Genetic Diversity May Improve Melanoma Therapy Response

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Whole-exome sequencing of tumor tissue reveals genetic basis for benefit from CTLA-4 blockade.
Whole-exome sequencing of tumor tissue reveals genetic basis for benefit from CTLA-4 blockade.

Evidence suggests a genetic basis for clinical response to cytotoxic T-lymphocyte antigen 4 (CTLA-4) blockade in melanoma, according to research published in the New England Journal of Medicine.

Alexandra Snyder, M.D., of the Memorial Sloan Kettering Cancer Center in New York City, and colleagues performed whole-exome sequencing of tumor tissue and matched blood samples from 64 patients with melanoma who were treated with ipilimumab or tremelimumab.

The researchers found that mutational load was associated with degree of clinical benefit from CTLA-4 blockade (P = 0.01) but by itself did not predict response. Genomewide somatic neoepitope analysis and patient-specific HLA typing were used to identify neoantigens in tumors that had a strong response to CTLA-4 blockade.

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This signature was validated in a second set of 39 patients with melanoma who received anti-CTLA-4 antibodies. These neoantigens activated lymphocytes from patients treated with ipilimumab.

"A high mutational burden increased the likelihood of the development of specific neoepitopes that would confer clinical benefit from CTLA-4 blockade," writes the author of an accompanying editorial.

Two authors are employees of Bristol-Myers Squibb.


  1. Snyder, Alexandra, MD, et al. "Genetic Basis for Clinical Response to CTLA-4 BLockade in Melanoma." The New England Journal of Medicine. DOI: 10.1056/NEJMoa1406498. November 19, 2014.

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