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Cristescu R , Mogg R , Ayers M , Albright A , Murphy E , Yearley J , Sher X , Liu XQ , Lu H , Nebozhyn M , Zhang C , Lunceford JK , Joe A , Cheng J , Webber AL , Ibrahim N , Plimack ER , Ott PA , Seiwert TY , Ribas A , McClanahan TK , Tomassini JE , Loboda A , Kaufman D
Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy
Science. 2018 Oct 12;362(6411)
PMID: 30309915    PMCID: PMC6718162    URL: https://www.ncbi.nlm.nih.gov/pubmed/30309915
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Programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1) checkpoint blockade immunotherapy elicits durable antitumor effects in multiple cancers, yet not all patients respond. We report the evaluation of >300 patient samples across 22 tumor types from four KEYNOTE clinical trials. Tumor mutational burden (TMB) and a T cell-inflamed gene expression profile (GEP) exhibited joint predictive utility in identifying responders and nonresponders to the PD-1 antibody pembrolizumab. TMB and GEP were independently predictive of response and demonstrated low correlation, suggesting that they capture distinct features of neoantigenicity and T cell activation. Analysis of The Cancer Genome Atlas database showed TMB and GEP to have a low correlation, and analysis by joint stratification revealed biomarker-defined patterns of targetable-resistance biology. These biomarkers may have utility in clinical trial design by guiding rational selection of anti-PD-1 monotherapy and combination immunotherapy regimens.
1095-9203 Cristescu, Razvan Orcid: 0000-0002-9978-0339 Mogg, Robin Ayers, Mark Albright, Andrew Murphy, Erin Yearley, Jennifer Sher, Xinwei Orcid: 0000-0003-3977-3695 Liu, Xiao Qiao Orcid: 0000-0002-6371-6503 Lu, Hongchao Nebozhyn, Michael Zhang, Chunsheng Lunceford, Jared K Orcid: 0000-0001-8120-2277 Joe, Andrew Cheng, Jonathan Webber, Andrea L Orcid: 0000-0003-2463-0878 Ibrahim, Nageatte Orcid: 0000-0003-0794-949x Plimack, Elizabeth R Orcid: 0000-0002-7618-0744 Ott, Patrick A Seiwert, Tanguy Y Orcid: 0000-0001-7919-8272 Ribas, Antoni Orcid: 0000-0003-3669-8458 McClanahan, Terrill K Tomassini, Joanne E Orcid: 0000-0002-9399-2867 Loboda, Andrey Kaufman, David Journal Article Research Support, Non-U.S. Gov't United States Science. 2018 Oct 12;362(6411). pii: 362/6411/eaar3593. doi: 10.1126/science.aar3593.