Targeted next generation sequencing identifies markers of response to PD-1 blockade

Douglas B. Johnson, Garrett M. Frampton, Matthew J. Rioth, Erik Yusko, Yaomin Xu, Xingyi Guo, Riley C. Ennis, David Fabrizio, Zachary R. Chalmers, Joel Greenbowe, Siraj M. Ali, Sohail Balasubramanian, James X. Sun, Yuting He, Dennie T. Frederick, Igor Puzanov, Justin M. Balko, Justin M. Cates, Jeffrey S. Ross, Catherine SandersHarlan Robins, Yu Shyr, Vincent A. Miller, Philip J. Stephens, Ryan J. Sullivan, Jeffrey A. Sosman, Christine M. Lovly

研究成果: Article同行評審

292 引文 斯高帕斯(Scopus)

摘要

Therapeutic antibodies blocking programmed death-1 and its ligand (PD-1/PD-L1) induce durable responses in a substantial fraction of melanoma patients. We sought to determine whether the number and/or type of mutations identified using a next-generation sequencing (NGS) panel available in the clinic was correlated with response to anti-PD-1 in melanoma. Using archival melanoma samples from anti-PD-1/PD-L1-treated patients, we performed hybrid capture-based NGS on 236-315 genes and T-cell receptor (TCR) sequencing on initial and validation cohorts from two centers. Patients who responded to anti-PD-1/PD-L1 had higher mutational loads in an initial cohort (median, 45.6 vs. 3.9 mutations/MB; P = 0.003) and a validation cohort (37.1 vs. 12.8 mutations/MB; P = 0.002) compared with nonresponders. Response rate, progression-free survival, and overall survival were superior in the high, compared with intermediate and low, mutation load groups. Melanomas with NF1 mutations harbored highmutational loads (median, 62.7 mutations/MB) and high response rates (74%), whereas BRAF/NRAS/NF1 wild-type melanomas had a lower mutational load. In these archival samples, TCR clonality did not predict response. Mutation numbers in the 315 genes in the NGS platform strongly correlated with those detected by whole-exome sequencing in The Cancer Genome Atlas samples, but was not associated with survival. In conclusion, mutational load, as determined by an NGS platform available in the clinic, effectively stratified patients by likelihood of response. This approach may provide a clinically feasible predictor of response to anti-PD-1/PD-L1.

原文English
頁(從 - 到)959-967
頁數9
期刊Cancer Immunology Research
4
發行號11
DOIs
出版狀態Published - 2016 十一月

All Science Journal Classification (ASJC) codes

  • 免疫學
  • 癌症研究

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