Immunotherapy in colon cancer

Immunotherapeutic approaches to cancer therapy are based upon the premise that the immune system plays a key role in surveillance and eradication of malignancy, and that tumors evolve ways to elude the immune system. Historically, mCRC was considered non-immunogenic, that is, incapable of inducing immune-mediated tumor destruction. However, the importance of the immune system in the biology of CRC is underscored by the finding that infiltration of the tumor by specific T cell immune infiltrates is highly correlated with better disease-free and overall survival at all tumor stages.These data suggest that an immune response to specific tumor antigens might drive improved outcomes. However, most tumor-associated antigens in CRC, while expressed at higher levels within tumor, are also expressed in other tissues. As a result, the tolerance mechanisms that suppress the immune response to self-antigens to minimize autoimmune disease may also serve to suppress the immune response to these tumor antigens. Based upon data on the immunogenicity of mutated antigens in melanoma, it has been hypothesized that neoantigens generated from tumor-specific mutations of self-antigens within CRC may be recognized by the immune system as foreign and could therefore trigger an antitumor immune response.Approximately 3.5 to 6.5 percent of stage IV CRCs are characterized as having high levels of microsatellite instability (MSI-H), which is the biologic footprint of deficiency in DNA mismatch repair enzymes (dMMR). Tumors that lack the mismatch repair mechanism harbor many more mutations (ie, they are hypermutated) than do tumors of the same type without such MMR defects, and as noted above, the neoantigens generated from mutations such as these have the potential to be recognized as non-self immunogenic antigens.One option for treatment at progression for patients who have MSI-H/dMMR tumors is immunotherapy with an immune checkpoint inhibitor that targets the programmed death receptor-1 (PD-1; ie, nivolumab, pembrolizumab). In clinical trials, objective response rates with these two PD-1 inhibitors are 30 to 50 percent, and some responses are durable. On May 23, 2017, the FDA granted accelerated approval to pembrolizumab for the treatment of patients with advanced MSI-H or dMMR mCRC that has progressed following conventional chemotherapy and in August 2017, the FDA extended the approval of nivolumab to MSI-H or dMMR mCRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan .