Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy

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 clinica...

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Published in:Science (American Association for the Advancement of Science) Vol. 362; no. 6411
Main Authors: Cristescu, Razvan, Mogg, Robin, Ayers, Mark, Albright, Andrew, Murphy, Erin, Yearley, Jennifer, Sher, Xinwei, Liu, Xiao Qiao, Lu, Hongchao, Nebozhyn, Michael, Zhang, Chunsheng, Lunceford, Jared K, Joe, Andrew, Cheng, Jonathan, Webber, Andrea L, Ibrahim, Nageatte, Plimack, Elizabeth R, Ott, Patrick A, Seiwert, Tanguy Y, Ribas, Antoni, McClanahan, Terrill K, Tomassini, Joanne E, Loboda, Andrey, Kaufman, David
Format: Journal Article
Language:English
Published: United States 12.10.2018
Subjects:
Antibodies, Monoclonal, Humanized - therapeutic use
Antineoplastic Agents, Immunological - therapeutic use
Biomarkers, Tumor - genetics
Cell Cycle Checkpoints
Genetic Markers
Humans
Immunotherapy
Inflammation - genetics
Molecular Targeted Therapy - methods
Mutation
Neoplasms - genetics
Neoplasms - therapy
Programmed Cell Death 1 Receptor - antagonists & inhibitors
T-Lymphocytes - immunology
Transcriptome
Tumor Burden - genetics
ISSN:1095-9203, 1095-9203
Online Access:Get more information
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Summary: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.
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ISSN:1095-9203
1095-9203
DOI:10.1126/science.aar3593