Journal
SCIENCE
Volume 357, Issue 6349, Pages 409-413Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aan6733
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Funding
- Swim Across America Laboratory at Johns Hopkins
- Ludwig Center for Cancer Genetics and Therapeutics
- Howard Hughes Medical Institutes
- Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins
- Stand Up to Cancer Colon Cancer Dream Team
- Commonwealth Fund
- Banyan Gate Foundation
- Lustgarten Foundation for Pancreatic Cancer Research
- Bloomberg Foundation
- Sol Goldman Pancreatic Cancer Research Center
- Merck Co. Inc.
- Gastrointestinal SPORE grant [P50CA062924]
- NIH [P30CA006973, CA163672, CA43460, CA203891, CA67941, CA16058, CA57345]
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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.
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