Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer Journal Article
| Authors: | Rizvi, N. A.; Hellmann, M. D.; Snyder, A.; Kvistborg, P.; Makarov, V.; Havel, J. J.; Lee, W.; Yuan, J.; Wong, P.; Ho, T. S. ; Miller, M. L.; Rekhtman, N.; Moreira, A. L.; Ibrahim, F.; Bruggeman, C.; Gasmi, B.; Zappasodi, R.; Maeda, Y.; Sander, C.; Garon, E. B.; Merghoub, T.; Wolchok, J. D.; Schumacher, T. N.; Chan, T. A. |
| Article Title: | Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer |
| 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. |
| Keywords: | survival; treatment response; disease-free survival; gene mutation; gene sequence; genetics; mutation; antineoplastic agents; disease free survival; antineoplastic agent; cd8+ t lymphocyte; cd8-positive t-lymphocytes; dna repair; progression free survival; cohort studies; carcinoma, non-small-cell lung; lung neoplasms; cohort analysis; smoking; drug resistance; drug resistance, neoplasm; inhibitor; monoclonal antibody; cancer regression; immunology; immunity; tumor; disease treatment; programmed death 1 ligand 1; programmed death 1 receptor; non small cell lung cancer; drug; antibodies, monoclonal, humanized; exome; cancer; humans; human; priority journal; article; pembrolizumab; antagonists and inhibitors; pdcd1 protein, human; programmed cell death 1 receptor |
| Journal Title: | Science |
| Volume: | 348 |
| Issue: | 6230 |
| ISSN: | 0036-8075 |
| Publisher: | American Association for the Advancement of Science |
| Date Published: | 2015-04-03 |
| Start Page: | 124 |
| End Page: | 128 |
| Language: | English |
| DOI: | 10.1126/science.aaa1348 |
| PUBMED: | 25765070 |
| PROVIDER: | scopus |
| PMCID: | PMC4993154 |
| DOI/URL: | |
| Notes: | Export Date: 3 June 2015 -- Source: Scopus |
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