Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade

TLDR

Cancers deficient in mismatch repair harbor exceptionally high somatic mutation loads, and colorectal tumors with this deficiency were previously shown to respond to PD‑1 blockade. The study expanded to assess PD‑1 blockade efficacy in advanced mismatch‑repair‑deficient cancers across 12 tumor types. In this expanded cohort, 53 % of patients achieved objective radiographic responses, 21 % achieved complete responses, and responses were durable with median progression‑free and overall survival not reached; functional analysis revealed rapid expansion of neoantigen‑specific T‑cell clones, supporting that the high neoantigen burden in mismatch‑repair‑deficient tumors confers sensitivity to PD‑1 blockade across tumor types.

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.