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      Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer

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          Abstract

          Immune checkpoint inhibitors, which unleash a patient’s own T cells to kill tumors, are revolutionizing cancer treatment. To unravel the genomic determinants of response to this therapy, we used whole-exome sequencing of non–small cell lung cancers treated with pembrolizumab, an antibody targeting programmed cell death-1 (PD-1). In two independent cohorts, higher nonsynonymous mutation burden in tumors was associated with improved objective response, durable clinical benefit, and progression-free survival. Efficacy also correlated with the molecular smoking signature, higher neoantigen burden, and DNA repair pathway mutations; each factor was also associated with mutation burden. In one responder, neoantigen-specific CD8+ T cell responses paralleled tumor regression, suggesting that anti–PD-1 therapy enhances neoantigen-specific T cell reactivity. Our results suggest that the genomic landscape of lung cancers shapes response to anti–PD-1 therapy.

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          Author and article information

          Journal
          Science
          Science
          American Association for the Advancement of Science (AAAS)
          0036-8075
          1095-9203
          April 02 2015
          April 03 2015
          April 03 2015
          March 12 2015
          : 348
          : 6230
          : 124-128
          Article
          10.1126/science.aaa1348
          4993154
          25765070
          55085500-209f-49db-8726-b81a4bf47eec
          © 2015

          http://www.sciencemag.org/about/science-licenses-journal-article-reuse

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