Deficient Mismatch Repair and the Role of Immunotherapy in Metastatic Colorectal Cancer
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Division of colorectal cancers (CRCs) into molecular subsets yields important consequences for prognosis and therapeutic response. The microsatellite instability (MSI) immune subgroup, accounting for 15 % of early-stage and 3 % of metastatic CRCs, are a result of deficient cellular DNA mismatch repair (dMMR) mechanisms. dMMR CRCs are notable for greater survivability, yet lack of benefit from fluoropyrimidine-based therapy in early-stage disease as compared to proficient DNA mismatch repair (pMMR) CRCs but are substantially lethal when metastatic. The surging interest in cancer immunotherapy, particularly checkpoint blockade, has further led to a focus on MSI tumors, which are notable for their substantial T cell infiltrate. In this review, we will discuss the biologic underpinnings for the immunogenicity of dMMR CRC and the preclinical development of therapies intended to modulate this immune response. Next, we will discuss the previous and ongoing clinical trials specifically designed to evaluate immunotherapeutic treatment of dMMR CRCs. Building on the success of the early immune checkpoint inhibitor clinical trials for dMMR CRC, combinations with other anti-tumor immunotherapies may provide an even more robust response, thereby, creating an alternative treatment regimen for those who have failed standard therapies or possibly resulting in prophylactic therapies for patients with highly oncogenic hereditary mismatch repair deficiencies.
KeywordsImmunotherapy Colorectal cancer Mismatch repair Microsatellite instability Immune checkpoint Tumor microenvironment
This work was partially funded by a 2015 Conquer Cancer Foundation of the American Society of Clinical Oncology Medical Student Rotation award (D.Q.).
Compliance with Ethical Standards
Conflict of Interest
Dionisia Quiroga declares that she has no conflict of interest.
H. Kim Lyerly declares that he has no conflict of interest.
Michael A. Morse will be participating as a clinical investigator in the Keynote-177 trial sponsored by Merck Sharp & Dohme Corporation (NCT02563002), but will not be receiving any direct financial compensation. He has also received financial support through grants from Bristol-Myers Squibb, Merck, Aduro Biotech, AlphaVax, and Advaxis, and has received compensation from EMD Serono for service as a consultant.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by either of the authors.
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