Targeting Metastatic Colorectal Cancer with Immune Oncological Therapies

Abstract

Metastatic colorectal cancer carries poor prognosis, and current therapeutic regimes convey limited improvements in survival and high rates of detrimental side effects in patients that may not stand to benefit. Immunotherapy has revolutionised cancer treatment by restoring antitumoural mechanisms. However, the efficacy in metastatic colorectal cancer, is limited. A literature search was performed using Pubmed (Medline), Web of Knowledge, and Embase. Search terms included combinations of immunotherapy and metastatic colorectal cancer, primarily focusing on clinical trials in humans. Analysis of these studies included status of MMR/MSS, presence of combination strategies, and disease control rate and median overall survival. Evidence shows that immune checkpoint inhibitors, such as anti-PD1 and anti-PD-L1, show efficacy in less than 10% of patients with microsatellite stable, MMR proficient colorectal cancer. In the small subset of patients with microsatellite unstable, MMR deficient cancers, response rates were 40–50%. Combination strategies with immunotherapy are under investigation but have not yet restored antitumoural mechanisms to permit durable disease regression. Immunotherapy provides the potential to offer additional strategies to established chemotherapeutic regimes in metastatic colorectal cancer. Further research needs to establish which adjuncts to immune checkpoint inhibition can unpick resistance, and better predict which patients are likely to respond to individualised therapies to not just improve response rates but to temper unwarranted side effects.

Does Elevated Pre-Treatment Plasma PD-L1 Level Indicate an Increased Tumor Burden and Worse Prognosis in Metastatic Colorectal Cancer?

“…These mechanisms ultimately help the tumor to escape anti-tumor immunity [ 3 , 4 , 5 , 28 , 29 , 30 , 31 ]. Therefore, monoclonal antibodies have been developed to antagonize this inhibitory signaling, and in the last decade, several randomized clinical trials have investigated the efficacy and safety of immune checkpoint inhibitors, including anti-PD-1 and anti-PD-L1 drugs [ 29 , 30 , 31 , 32 , 33 , 34 ]. The most immunological response is expected in those (metastatic) CRC patients who have tumors with deficient mismatch-repair and/or high levels of microsatellite instability [ 29 , 35 , 36 ].…”

Real‐world effectiveness of regorafenib in the treatment of patients with metastatic colorectal cancer: A retrospective, observational study

“…The KEYNOTE‐177 study revealed that for patients with dMMR/MSI‐H, pembrolizumab was superior to chemotherapy as first‐line treatment in patients with mCRC, 20 but a phase 2 study showed that there are no clear clinical benefits of pembrolizumab in patients with pMMR/MSS 21 . Combination strategies of regorafenib with immunotherapy are still under investigation 22 . In the REGONIVO study, patients receiving regorafenib plus nivolumab had a significant benefit in terms of with a median PFS (7.9 months) 23 .…”

“…21 Combination strategies of regorafenib with immunotherapy are still under investigation. 22 In the REGONIVO study, patients receiving regorafenib plus nivolumab had a significant benefit in terms of with a median PFS (7.9 months). 23 VEGF inhibitors in combination with immune checkpoint inhibitors (ICIs) can restore tumor blood vessels to normal, increase the efficient initiation and activation of T-cell response, and reorganize the typical immunosuppressive tumor microenvironment, suggesting the synergistic effect between tumor immunotherapy and anti-VEGF therapy.…”

Integrative Analysis Revealed Stemness Features and a Novel Stemness-Related Classification in Colorectal Cancer Patients

“…These are crucial factors contributing to CRC development, treatment response, and prognosis. Although significant advancement has been made in the treatment of CRC, the prognosis of patients at later stages remains poor due to tumor metastasis, chemoresistance, and other factors (Galbraith et al, 2021;Zaborowski et al, 2021). Therefore, screening patients at a high potential risk of treatment failure or poor prognosis is critical.…”