Immunotherapy for Colorectal Cancer: A Review of Current and Novel Therapeutic Approaches

Abstract

Colorectal cancer (CRC) remains a leading cause of cancer-related deaths in the United States. Although immunotherapy has dramatically changed the landscape of treatment for many advanced cancers, the benefit in CRC has thus far been limited to patients with microsatellite instability high (MSI-H):DNA mismatch repair-deficient (dMMR) tumors. Recent studies in the refractory CRC setting have led to US Food and Drug Administration approvals for pembrolizumab as well as nivolumab (with or without ipilimumab) for tumors harboring an MSI-H:dMMR molecular profile. Several randomized controlled trials are underway to move immunotherapy into the frontline for metastatic cancer (with or without chemotherapy) and the adjuvant setting. Awareness of these studies is critical given the relatively low incidence (approximately 3%-5%) of MSI-H:dMMR in advanced or metastatic CRC to support study completion, because the results could be potentially practice changing. The real challenge in this disease is related to demonstrating the benefit of immunotherapy for the vast majority of patients with CRC not harboring MSI-H:dMMR. Given the rapid pace of scientific changes, this article provides a narrative review regarding the current landscape of immunotherapy for CRC. Particular attention is paid to the currently available data that inform today's clinical practice along with upcoming randomized controlled trials that may soon dramatically change the treatment landscape for CRC.

Figure 1.

Select targets of immunotherapy therapeutics currently under investigation in colorectal cancer clinical trials. AKT = protein kinase B kinase (AKT8 virus oncogene cellular homolog); APC = antigen-presenting cell; CTLA-4 = cytotoxic T-lymphocyte-associated protein 4; EGFR = epidermal growth factor receptor; ERK = extracellular signal-regulated kinase; GITR = glucocorticoid-induced TNF receptor family-related protein; IDO = indoleamine 2, 3-dioxygenase; LAG3 = lymphocyte-activation gene 3; MEK = mitogen-activated protein extracellular signal-regulated kinase; MHC = major histocompatibility complex; NF-kB = nuclear factor kappa-light-chain-enhancer of activated B cells; PD-1 = programmed cell death 1; PD-L1 = PD-1 ligand; PI3K = phosphoinositide 3-kinase; RAF = rapidly accelerated fibrosarcoma; RAS = rat sarcoma; TLR = Toll-like receptor; VEGF = vascular endothelial growth factor.