Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy
Razvan Cristescu, Robin Mogg, Mark Ayers, Andrew Albright, Erin Murphy, Jennifer Yearley, Xinwei Sher, Xiao Qiao Liu, Hongchao Lu, Michael Nebozhyn, Chunsheng Zhang, Jared K Lunceford, Andrew Joe, Jonathan Cheng, Andrea L Webber, Nageatte Ibrahim, Elizabeth R Plimack, Patrick A Ott, Tanguy Y Seiwert, Antoni Ribas, Terrill K McClanahan, Joanne E Tomassini, Andrey Loboda, David Kaufman, Razvan Cristescu, Robin Mogg, Mark Ayers, Andrew Albright, Erin Murphy, Jennifer Yearley, Xinwei Sher, Xiao Qiao Liu, Hongchao Lu, Michael Nebozhyn, Chunsheng Zhang, Jared K Lunceford, Andrew Joe, Jonathan Cheng, Andrea L Webber, Nageatte Ibrahim, Elizabeth R Plimack, Patrick A Ott, Tanguy Y Seiwert, Antoni Ribas, Terrill K McClanahan, Joanne E Tomassini, Andrey Loboda, David Kaufman
Abstract
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.
Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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Source: PubMed