Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer Academic Article uri icon

Overview

MeSH Major

  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • Carcinoma, Non-Small-Cell Lung
  • Drug Resistance, Neoplasm
  • Lung Neoplasms
  • Programmed Cell Death 1 Receptor

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.

publication date

  • April 3, 2015

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4993154

Digital Object Identifier (DOI)

  • 10.1126/science.aaa1348

PubMed ID

  • 25765070

Additional Document Info

start page

  • 124

end page

  • 8

volume

  • 348

number

  • 6230