The Emerging Role of Checkpoint Inhibition in Microsatellite Stable Colorectal Cancer

Abstract

Checkpoint inhibitor therapy has introduced a revolution in contemporary anticancer therapy. It has led to dramatic improvements in patient outcomes and has spawned tremendous research into novel immunomodulatory agents and combination therapy that has changed the trajectory of cancer care. However, clinical benefit in patients with colorectal cancer has been generally limited to tumors with loss of mismatch repair function and those with specific germline mutations in the DNA polymerase gene. Unfortunately, tumors with these specific mutator phenotypes are in the minority. Recent pre-clinical and clinical studies have begun to reveal encouraging results suggesting that checkpoint inhibitor therapy can be expanded to an increasing number of colorectal tumors with microsatellite stability and the absence of traditional predictive biomarkers of checkpoint inhibitor response. These studies generally rely on combinations of checkpoint inhibitors with chemotherapy, molecular targeted therapy, radiation therapy, or other novel immunomodulatory agents. This article will review the most current data in microsatellite stable colorectal cancer.

Relationship between microsatellite status and immune microenvironment of colorectal cancer and its application to diagnosis and treatment

“…Recent preclinical and clinical studies have shown that ICIs combined with chemotherapy, molecular targeted therapy, radiotherapy, or new immunomodulators can act synergistically and extend the application of ICIs to MSS type CRC. 7,110,111…”

Genomic Alterations and Their Implications on Survival in Nonmetastatic Colorectal Cancer: Status Quo and Future Perspectives

“…Although improved responses with immunotherapy have been reported in patients with metastatic MSI-H/dMMR CRCs, these responses are not seen in the majority of MSS/pMMR CRCs. Numerous trials of combined immunotherapy with other agents aimed at "sensitizing" these tumors are ongoing [132,133].…”

Antibiotics and immunotherapy in gastrointestinal tumors: Friend or foe?

“…The immunological benefit in patients with colorectal cancer has been limited to those who had a loss of mismatch repair function and had specific germline mutations in the DNA polymerase gene[34,35]. A host of current trials are underway in patients with microsatellite stable (MSS) CRC to evaluate the utility of concurrent chemotherapy, VEGF/EGFR inhibitors, radiotherapy, or MEK inhibitors with ICIs; however, more data are still needed to address the efficacy and tolerability of ICIs in MSS CRC patients[36].…”