2017/07/27 by Dung T. Le, Jennifer N. Durham, Kellie N. Smith +43 · 6,732 citations
Medicine · #Genetic factors in colorectal cancer #Cancer Immunotherapy and Biomarkers #Colorectal Cancer Treatments and Studies #Blockade #Solid tumor #Medicine #Cancer research #Internal medicine #Cancer #Receptor
paper · doi:10.1126/science.aan6733
published in Science 357(6349), 409-413 (American Association for the Advancement of Science)
openalex publication_date 2017/07/27 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/06
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.