Cancer Genetics and Epigenetics 2024, Vol.12, No.5, 234-253 http://medscipublisher.com/index.php/cge 238 In colon cancer, particularly in cases with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) tumors, PD-1 inhibitors have demonstrated significant efficacy. These tumors exhibit high mutational burdens, leading to the production of numerous neoantigens that make them more recognizable to the immune system (Lazarus et al., 2018). Clinical trials have shown that PD-1 inhibitors can achieve durable responses in a subset of patients with MSI-H colon cancer, providing a new therapeutic option for these individuals (André et al., 2020). Table 1 showed immunotherapy response in CRC patients based on clinical trials. Table 1 Mono or dual ICIs Trail name Sample size Treatment Phase Primary outcomes Results KEYNOTE-177 (André et al., 2020) 307 Pembrolizumab vs. Chemotherapy III Survival rate and PFS at 12 months and 24 months Pembrolizumab group: 55.3% (95% CI: 47.0-62.9) and 48.3% (95% CI: 39.9-56.2); Chemotherapy group: 37.3% (95% CI: 29.0-45.5) and 18.6% (95% CI: 12.1-26.3). Checkmate 142 (Lenz et al., 2022) 45 Nivolumab + Ipilimumab II ORR, DCR ORR: 69% (95% CI: 53 to 82) Disease control rate: 84% (95% CI, 70.5 to 93.5), with a 13% complete response rate. ANICCA (Middleton et al., 2022) 35 Nivolumab II DCB – no progression at 27 weeks, OR, PFS, OS DCB: 3/35 (8.6%), OR: 0%, mPFS: 9.1 weeks (95% CI: 9.0, 9.8), mOS 29.6 weeks (95% CI: 17.3, 42.1). NCT03860272 (Bullock et al., 2022) 59 Botensilimab + balstilimab I ORR, DCR; DOR, PFS,OS ORR: 24% (10/41), DCR: 73% (30/41), and DOR ranged from 0.0+-17.0+months; The updated data from the World GI Congress (n = 87): ORR in patients without liver mets 23%, ORR in patients with liver mets 0% Ongoing. CO.26 Study (Chen et al., 2020) 180 Tremelimumab + durvalumab vs. BSC II OS and a 2-sided P<.10 Durvalumab and tremelimumab group: 6.6 months BSC group: 4.1 months(HR, 0.72; 90% CI, 0.54-0.97; P = .07) Abbreviations: Objective response rate (ORR), Disease control rate (DCR), Durable clinical benefit (DCB), objective response (OR), Progression-Free-Survival (PFS), Overall survival (OS) 4.1.2 CTLA-4 Inhibitors CTLA-4 is another critical immune checkpoint that downregulates immune responses. It is expressed on T cells and competes with the costimulatory receptor CD28 for binding to B7 molecules (CD80/CD86) on antigen-presenting cells (APCs). CTLA-4 has a higher affinity for B7 molecules than CD28, thereby outcompeting it and delivering an inhibitory signal that limits T cell activation. CTLA-4 inhibitors, such as ipilimumab, block this interaction, enhancing T cell activation and proliferation (Giannone et al., 2020). Although CTLA-4 inhibitors have been primarily studied in melanoma, their application in colon cancer is being actively explored. The combination of CTLA-4 inhibitors with PD-1 inhibitors is particularly promising, as it can potentially overcome resistance mechanisms and provide synergistic effects (Lenz et al., 2022). This combination therapy aims to enhance both the priming and effector phases of the T cell response, leading to a more robust and sustained anti-tumor activity (Guerrouahen et al., 2019).
RkJQdWJsaXNoZXIy MjQ4ODYzNQ==