Authors:
NA Rizvi, MD Hellmann, A Snyder, P Kvistborg, V Makarov, JJ Havel, W Lee, J Yuan, P Wong, TS Ho, ML Miller, N Rekhtman, AL Moreira, F Ibrahim, C Bruggeman, B Gasmi, R Zappasodi, Y Maeda, C Sander, EB Garon, T Merghoub, JD Wolchok, TN Schumacher, TA Chan
Journal name: 
Science
Citation info: 
348(6230):124-128
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.
DOI: 
http://doi.org/10.1126/science.aaa1348
Research group: 
Miller Group
E-pub date: 
03 Apr 2015