Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer

被引：6317

作者：

Rizvi, Naiyer A. ^{[1
,2
]}

Hellmann, Matthew D. ^{[1
,2
]}

Snyder, Alexandra ^{[1
,2
,3
]}

Kvistborg, Pia ^{[4
]}

Makarov, Vladimir ^{[3
]}

Havel, Jonathan J. ^{[3
]}

Lee, William ^{[5
]}

Yuan, Jianda ^{[6
]}

Wong, Phillip ^{[6
]}

Ho, Teresa S. ^{[6
]}

Miller, Martin L. ^{[7
]}

Rekhtman, Natasha ^{[8
]}

Moreira, Andre L. ^{[8
]}

Ibrahim, Fawzia ^{[1
]}

Bruggeman, Cameron ^{[9
]}

Gasmi, Billel ^{[10
]}

Zappasodi, Roberta ^{[10
]}

Maeda, Yuka ^{[10
]}

Sander, Chris ^{[7
]}

Garon, Edward B. ^{[11
]}

Merghoub, Taha ^{[1
,10
]}

Wolchok, Jedd D. ^{[1
,2
,10
]}

Schumacher, Ton N. ^{[4
]}

Chan, Timothy A. ^{[2
,3
,5
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA

[2] Weill Cornell Med Coll, New York, NY 10065 USA

[3] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[4] Netherlands Canc Inst, Div Immunol, NL-1066 CX Amsterdam, Netherlands

[5] Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, New York, NY 10065 USA

[6] Mem Sloan Kettering Canc Ctr, Ludwig Ctr Canc Immunotherapy, Immune Monitoring Core, New York, NY 10065 USA

[7] Mem Sloan Kettering Canc Ctr, Computat Biol Program, New York, NY 10065 USA

[8] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA

[9] Columbia Univ, Dept Math, New York, NY 10027 USA

[10] Mem Sloan Kettering Canc Ctr, Ludwig Collaborat Lab, New York, NY 10065 USA

[11] Univ Calif Los Angeles, David Geffen Sch Med, Santa Monica, CA 90404 USA

来源：

SCIENCE | 2015年 / 348卷 / 6230期

关键词：

EXOME ANALYSIS REVEALS; TUMOR; IPILIMUMAB; NIVOLUMAB; MPDL3280A; RESPONSES; ANTIGENS; ANTIBODY; EPITOPE;

D O I：

10.1126/science.aaa1348

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：

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.

引用

页码：124 / 128

页数：5

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