Fine-Tuning Immunotherapy in MMR-D/MSI-H Colorectal Cancer

Abstract

Keywords: colorectal cancer • immune checkpoint inhibitor • immunotherapy • ipilimumab • MLH-1 • MMR-D • MSH-2 • MSH-6 • MSI-H • nivolumab • pembrolizumab • PMS-2 Colorectal cancer with mismatch repair deficiency (MMR-D) has been a focus of interest for cancer researchers due to its unique features, including increased mutation-associated neoantigen (MANA) generation and the presence of tumor-infiltrating lymphocytes in the tumor microenvironment. MMR-D, defined as the loss of function in any of four MMR genes (MLH1, PMS2, MSH2 and MSH6), sets off defective DNA repair-particularly during the DNA replication process-leading to microsatellite instability (MSI), which causes frameshift mutations in the DNA [1]. Based on the number or percentage of altered microsatellite markers, MSI can be classified into MSI-low (MSI-L) and MSI-high (MSI-H) [2]. Unlike point mutations, frameshift mutations frequently result in significant changes in the amino acid sequence of affected proteins. This change forms MANAs leading to the induction of adaptive immune system elements, particularly cytotoxic T cells [3]. This immune response against MANA constitutes the basis for the recent therapeutic success of immune checkpoint inhibitors in MMR-D/MSI-H colorectal cancer patients. Pembrolizumab, an anti-PD-1 antibody, became the first immune checkpoint inhibitor approved in MMR-D/MSI-H cancer patients based on an objective response rate (ORR) of 40%, which was durable [4]. Notably, this benefit was observed across all MMR-D/MSI-H cancers and thus, regardless of the tumor histology, the US FDA granted approval to pembrolizumab as a second line or subsequent therapy [5]. In this study, the authors identified that the MANAs may be the surrogate for the duration of response, suggesting that the major determinant of the immune response is the quality/nature of the mutation(s), rather than their quantity. This study was followed by clinical trials investigating the efficacy of nivolumab (an anti-PD1 antibody) and nivolumab, in combination with ipilimumab (a cytotoxic T lymphocyte-associated protein-4 [CTLA4] antibody). Both studies revealed promising results with ORR ranging between 31 and 55%, in metastatic MMR-D/MSI-H colorectal cancer patients who were previously treated with at least one line of chemotherapy [6,7]. Notably, in these studies, the authors investigated biomarkers of immune checkpoint inhibitor response including, PD-1 expression and BRAF/KRAS mutations. Curiously, none of these markers correlated with clinical outcomes. However, in the study of nivolumab and ipilimumab combination [7], the ORR was 71% in patients with a history of Lynch syndrome, which was numerically higher than when compared with patients who had sporadic MMR-D/MSI-H disease (48%). This notable finding suggests that there may be disease heterogeneity among MMR-D/MSI-H colorectal cancer patients, particularly with BRAF-driven MMR-D/MSI-H colorectal cancer, which frequently occurs as a result of hypermethylation of the MLH1 promoter region. However, the durability of response was not examined by BRAF mutation and Lynch syndrome status, which are fundamental causes of disease heterogeneity among MMR-D/MSI-H colorectal cancer patients. It is also important to note, MMR-D-associated colorectal cancer may present as MSI-L disease, which carries a relatively low mutation burden when compared with MSI-H tumors. It is unclear at this time if this leads to a distinct clinical course in patients treated with immune checkpoint inhibitors [2]. Notably, immunohistochemistry,