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Hypermutated Tumors and Immune Checkpoint Inhibition

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Abstract

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.

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Authors and Affiliations

  1. Division of Hematology and Oncology, Department of Internal Medicine, Vanderbilt-Ingram Cancer Center, 2220 Pierce Avenue, 777 Preston Research Building, Nashville, TN, 37232, USA

    Kristen K. Ciombor

  2. West Virginia University Cancer Institute, P.O. Box 9300, 1801 HSS, 1 Medical Center Drive, Morgantown, WV, 26506, USA

    Richard M. Goldberg

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  1. Kristen K. Ciombor
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  2. Richard M. Goldberg
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Correspondence to Richard M. Goldberg.

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Conflict of interest

Both authors (KKC, RMG) have received research funding from Merck. KKC has also received research funding from Bristol-Myers Squibb. RMG has served as a paid consultant to Merck and Merck KGA.

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Ciombor, K.K., Goldberg, R.M. Hypermutated Tumors and Immune Checkpoint Inhibition. Drugs 78, 155–162 (2018). https://doi.org/10.1007/s40265-018-0863-0

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