Publication Date:
2015-03-15
Description:
Immune checkpoint inhibitors, which unleash a patient's own T cells to kill tumors, are revolutionizing cancer treatment. To unravel the genomic determinants of response to this therapy, we used whole-exome sequencing of non-small cell lung cancers treated with pembrolizumab, an antibody targeting programmed cell death-1 (PD-1). In two independent cohorts, higher nonsynonymous mutation burden in tumors was associated with improved objective response, durable clinical benefit, and progression-free survival. Efficacy also correlated with the molecular smoking signature, higher neoantigen burden, and DNA repair pathway mutations; each factor was also associated with mutation burden. In one responder, neoantigen-specific CD8+ T cell responses paralleled tumor regression, suggesting that anti-PD-1 therapy enhances neoantigen-specific T cell reactivity. Our results suggest that the genomic landscape of lung cancers shapes response to anti-PD-1 therapy.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rizvi, Naiyer A -- Hellmann, Matthew D -- Snyder, Alexandra -- Kvistborg, Pia -- Makarov, Vladimir -- Havel, Jonathan J -- Lee, William -- Yuan, Jianda -- Wong, Phillip -- Ho, Teresa S -- Miller, Martin L -- Rekhtman, Natasha -- Moreira, Andre L -- Ibrahim, Fawzia -- Bruggeman, Cameron -- Gasmi, Billel -- Zappasodi, Roberta -- Maeda, Yuka -- Sander, Chris -- Garon, Edward B -- Merghoub, Taha -- Wolchok, Jedd D -- Schumacher, Ton N -- Chan, Timothy A -- K23 CA149079/CA/NCI NIH HHS/ -- P30 CA008748/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2015 Apr 3;348(6230):124-8. doi: 10.1126/science.aaa1348. Epub 2015 Mar 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY, 10065, USA. chant@mskcc.org. ; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY, 10065, USA. ; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY, 10065, USA. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. ; Division of Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands. ; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. ; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. ; Immune Monitoring Core, Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. ; Computation Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. ; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. ; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. ; Department of Mathematics, Columbia University, New York, NY, 10027, USA. ; Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. ; David Geffen School of Medicine at UCLA, 2825 Santa Monica Boulevard, Suite 200, Santa Monica, CA 90404, USA. ; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. ; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY, 10065, USA. Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. ; Weill Cornell Medical College, New York, NY, 10065, USA. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. chant@mskcc.org.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25765070" target="_blank"〉PubMed〈/a〉
Keywords:
Antibodies, Monoclonal, Humanized/*therapeutic use
;
Antineoplastic Agents/*therapeutic use
;
CD8-Positive T-Lymphocytes/immunology
;
Carcinoma, Non-Small-Cell Lung/*drug therapy/*genetics/immunology
;
Cohort Studies
;
DNA Repair/genetics
;
Disease-Free Survival
;
Drug Resistance, Neoplasm/*genetics
;
Humans
;
Lung Neoplasms/*drug therapy/*genetics/immunology
;
Mutation
;
Programmed Cell Death 1 Receptor/*antagonists & inhibitors
;
Smoking/genetics
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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