Publication Title
Science
Document Type
Article
Publication Date
7-28-2017
Keywords
Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antigens, Neoplasm; Biomarkers, Tumor; Brain Neoplasms; Cell Cycle Checkpoints; Colorectal Neoplasms; DNA Mismatch Repair; Disease-Free Survival; Female; Humans; Male; Middle Aged; Mutation; Neoplastic Syndromes, Hereditary; Programmed Cell Death 1 Receptor; T-Lymphocytes; Young Adult
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.
Area of Special Interest
Cancer
Specialty/Research Institute
Oncology
