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

被引：1688

作者：

Cristescu, Razvan ^{[1
]}

Mogg, Robin ^{[1
,6
]}

Ayers, Mark ^{[1
]}

Albright, Andrew ^{[1
]}

Murphy, Erin ^{[1
]}

Yearley, Jennifer ^{[1
]}

Sher, Xinwei ^{[1
]}

Liu, Xiao Qiao ^{[1
]}

Lu, Hongchao ^{[1
]}

Nebozhyn, Michael ^{[1
]}

Zhang, Chunsheng ^{[1
]}

Lunceford, Jared ^{[1
]}

Joe, Andrew ^{[1
]}

Cheng, Jonathan ^{[1
]}

Webber, Andrea L. ^{[1
]}

Ibrahim, Nageatte ^{[1
]}

Plimack, Elizabeth R. ^{[2
]}

Ott, Patrick A. ^{[3
]}

Seiwert, Tanguy ^{[4
]}

Ribas, Antoni ^{[5
]}

McClanahan, Terrill K. ^{[1
]}

Tomassini, Joanne E. ^{[1
]}

Loboda, Andrey ^{[1
]}

Kaufman, David ^{[1
,6
]}

机构：

[1] Merck & Co Inc, Kenilworth, NJ 07033 USA

[2] Fox Chase Canc Ctr, 7701 Burholme Ave, Philadelphia, PA 19111 USA

[3] Dana Farber Canc Inst, Boston, MA 02215 USA

[4] Univ Chicago, Chicago, IL 60637 USA

[5] Univ Calif Los Angeles, Los Angeles, CA 90095 USA

[6] Bill & Melinda Gates Med Res Inst, Cambridge, MA 02139 USA

来源：

SCIENCE | 2018年 / 362卷 / 6411期

关键词：

CELL LUNG-CANCER; MISMATCH-REPAIR DEFICIENCY; PROGRAMMED DEATH LIGAND-1; SEQUENCING DATA; MUTATIONAL PROCESSES; METASTATIC MELANOMA; SOMATIC MUTATIONS; CLINICAL-RESPONSE; CTLA-4; BLOCKADE; COPY NUMBER;

D O I：

10.1126/science.aar3593

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：197 / +

页数：11

共 59 条

[1] Mutational signatures: the patterns of somatic mutations hidden in cancer genomes [J].

Alexandrov, Ludmil B. ;

Stratton, Michael R. .

CURRENT OPINION IN GENETICS & DEVELOPMENT, 2014, 24 :52-60

[2] Signatures of mutational processes in human cancer [J].

Alexandrov, Ludmil B. ;

Nik-Zainal, Serena ;

Wedge, David C. ;

Aparicio, Samuel A. J. R. ;

Behjati, Sam ;

Biankin, Andrew V. ;

Bignell, Graham R. ;

Bolli, Niccolo ;

Borg, Ake ;

Borresen-Dale, Anne-Lise ;

Boyault, Sandrine ;

Burkhardt, Birgit ;

Butler, Adam P. ;

Caldas, Carlos ;

Davies, Helen R. ;

Desmedt, Christine ;

Eils, Roland ;

Eyfjord, Jorunn Erla ;

Foekens, John A. ;

Greaves, Mel ;

Hosoda, Fumie ;

Hutter, Barbara ;

Ilicic, Tomislav ;

Imbeaud, Sandrine ;

Imielinsk, Marcin ;

Jaeger, Natalie ;

Jones, David T. W. ;

Jones, David ;

Knappskog, Stian ;

Kool, Marcel ;

Lakhani, Sunil R. ;

Lopez-Otin, Carlos ;

Martin, Sancha ;

Munshi, Nikhil C. ;

Nakamura, Hiromi ;

Northcott, Paul A. ;

Pajic, Marina ;

Papaemmanuil, Elli ;

Paradiso, Angelo ;

Pearson, John V. ;

Puente, Xose S. ;

Raine, Keiran ;

Ramakrishna, Manasa ;

Richardson, Andrea L. ;

Richter, Julia ;

Rosenstiel, Philip ;

Schlesner, Matthias ;

Schumacher, Ton N. ;

Span, Paul N. ;

Teague, Jon W. .

