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.

Cancer Stem Cell Marker DCLK1 Correlates with Tumorigenic Immune Infiltrates in the Colon and Gastric Adenocarcinoma Microenvironments

“…Despite advances in the understanding of GI cancer biology and in surgery and immunotherapy in recent years, little impact has been made on the mortality associated with advanced GI cancers [15,16,66]. Therefore, there is an unmet need to find new immune-related therapeutic approaches against GI cancer.…”

“…To determine the DCLK1 expression in these contexts, we performed the CMS analysis of COAD dataset ( Figure 7A). DCLK1 expression was upregulated specifically in the CMS4 which has the worst outcomes among the four subtypes ( Figure 7B) [66]. In addition, we analyzed the CMS subtypes of left-sided and right-sided colon cancers, and found that left-sided colon cancer was more likely to be CMS4 ( Figure 7C).…”

Identification of Distinct Immune Subtypes in Colorectal Cancer Based on the Stromal Compartment

“…Taken together, our results provide a systematic analysis of the biological changes in the epithelial and stromal compartments of colorectal cancer. Immunotherapy for colorectal cancer is approved only for microsatellite instability-high (MSI-H) patients, which comprise only a small subset (64), by the Food and Drug Administration (FDA). Since the TMB level of colorectal cancer ranks higher than that in other cancers (e.g., TCGA pan-cancer) (65), we have good reason to believe that the prospects for immunotherapy in colorectal cancer are optimistic.…”

Immunotherapy, Inflammation and Colorectal Cancer

“…Immunotherapy, particularly ICI, has revolutionized cancer treatment, and although response rates rarely exceed 20%, those who do respond show a durable response [95][96][97]. The responsiveness to ICI was suggested to depend on several key factors, including mutational load (high levels of tumor neoantigens), tumor-infiltrating lymphocytes and regulatory checkpoint receptors.…”