Document Type

Article

Publication Title

Discovery Medicine

Abstract

Colon cancer accounts for nearly 10% of all cancer diagnoses annually. Microsatellite instability-high (MSI-H) colon cancer is a particularly aggressive subtype of colon cancer that is known to have a significant number of genetic mutations. Microsatellite instability (MSI) refers to genetic hypermutability caused by the dysfunction of the DNA mismatch repair (MMR) system, which leads to errors in repetitive DNA sequences and is a hallmark of certain cancers, including MSI-H colon cancer. MSI-H colon cancer acts on the DNA mismatch repair system causing an accumulation of mutations in microsatellite regions of the DNA. These mutations have been linked with increased tumorigenesis and decreased response to conventional forms of chemotherapy for colon cancer. However, this increased tumor burden results in significant production of neoantigens which makes these tumors immunogenic and therefore perfect candidates for pairing with immunotherapy. As a result, adjuvant immunotherapy in MSI-H colon cancer has become a burgeoning field of research, and synthesizing information regarding the efficacy of these immunotherapies is the goal of this literature review. Pembrolizumab, a monoclonal antibody targeting programmed cell death protein 1 (PD-1), was among the first to receive approval for the treatment of MSI-H colon cancer and was observed to have significant efficacy versus traditional chemotherapy with statistically significant improvements in metrics such as progression-free survival (PFS), overall response (OR), and disease-free survival (DFS). Similarly, Nivolumab, another PD-1 inhibitor, and the combination of nivolumab and ipilimumab (a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor) were granted Food and Drug Administration (FDA) approval for the treatment of MSI-H colon cancer and have also shown the ability to outperform traditional chemotherapy with a higher overall response rate (ORR), mean PFS, and overall survival rates. Off-label uses of existing adjuvant immunotherapies such as Atezolizumab (a programmed death-ligand 1 (PD-L1) inhibitor) and Durvalumab (a PD-L1 inhibitor) have shown promise with preliminary results showing higher DFS and recurrence-free survival but need further data collection. Emerging immunotherapy targets such as lymphocyte activation gene 3 (LAG-3) and T-cell immunoreceptor with immunoglobin and Immunoreceptor Tyrosine-based Inhibitory Motif domains (TIGIT) inhibitors show preliminary promise and may one day become a part of the approach to the treatment of MSI-H colon cancer. This review highlights current advancements, challenges, and emerging trends in the application of immunotherapy for MSI-H colon cancer, with a focus on improving patient outcomes.

DOI

10.24976/Discov.Med.202537196.71

Publication Date

5-2025

Keywords

MSI-H, adjuvant immunotherapy, colon cancer, emerging immunotherapies, immune checkpoint inhibitors, translational oncology, tumor microenvironment

ISSN

1944-7930

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