanoma
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Genomic correlates of response to CTLA-4 blockade in metastatic melanoma
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Genomic correlates of response to CTLA-4 blockade in metastatic melanoma
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Journal Article
Genomic correlates of response to CTLA-4 blockade in metastatic melanoma
2015
Overview
Monoclonal antibodies directed against cytotoxic T lymphocyte–associated antigen-4 (CTLA-4), such as ipilimumab, yield considerable clinical benefit for patients with metastatic melanoma by inhibiting immune checkpoint activity, but clinical predictors of response to these therapies remain incompletely characterized. To investigate the roles of tumor-specific neoantigens and alterations in the tumor microenvironment in the response to ipilimumab, we analyzed whole exomes from pretreatment melanoma tumor biopsies and matching germline tissue samples from 110 patients. For 40 of these patients, we also obtained and analyzed transcriptome data from the pretreatment tumor samples. Overall mutational load, neoantigen load, and expression of cytolytic markers in the immune microenvironment were significantly associated with clinical benefit. However, no recurrent neoantigen peptide sequences predicted responder patient populations. Thus, detailed integrated molecular characterization of large patient cohorts may be needed to identify robust determinants of response and resistance to immune checkpoint inhibitors.
Publisher
American Association for the Advancement of Science,The American Association for the Advancement of Science
Subject
/ Aged
/ Antibodies, Monoclonal - pharmacology
/ Antibodies, Monoclonal - therapeutic use
/ Antigens, Neoplasm - genetics
/ Cancer
/ Cell Cycle Checkpoints - genetics
/ Cell Cycle Checkpoints - immunology
/ CTLA-4 Antigen - antagonists & inhibitors
/ Drug Resistance, Neoplasm - genetics
/ Exome
/ Female
/ Genomics
/ Humans
/ Male
/ Markers
/ Melanoma
/ Mutation
/ Patients
/ Peptides
/ Skin Neoplasms - drug therapy
/ Survival
/ Tumor Microenvironment - drug effects
/ Tumor Microenvironment - immunology
/ Tumors
