Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer
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- Naiyer A. Rizvi
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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- Matthew D. Hellmann
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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- Alexandra Snyder
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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- Pia Kvistborg
- Division of Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.
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- Vladimir Makarov
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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- Jonathan J. Havel
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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- William Lee
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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- Jianda Yuan
- Immune Monitoring Core, Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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- Phillip Wong
- Immune Monitoring Core, Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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- Teresa S. Ho
- Immune Monitoring Core, Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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- Martin L. Miller
- Computation Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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- Natasha Rekhtman
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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- Andre L. Moreira
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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- Fawzia Ibrahim
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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- Cameron Bruggeman
- Department of Mathematics, Columbia University, New York, NY, 10027, USA.
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- Billel Gasmi
- Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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- Roberta Zappasodi
- Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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- Yuka Maeda
- Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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- Chris Sander
- Computation Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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- Edward B. Garon
- David Geffen School of Medicine at UCLA, 2825 Santa Monica Boulevard, Suite 200, Santa Monica, CA 90404, USA.
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- Taha Merghoub
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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- Jedd D. Wolchok
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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- Ton N. Schumacher
- Division of Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.
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- Timothy A. Chan
- Weill Cornell Medical College, New York, NY, 10065, USA.
抄録
<jats:p>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.</jats:p>
収録刊行物
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- Science
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Science 348 (6230), 124-128, 2015-04-03
American Association for the Advancement of Science (AAAS)