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

doi:10.1126/science.aar3593

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 RibasTerrill K. McClanahan, Joanne E. Tomassini, Andrey Loboda, David Kaufman

Research output: Contribution to journal › Article › peer-review

1641 Scopus citations

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 Tcell-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 Tcell 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.

Original language	English
Article number	eaar3593
Journal	Science
Volume	362
Issue number	6411
DOIs	https://doi.org/10.1126/science.aar3593
State	Published - Oct 12 2018

Keywords

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
Programmed Cell Death 1 Receptor/antagonists & inhibitors
T-Lymphocytes/immunology
Transcriptome
Tumor Burden/genetics

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Cristescu, R., Mogg, R., Ayers, M., Albright, A., Murphy, E., Yearley, J., Sher, X., Liu, X. Q., Lu, H., Nebozhyn, M., Zhang, C., Lunceford, J. K., Joe, A., Cheng, J., Webber, A. L., Ibrahim, N., Plimack, E. R., Ott, P. A., Seiwert, T. Y., ... Kaufman, D. (2018). Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science, 362(6411), Article eaar3593. https://doi.org/10.1126/science.aar3593

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title = "Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy",

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 Tcell-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 Tcell 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.",

keywords = "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, Programmed Cell Death 1 Receptor/antagonists & inhibitors, T-Lymphocytes/immunology, Transcriptome, Tumor Burden/genetics",

author = "Razvan Cristescu and Robin Mogg and Mark Ayers and Andrew Albright and Erin Murphy and Jennifer Yearley and Xinwei Sher and Liu, {Xiao Qiao} and Hongchao Lu and Michael Nebozhyn and Chunsheng Zhang and Lunceford, {Jared K.} and Andrew Joe and Jonathan Cheng and Webber, {Andrea L.} and Nageatte Ibrahim and Plimack, {Elizabeth R.} and Ott, {Patrick A.} and Seiwert, {Tanguy Y.} and Antoni Ribas and McClanahan, {Terrill K.} and Tomassini, {Joanne E.} and Andrey Loboda and David Kaufman",

year = "2018",

month = oct,

day = "12",

doi = "10.1126/science.aar3593",

language = "English",

volume = "362",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

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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 2018, 'Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy', Science, vol. 362, no. 6411, eaar3593. https://doi.org/10.1126/science.aar3593

TY - JOUR

T1 - Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy

AU - Cristescu, Razvan

AU - Mogg, Robin

AU - Ayers, Mark

AU - Albright, Andrew

AU - Murphy, Erin

AU - Yearley, Jennifer

AU - Sher, Xinwei

AU - Liu, Xiao Qiao

AU - Lu, Hongchao

AU - Nebozhyn, Michael

AU - Zhang, Chunsheng

AU - Lunceford, Jared K.

AU - Joe, Andrew

AU - Cheng, Jonathan

AU - Webber, Andrea L.

AU - Ibrahim, Nageatte

AU - Plimack, Elizabeth R.

AU - Ott, Patrick A.

AU - Seiwert, Tanguy Y.

AU - Ribas, Antoni

AU - McClanahan, Terrill K.

AU - Tomassini, Joanne E.

AU - Loboda, Andrey

AU - Kaufman, David

PY - 2018/10/12

Y1 - 2018/10/12

N2 - 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 Tcell-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 Tcell 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.

AB - 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 Tcell-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 Tcell 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.

KW - Antibodies, Monoclonal, Humanized/therapeutic use

KW - Antineoplastic Agents, Immunological/therapeutic use

KW - Biomarkers, Tumor/genetics

KW - Cell Cycle Checkpoints

KW - Genetic Markers

KW - Humans

KW - Immunotherapy

KW - Inflammation/genetics

KW - Molecular Targeted Therapy/methods

KW - Mutation

KW - Neoplasms/genetics

KW - Programmed Cell Death 1 Receptor/antagonists & inhibitors

KW - T-Lymphocytes/immunology

KW - Transcriptome

KW - Tumor Burden/genetics

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U2 - 10.1126/science.aar3593

DO - 10.1126/science.aar3593

M3 - Article

C2 - 30309915

SN - 0036-8075

VL - 362

JO - Science

JF - Science

IS - 6411

M1 - eaar3593

ER -

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

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Keywords

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