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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Vydáno v:Science (American Association for the Advancement of Science) Ročník 362; číslo 6411
Hlavní autoři: 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
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 12.10.2018
Témata:
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
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Shrnutí: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.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1095-9203
1095-9203
DOI:10.1126/science.aar3593