NATURE, 2013, 500 (7463) :415-+

[3] IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade [J].

Ayers, Mark ;

Lunceford, Jared ;

Nebozhyn, Michael ;

Murphy, Erin ;

Loboda, Andrey ;

Kaufman, David R. ;

Albright, Andrew ;

Cheng, Jonathan D. ;

Kang, S. Peter ;

Shankaran, Veena ;

Piha-Paul, Sarina A. ;

Yearley, Jennifer ;

Seiwert, Tanguy Y. ;

Ribas, Antoni ;

McClanahan, Terrill K. .

JOURNAL OF CLINICAL INVESTIGATION, 2017, 127 (08) :2930-2940

[4]

Chow L. Q., 2014, ANN ONCOL S4, V25, P14

[5] Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples [J].

Cibulskis, Kristian ;

Lawrence, Michael S. ;

Carter, Scott L. ;

Sivachenko, Andrey ;

Jaffe, David ;

Sougnez, Carrie ;

Gabriel, Stacey ;

Meyerson, Matthew ;

Lander, Eric S. ;

Getz, Gad .

NATURE BIOTECHNOLOGY, 2013, 31 (03) :213-219

[6] Unique Ectopic Lymph Node-Like Structures Present in Human Primary Colorectal Carcinoma Are Identified by Immune Gene Array Profiling [J].

Coppola, Domenico ;

Nebozhyn, Michael ;

Khalil, Farah ;

Dai, Hongyue ;

Yeatman, Timothy ;

Loboda, Andrey ;

Mule, James J. .

AMERICAN JOURNAL OF PATHOLOGY, 2011, 179 (01) :37-45

[7] A cell proliferation signature is a marker of extremely poor outcome in a subpopulation of breast cancer patients [J].

Dai, HY ;

van't Veer, L ;

Lamb, J ;

He, YD ;

Mao, M ;

Fine, BM ;

Bernards, R ;

de Vijver, MV ;

Deutsch, P ;

Sachs, A ;

Stoughton, R ;

Friend, S .

CANCER RESEARCH, 2005, 65 (10) :4059-4066

[8] Programmed Death-Ligand 1 Expression and Response to the Anti-Programmed Death 1 Antibody Pembrolizumab in Melanoma [J].

Daud, Adil I. ;

Wolchok, Jedd D. ;

Robert, Caroline ;

Hwu, Wen-Jen ;

Weber, Jeffrey S. ;

Ribas, Antoni ;

Hodi, F. Stephen ;

Joshua, Anthony M. ;

Kefford, Richard ;

Hersey, Peter ;

Joseph, Richard ;

Gangadhar, Tara C. ;

Dronca, Roxana ;

Patnaik, Amita ;

Zarour, Hassane ;

Roach, Charlotte ;

Toland, Grant ;

Lunceford, Jared K. ;

Li, Xiaoyun Nicole ;

Emancipator, Kenneth ;

Dolled-Filhart, Marisa ;

Kang, S. Peter ;

Ebbinghaus, Scot ;

Hamid, Omid .

JOURNAL OF CLINICAL ONCOLOGY, 2016, 34 (34) :4102-+

[9] Development of a Companion Diagnostic for Pembrolizumab in Non-Small Cell Lung Cancer Using Immunohistochemistry for Programmed Death Ligand-1 [J].

Dolled-Filhart, Marisa ;

Roach, Charlotte ;

Toland, Grant ;

Stanforth, Dave ;

Jansson, Malinka ;

Lubiniecki, Gregory M. ;

Ponto, Gary ;

Emancipator, Kenneth .

ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE, 2016, 140 (11) :1243-1249

[10] Development of a Prototype Immunohistochemistry Assay to Measure Programmed Death Ligand-1 Expression in Tumor Tissue [J].

Dolled-Filhart, Marisa ;

Locke, Darren ;

Murphy, Tiffany ;

Lynch, Frank ;

Yearley, Jennifer H. ;

Frisman, Dennis ;

Pierce, Robert ;

Weiner, Russell ;

Wu, Dianna ;

Emancipator, Kenneth .

ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE, 2016, 140 (11) :1259-1266

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