Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade

被引：5264

作者：

Le, Dung T. ^{[1
,2
,3
]}

Durham, Jennifer N. ^{[1
,2
,3
]}

Smith, Kellie N. ^{[1
,3
]}

Wang, Hao ^{[3
]}

Bartlett, Bjarne R. ^{[2
,4
]}

Aulakh, Laveet K. ^{[2
,4
]}

Lu, Steve ^{[2
,4
]}

Kemberling, Holly ^{[3
]}

Wilt, Cara ^{[3
]}

Luber, Brandon S. ^{[3
]}

Wong, Fay ^{[2
,4
]}

Azad, Nilofer S. ^{[1
,3
]}

Rucki, Agnieszka A. ^{[1
,3
]}

Laheru, Dan ^{[3
]}

Donehower, Ross ^{[3
]}

Zaheer, Atif ^{[5
]}

Fisher, George A. ^{[6
]}

Crocenzi, Todd S. ^{[7
]}

Lee, James J. ^{[8
]}

Greten, Tim F. ^{[9
]}

Duffy, Austin G. ^{[9
]}

Ciombor, Kristen K. ^{[10
]}

Eyring, Aleksandra D. ^{[11
]}

Lam, Bao H. ^{[11
]}

Joe, Andrew ^{[11
]}

Kang, S. Peter ^{[11
]}

Holdhoff, Matthias ^{[3
]}

Danilova, Ludmila ^{[1
,3
]}

Cope, Leslie ^{[1
,3
]}

Meyer, Christian ^{[3
]}

Zhou, Shibin ^{[1
,3
,4
]}

Goldberg, Richard M. ^{[12
]}

Armstrong, Deborah K. ^{[3
]}

Bever, Katherine M. ^{[3
]}

Fader, Amanda N. ^{[13
]}

Taube, Janis ^{[1
,3
]}

Housseau, Franck ^{[1
,3
]}

Spetzler, David ^{[14
]}

Xiao, Nianqing ^{[14
]}

Pardoll, Drew M. ^{[1
,3
]}

Papadopoulos, Nickolas ^{[3
,4
]}

Kinzler, Kenneth W. ^{[3
,4
]}

Eshleman, James R. ^{[15
]}

Vogelstein, Bert ^{[1
,3
,4
]}

Anders, Robert A. ^{[1
,3
,15
]}

Diaz, Luis A., Jr. ^{[1
,2
,3
,16
]}

机构：

[1] Bloomberg Kimmel Inst Canc Immunotherapy Johns Ho, Baltimore, MD 21287 USA

[2] Swim Amer Lab Johns Hopkins, Baltimore, MD 21287 USA

[3] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD 21287 USA

[4] Ludwig Ctr & Howard Hughes Med Inst Johns Hopkins, Baltimore, MD 21287 USA

[5] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21287 USA

[6] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA

[7] Providence Canc Ctr Providence Hlth & Serv, Portland, OR 97213 USA

[8] Univ Pittsburgh, Sch Med, Dept Med, Canc Inst, Pittsburgh, PA 15232 USA

[9] NIH, Gastrointestinal Malignancies Sect, Thoracic GI Oncol Branch, Ctr Canc Res, Bldg 10, Bethesda, MD 20892 USA

[10] Ohio State Univ, Ctr Comprehens Canc, Div Med Oncol, Columbus, OH 43210 USA

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

[12] West Virginia Univ, Canc Inst, Morgantown, WV 26506 USA

[13] Johns Hopkins Med, Dept Gynecol & Obstet, Baltimore, MD 21287 USA

[14] Caris Life Sci, Phoenix, AZ 85040 USA

[15] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21287 USA

[16] Mem Sloan Kettering Canc Ctr, Div Solid Tumor Oncol, New York, NY 10065 USA

来源：

SCIENCE | 2017年 / 357卷 / 6349期

关键词：

LONG-TERM SAFETY; CELL LUNG-CANCER; MICROSATELLITE INSTABILITY; COLORECTAL CARCINOMAS; RECEIVING NIVOLUMAB; CHECKPOINT BLOCKADE; SURVIVAL; IMMUNOTHERAPY; LYMPHOCYTES; NEOANTIGENS;

D O I：

10.1126/science.aan6733

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：

The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor-1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair-deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repair-deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers' tissue of origin.

引用

页码：409 / 413

页数：5

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