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

TLDR

CTLA‑4 blockade with ipilimumab benefits metastatic melanoma patients, yet clinical predictors of response are poorly defined, underscoring the need for integrated molecular profiling of large cohorts. The study aimed to determine how tumor neoantigens and microenvironmental changes influence ipilimumab response by analyzing whole‑exome data from 110 pretreatment melanoma biopsies and matched germline samples. Whole‑exome sequencing of 110 pretreatment melanoma biopsies and matched germline samples was performed, and transcriptomic profiling was additionally conducted on 40 of these tumors. Higher mutational and neoantigen loads, along with increased cytolytic marker expression, correlated with clinical benefit, but no recurrent neoantigen peptides distinguished responders.

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.