Hypermutated Tumors and Immune Checkpoint Inhibition

Microsatellite instability-high/DNA mismatch repair deficient tumors are found across the cancer spectrum and often harbor markedly increased numbers of mutations when compared to microsatellite stable/DNA mismatch repair proficient tumors. As a result of this high mutational load, tumor-infiltrating lymphocyte density is increased and more immunogenic neoepitopes are expressed, leading to upregulation of immune checkpoints in these tumors. Checkpoint inhibitors such as pembrolizumab and nivolumab, both immunoglobulin G4 (IgG4) monoclonal antibodies that block interactions between the programmed cell death receptor-1 and its ligands, have significant activity in this tumor class. This review will focus on hypermutated tumors and immuno-oncology drug development for this biologically unique tumor type, with an emphasis on FDA-approved immunotherapies for these cancers, as well as a short discussion of the many therapeutic and scientific challenges ahead in order to optimize the uses of this new class of drug.