Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. - PubMed - NCBI
Science. 2017 Jul 28;357(6349):409-413. doi: 10.1126/science.aan6733. Epub 2017 Jun 8.
Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.
Le DT1,2,3,
Durham JN1,2,3,
Smith KN1,3,
Wang H3,
Bartlett BR2,4,
Aulakh LK2,4,
Lu S2,4,
Kemberling H3,
Wilt C3,
Luber BS3,
Wong F2,4,
Azad NS1,3,
Rucki AA1,3,
Laheru D3,
Donehower R3,
Zaheer A5,
Fisher GA6,
Crocenzi TS7,
Lee JJ8,
Greten TF9,
Duffy AG9,
Ciombor KK10,
Eyring AD11,
Lam BH11,
Joe A11,
Kang SP11,
Holdhoff M3,
Danilova L1,3,
Cope L1,3,
Meyer C3,
Zhou S1,3,4,
Goldberg RM12,
Armstrong DK3,
Bever KM3,
Fader AN13,
Taube J1,3,
Housseau F1,3,
Spetzler D14,
Xiao N14,
Pardoll DM1,3,
Papadopoulos N3,4,
Kinzler KW3,4,
Eshleman JR15,
Vogelstein B1,3,4,
Anders RA1,3,15,
Diaz LA Jr16,2,3.
Abstract
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. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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