Cancer Genetics and Epigenetics 2024, Vol.12, No.5, 234-253 http://medscipublisher.com/index.php/cge 241 5 Combination Therapies 5.1 Rationale for combining immunotherapies Combining immunotherapies aims to enhance the therapeutic efficacy by targeting multiple mechanisms of tumor immune evasion. While single-agent immunotherapies have shown promise, their effectiveness is often limited by the complex and adaptive nature of the tumor immune microenvironment. By employing combination therapies, it is possible to overcome resistance mechanisms, potentiate immune responses, and achieve more durable clinical benefits. For instance, combining immune checkpoint inhibitors with other immunomodulatory agents can synergistically enhance anti-tumor immunity (Shi et al., 2019). 5.2 Combination of immune checkpoint inhibitors The combination of different immune checkpoint inhibitors, such as PD-1/PD-L1 and CTLA-4 inhibitors, has shown to be effective in various cancers, including colon cancer. This approach leverages the distinct mechanisms of action of these inhibitors to enhance T cell activation and reduce immune suppression. Clinical studies have demonstrated that combining anti-PD-1 with anti-CTLA-4 can result in superior anti-tumor activity compared to monotherapy, detailed shown in Table 1 (Fan et al., 2019; Lenz et al., 2022). Table 2 Combining Immunotherapy with Targeted Therapy in colon cancer Trail name Sample size Treatment Phase Primary outcomes Results REGONIVO/ EPOC1603) (Fukuoka et al., 2020) 25 Regorafenib+ni volumab I/II ORR 33.3% ChiCTR20000289 65 (Ma et al., 2023) 30 Fruquintinib+tor ipalimab II ORR, DCR, PFS, OS ORR: 16.7% (95% CI ： 59.7%-94.8%), DCR: 54.1% , mPFS: 6.0 months (95% CI ： 3.511-12.489), the 1-year PFS rate: 18%; mOS: 8.0 months (95% CI: 1.452-10.548). AVETUX (Tintelnot et al., 2022) 43 Avelumab+FOL FOX+cetuximab II PFS,OS mPFS: 11.1 mo mOS: 32.9 mo CAVE (Martinelli et al., 2021) 77 Avelumab+cetu ximab II OS, PFS, ORR mOS: 11.6 months (95% CI, 8.4-14.8 months); mPFS: 3.6 months (95% CI, 3.2-4.1 months) REGOMUNE (Cousin et al., 2022) 48 Regorafenib+av elumab II ORR, DCR, PFS, OS The best response was stable disease for 23 pts (57.5%) and progressive disease for 17 pts (42.5%); mPFS: 3.6 months (95%CI: [1.8–5.4]), mOS: 10.8 months (95%CI: [5.9 – NA]). Abbreviations: Objective response rate (ORR), Disease control rate (DCR), Progression-Free-Survival (PFS), Overall survival (OS) Cuiffo et al. focused on investigating the antitumor effects of Phio Pharmaceuticals' self-delivering RNAi therapeutic technology, INTASYL™, in a mouse colorectal cancer model(Cuiffo et al., 2023). This technology targets two immune checkpoints, PD-1 and CTLA-4, demonstrating that intratumoral (IT) injections can significantly enhance antitumor effects while reducing systemic immune-related side effects. In the experiments, the treatment of the mouse colorectal cancer cell model CT26 was compared using single-target and dual-target
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