Treating Colorectal Cancer with Immunotherapy: Implications for Single versus Combination Therapy

Abstract

Purpose of review: Colorectal cancer (CRC) is the second leading cause of cancer-associated deaths in the United States, with most metastatic cases subsequently turning refractory to standard chemotherapy. One of the promising current interventions is immunotherapy that relies on harnessing the body's immune mechanisms to kill the cancer cells. The aim of this review is to highlight the implications of single versus combination immunotherapy and identify the molecular features and mutations that enhance or deter responsiveness.

Recent findings: Based on current findings, responsiveness is associated with deficiency of mismatch repair (dMMR) genes or presence of microsatellite instability (MSI-high), with high immunoscore and tumor-mutational burden contributing to better efficacy while BRAF mutation conferring no significant effect. Combination immunotherapy demonstrates better efficacy in treating MSI-high CRC compared to single agent immunotherapy or chemotherapy.

Summary: Given improved responsiveness and overall survival, there is potential for immunotherapy to change the standard of care for metastatic CRC. Furthermore, stratifying the patients by their molecular features and mutation status is critical for establishing care.

Keywords: Colorectal Cancer; Immunotherapy; Microsatellite Instability; Mismatch-repair; Nivolumab; Pembrolizumab.

Figure 1.

T-cell activation in the tumor microenvironment. A) CD8 T-cells recognizing tumor-associated antigens expressed on MHC class I on tumor cells, receiving co-stimulation from the interaction between CD28 and B7 molecules and resulting in the cytotoxic killing of the tumor cells via release of granzymes and perforins. The inhibitory receptors PD-1 and CTLA4 are not engaged with tumor-cells. B) Immune evasion by tumor cells by expressing inhibitory ligand PDL-1, which binds to PD-1 on T cells, and B7 molecules, which bind to CTLA4. Engagement with inhibitory ligands prevents the cytotoxic killing of tumor cells. C) Blockade of inhibitory receptors ligands interactions with a-PD1 and a-CTLA4 monoclonal antibodies, which results in the restoration of T cell function (Created with BioRender.com).