@article{31c85e10e979491ea44232e473e5624a,
title = "Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade",
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{\textquoteright} tissue of origin.",
author = "Le, {Dung T.} and Durham, {Jennifer N.} and Smith, {Kellie N.} and Hao Wang and Bartlett, {Bjarne R.} and Aulakh, {Laveet K.} and Steve Lu and Holly Kemberling and Cara Wilt and Luber, {Brandon S.} and Fay Wong and Azad, {Nilofer S.} and Rucki, {Agnieszka A.} and Dan Laheru and Ross Donehower and Atif Zaheer and Fisher, {George A.} and Crocenzi, {Todd S.} and Lee, {James J.} and Greten, {Tim F.} and Duffy, {Austin G.} and Ciombor, {Kristen K.} and Eyring, {Aleksandra D.} and Lam, {Bao H.} and Andrew Joe and Kang, {S. Peter} and Matthias Holdhoff and Ludmila Danilova and Leslie Cope and Christian Meyer and Shibin Zhou and Goldberg, {Richard M.} and Armstrong, {Deborah K.} and Bever, {Katherine M.} and Fader, {Amanda N.} and Janis Taube and Franck Housseau and David Spetzler and Nianqing Xiao and Pardoll, {Drew M.} and Nickolas Papadopoulos and Kinzler, {Kenneth W.} and Eshleman, {James R.} and Bert Vogelstein and Anders, {Robert A.} and Diaz, {Luis A.}",
note = "Funding Information: The data reported are tabulated in the main text and supplementary materials. The raw TCR RNA sequence data have been deposited into the ImmuneACCESS project repository of the Adaptive Biotech database, under the following link: https://clients.adaptivebiotech.com/pub/diaz-2017-science. We thank K. Helwig for administrative support, C. Blair for outstanding technical assistance, and E. H. Rubin, R. Dansey, and R. Perlmutter at Merck & Co. Inc. (Kenilworth, NJ) for supporting this research. Funded by the Swim Across America Laboratory at Johns Hopkins, the Ludwig Center for Cancer Genetics and Therapeutics, the Howard Hughes Medical Institutes, the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, the 2017 Stand Up to Cancer Colon Cancer Dream Team, the Commonwealth Fund, the Banyan Gate Foundation, the Lustgarten Foundation for Pancreatic Cancer Research, the Bloomberg Foundation, the Sol Goldman Pancreatic Cancer Research Center, Merck & Co. Inc., Gastrointestinal SPORE grant P50CA062924, and NIH grants P30CA006973, CA163672, CA43460, CA203891, CA67941, CA16058, and CA57345. L.D., D.L., B.V., N.P., and K.W.K. are inventors on a patent application (PCT/US2015/060331 or WO 2016077553 A1) submitted by Johns Hopkins University that covers checkpoint blockade and microsatellite instability. L.D., B.V., N.P., and K.W.K. are founders of PapGene and Personal Genome Diagnostics (PGDx). L.D. is a consultant for Merck, Illumina, PGDx, and Cell Design Labs. PGDx and PapGene, as well as other companies, have licensed technologies from Johns Hopkins University, on which L.D., B.V., N.P., and K.W.K. are inventors. Some of these licenses and relationships are associated with equity or royalty payments. The terms of these arrangements are being managed by Johns Hopkins and Memorial Sloan Kettering in accordance with its conflict-of-interest policies. Publisher Copyright: {\textcopyright} 2017, American Association for the Advancement of Science. All rights reserved.",
year = "2017",
month = jul,
day = "28",
doi = "10.1126/science.aan6733",
language = "English (US)",
volume = "357",
pages = "409--413",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6349",
}