Genomic correlates of response to CTLA-4 blockade in metastatic melanoma.

Science
Authors
Keywords
Abstract

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.

Year of Publication
2015
Journal
Science
Volume
350
Issue
6257
Pages
207-11
Date Published
2015 Oct 09
ISSN
1095-9203
URL
DOI
10.1126/science.aad0095
PubMed ID
26359337
PubMed Central ID
PMC5054517
Links
Grant list
U54 HG003067 / HG / NHGRI NIH HHS / United States