Efficacy and side effects of immune checkpoint inhibitors in the treatment of colorectal cancer

Abstract

Colorectal cancers (CRCs) remain one of the most common and challenging neoplasia in the Western world. The response rate of immunotherapeutic treatment approaches in a subset of advanced CRCs is remarkable and has sustainably changed treatment regimens. Unfortunately, currently available immunotherapeutics only displayed significant antitumoral activity - in terms of progression free survival (PFS) and objective response rate (ORR) - in microsatellite instability-high (MSI-H)/DNA mismatch repair deficient (dMMR) CRCs. Subsequently, these remarkable results had led to the US Food and Drug Administration's approval of both immune checkpoint inhibitors (ICIs) pembrolizumab and nivolumab in the treatment of advanced MSI-H/dMMR CRCs. However, in microsatellite stable (MSS)/DNA mismatch repair proficient (pMMR) CRCs, ICIs have clearly failed to meet their expectations and are therefore not considered effective. As the vast majority of CRCs display a molecular MSS/pMMR profile, current treatment approaches endeavor to improve tumor immunogenicity that consecutively leads to increased proinflammatory cytokine levels as well as tumor infiltrating T-cells, which in turn may be targeted by various immunotherapeutic agents. Therefore, ongoing studies are investigating novel synergistic therapy modalities and approaches to overcome a "cold" to "hot" tumor conversion in MSS/pMMR CRCs. In this review, we summarize the efficacy and possible immune-related adverse events as well as novel therapeutic approaches of ICIs in the treatment of MSI-H/dMMR and MSS/pMMR CRCs.

Keywords: colorectal carcinoma (CRC); efficacy; immune checkpoint inhibitors (ICIs); side and adverse effects.

Figure 1.

Effect mechanism of PD-1-, PD-L1- and CTLA-4-inhibitors. (a) Interaction of PD-1 on T-cells with PD-L1 on tumor cells is blocked by inhibitors preventing cancer evasion from the immune system. (b) CTLA-4, which mediates immunosuppression via the co-stimulatory receptor 28, leads to an activation of the immune system when inhibited. APC, antigen presenting cell; MHC, major histocompatibility complex; PD-1, programmed cell death 1; PD-L1, programmed cell death ligand 1; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; TCR, T-cell receptor.

Figure 2.

Endoscopic finding of a severe immune checkpoint inhibitor colitis with large ulcers and mucosal erythema.