Abstract
Checkpoint inhibitor therapy has introduced a revolution in contemporary anticancer therapy. It has led to dramatic improvements in patient outcomes and has spawned tremendous research into novel immunomodulatory agents and combination therapy that has changed the trajectory of cancer care. However, clinical benefit in patients with colorectal cancer has been generally limited to tumors with loss of mismatch repair function and those with specific germline mutations in the DNA polymerase gene. Unfortunately, tumors with these specific mutator phenotypes are in the minority. Recent pre-clinical and clinical studies have begun to reveal encouraging results suggesting that checkpoint inhibitor therapy can be expanded to an increasing number of colorectal tumors with microsatellite stability and the absence of traditional predictive biomarkers of checkpoint inhibitor response. These studies generally rely on combinations of checkpoint inhibitors with chemotherapy, molecular targeted therapy, radiation therapy, or other novel immunomodulatory agents. This article will review the most current data in microsatellite stable colorectal cancer.
Highlights
The dynamic interplay between tumor cells and the host immune system is instrumental in the evolution, progression and therapeutic susceptibility of colorectal cancer (CRC)
A randomized phase II trial of FOLFOX plus bevacizumab with or without pelareorep, an oncolytic reovirus that replicates in RAS mutated cells, in patients with metastatic CRC noted that the study cohort had a statistically increased objective response rate (ORR) and a statistically reduced progression-free survival (PFS) and duration of response [35]
Cells include heat shock protein 90 (HSP90), for which the inhibitor XL888 is being combined with pembrolizumab, as well as Bruton’s tyrosine kinase (BTK) on myeloid-derived suppressor cells suppressor cells (MDSCs), for which the BTK-inhibitor ibrutinib is being combined with pembrolizumab in microsatellite stable (MSS) CRC [46,47]
Summary
The dynamic interplay between tumor cells and the host immune system is instrumental in the evolution, progression and therapeutic susceptibility of colorectal cancer (CRC). Strategies involve innovative therapeutic combinatorial approaches to sensitize “immuno-cold” MSS tumors to the overcoming the immunosuppressive tumor microenvironment (see Figure 2), boosting effector T-cell activating effect of ICIs are currently under investigation, with the goal of surmounting intrinsic function, increasing tumor antigenicity, and up-regulating diverse molecular mediators to elicit a more mechanisms of immune resistance that impair checkpoint monotherapy efficacy. As a proof-of-principle, administration of oxaliplatin led to an increase in the overall immune response to a PD-L1 trap fusion protein in an in vivo murine pMMR CRC model [12] Substantiated by these preclinical findings, results from a phase 3 trial of 559 patients with untreated, metastatic squamous non-small cell lung cancer (Keynote 407) showed an improved median overall survival (15.9 mo vs 11.3 mo, P < 0.001) in patients receiving the PD-1 inhibitor pembrolizumab in combination with platinum-based chemotherapy first-line, irrespective of PD-L1 status [13]. The following is a table of ongoing studies testing these agents together (see Table 4)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
