Neoadjuvant Immunotherapy for MSI-H/dMMR Locally Advanced Colorectal Cancer: New Strategies and Unveiled Opportunities

Abstract

Patients with locally advanced colorectal cancer (LACRC) have a high risk of recurrence and metastasis, although neoadjuvant therapy may provide some benefit. However, patients with high microsatellite instability/deficient mismatch repair (MSI-H/dMMR) LACRC receive little benefit from neoadjuvant chemoradiotherapy (nCRT) or neoadjuvant chemotherapy (nCT). The 2015 KEYNOTE-016 trial identified MSI-H/dMMR as a biomarker indicative of immunotherapy efficacy, and pointed to the potential use of immune checkpoint inhibitors (ICIs). In 2017, the FDA approved two ICIs (pembrolizumab and nivolumab) for treatment of MSI-H/dMMR metastatic CRC (mCRC). In 2018, the CheckMate-142 trial demonstrated successful treatment of mCRC based on “double immunity” provided by nivolumab with ipilimumab, a regimen that may become a standard first-line treatment for MSI-H mCRC. In 2018, the FDA approved nivolumab alone or with ipilimumab for patients who progressed to MSI-H/dMMR mCRC after standard chemotherapy. The FDA then approved pembrolizumab alone as a first-line treatment for patients with MSI-H/dMMR CRC that was unresectable or metastatic. There is now interest in using these drugs in neoadjuvant immunotherapy (nIT) for patients with MSI-H/dMMR non-mCRC. In 2020, the NICHE trial marked the start of using nIT for CRC. This novel treatment of MSI-H/dMMR LACRC may change the approaches used for neoadjuvant therapy of other cancers. Our review of immunotherapy for CRC covers diagnosis and treatment, clinical prognostic characteristics, the mechanism of nIT, analysis of completed prospective and retrospective studies, and ongoing clinical trials, and the clinical practice of using nIT for MSI-H/dMMR LACRC. Our team also proposes a new organ-preservation strategy for patients with MSI-H/dMMR low LARC.

An immuno-score signature of tumor immune microenvironment predicts clinical outcomes in locally advanced rectal cancer

“…In the past, immune factors in the nCRT response of LARCs have been largely ignored. Recently, the presence of pretherapy immune cell infiltration correlated with response to radiotherapy or chemotherapy in LARC has gradually begun to be emphasized (27)(28)(29). In consequence, identifying a reliable and feasible scoring system related to the immune microenvironment may play a significant role in the clinical management of LARCs.…”

Association between microsatellite instability and tumor response to neoadjuvant chemoradiotherapy for rectal cancer

“…In fact, some studies have reported that patients with MSI-H rectal cancers showed worse survival [ 21 22 ], which is in accordance with the poor response to nCRT in the present study. These results may be the basis for performing tailored treatments such as neoadjuvant immunotherapy in patients with MSI-H rectal cancer [ 23 ] according to the results of pretreatment MSI testing on colonoscopic biopsy [ 18 22 ].…”

Long-term benefit of immunotherapy in a patient with mismatch repair deficient/microsatellite instability-high/high tumor mutational burden lung cancer: case report and literature review

“…As a result, pembrolizumab was approved by the FDA for the treatment of MSI-H/dMMR cancer that are unresectable and have metastasized. [14] In the CheckMate-142 study, [15] nivolumab alone and nivolunmab plus ipilimumab were used to treat dMMR/MSI-H colorectal cancer; the patients were followed up for a median of 21 and 25.4 months, respectively, and demonstrated objective response rates of 34% and 58%, respectively. Furthermore, the nivolunmab plus ipilimumab group had a disease control rate of 81%, 12-month progression-free survival(PFS) rate of 71%, and 12-month overall survival rate of 85%.…”