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Original Article Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma Alexandra Snyder, M.D., Vladimir Makarov, M.D., Taha Merghoub, Ph.D., Jianda Yuan, M.D., Ph.D., Jesse M. Zaretsky, B.S., Alexis Desrichard, Ph.D., Logan A. Walsh, Ph.D., Michael A. Postow, M.D., Phillip Wong, Ph.D., Teresa S.

Ho, B.S., Travis J. Hollmann, M.D., Ph.D., Cameron Bruggeman, M.A., Kasthuri Kannan, Ph.D., Yanyun Li, M.D., Ph.D., Ceyhan Elipenahli, B.S., Cailian Liu, M.D., Christopher T. Harbison, Ph.D., Lisu Wang, M.D., Antoni Ribas, M.D., Ph.D., Jedd D. Wolchok, M.D., Ph.D., and Timothy A.

Chan, M.D., Ph.D. N Engl J Med 2014; 371:2189-2199 DOI: 10.1056/NEJMoa1406498. Results Malignant melanoma exomes from 64 patients treated with CTLA-4 blockade were characterized with the use of massively parallel sequencing. A discovery set consisted of 11 patients who derived a long-term clinical benefit and 14 patients who derived a minimal benefit or no benefit. Mutational load was associated with the degree of clinical benefit (P=0.01) but alone was not sufficient to predict benefit. Using genomewide somatic neoepitope analysis and patient-specific HLA typing, we identified candidate tumor neoantigens for each patient. We elucidated a neoantigen landscape that is specifically present in tumors with a strong response to CTLA-4 blockade.