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

作者：Dung Thi Le, Jennifer N. Durham, Kellie Nicole Smith, Hao Wang, Bjarne R. Bartlett, Laveet K. Aulakh, Steve Lu, Holly Kemberling, Cara Wilt, Brandon S. Luber, Fay Wong, Nilofer Saba Azad, Agnieszka A. Rucki, Dan A. Laheru, Ross C. Donehower, Atif Zaheer, George Albert Fisher, Todd S. Crocenzi, James J. Lee, Tim F. Greten, Austin G. Duffy, Kristen Keon Ciombor, Aleksandra D. Eyring, Bao H. Lam, Andrew K. Joe, Soonmo Peter Kang, Matthias Holdhoff, Ludmila Danilova, Leslie Cope, Christian Frederick Meyer, Shibin Zhou, Richard M. Goldberg, Deborah Kay Armstrong, Katherine M. Bever, Amanda N. Fader, Janis Marie Taube, Franck Housseau, David B. Spetzler, Nianqing Xiao, Drew M. Pardoll, Nickolas Papadopoulos, Kenneth W. Kinzler, James R. Eshleman, Bert Vogelstein, Robert A. Anders, Luis Alberto Diaz · 发表于：Science · 年份：2017 · DOI：10.1126/science.aan6733 · 被引用次数：6822 · 研究领域：Genetic factors in colorectal cancer、Cancer Immunotherapy and Biomarkers、Colorectal Cancer Treatments and Studies

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.