Cancer Genetics and Epigenetics 2024, Vol.12, No.5, 234-253 http://medscipublisher.com/index.php/cge 243 5.5 Combining immunotherapy with radiotherapy Radiotherapy can potentiate the effects of immunotherapy by causing localized tumor cell death and releasing tumor-associated antigens, which can prime the immune system. Moreover, radiotherapy can modulate the tumor microenvironment to make it more conducive to immune infiltration and activation. Studies have shown that combining radiotherapy with immune checkpoint inhibitors can lead to enhanced anti-tumor responses and improved survival outcomes (Hanoteau et al., 2019; Tang et al., 2020). Table 4 showed clinical trials with ICIs and radiotherapy. Table 4 Combining Immunotherapy with Radiotheraty in colon cancer Trail name Sample size Treatment Phase Primary outcomes Results ETCTN 10021 (Monjazeb et al., 2021) 20 Durvalumab+tremelimu mab+RT II ORR, DCR ORR:0%; DCR: 5.5% NCT02837263 (Bassetti et al., 2019) 15 SBRT+Pembrolizumab (All patients had received prior FOLFOX.) I AEs, 1-year RFS No grade 3/4 immunotherapy AEs, 1-year RFS: 67% NCT03104439 (Parikh et al., 2021) 40 RT, Nivolumab +Ipilimumab II DCR, ORR, PFS, OS DCR: 37%, ORR: 15%, mPFS: 2.5 months, mOS: 10.9 months Abbreviations: Radiotheraty (RT), Objective response rate (ORR), Disease control rate (DCR), Relapse-Free Survival (RFS), Progression-Free-Survival (PFS), Overall survival (OS) 5.6 Emerging Combinatorial Approaches Emerging combinatorial approaches aim to further enhance the efficacy of cancer immunotherapy by targeting various aspects of the tumor microenvironment and immune response. These include the use of oncolytic viruses, which selectively infect and kill tumor cells while stimulating an anti-tumor immune response, in combination with immune checkpoint inhibitors (Yoo et al., 2020). Additionally, combining metabolic modulators with immunotherapy to reprogram the immune cell metabolism within the tumor microenvironment has shown promise in preclinical studies (Bader et al., 2020). By leveraging the synergistic effects of these various therapeutic strategies, combination therapies hold the potential to significantly improve the treatment outcomes for patients with colon cancer. 6 Biomarkers for Predicting Response to Immunotherapy 6.1 Immune-related biomarkers 6.1.1 Microsatellite instability Microsatellite Instability (MSI) is a key biomarker for predicting response to immunotherapy, particularly in colon cancer. MSI-high (MSI-H) tumors have defects in the DNA mismatch repair system, leading to a high mutation rate and increased neoantigen load. These tumors are more likely to respond to immune checkpoint inhibitors, and MSI status is an FDA-approved biomarker for selecting patients for pembrolizumab treatment in colon cancer (Hou et al., 2022). The predictive value of MSI status in predicting immunotherapy response in CRC is significant, and has been established in clinical practice. Regrettably, our previous research found that approximately 25% of patients with MSI-H CRC had intrinsic resistance to immunotherapy (Wang et al., 2023). Therefore, there is still a need to explore more appropriate biomarkers to predict the effect of immunotherapy in colorectal cancer. 6.1.2 Tumor mutational burden Tumor Mutational Burden (TMB) is a measure of the number of mutations within a tumor genome. High TMB is associated with the presence of more neoantigens, which can make the tumor more recognizable to the immune system. As a result, patients with high TMB are often more responsive to immune checkpoint inhibitors. This biomarker has been validated in various cancers, including colon cancer, where a higher TMB has correlated with better responses to immunotherapy (Duffy and Crown, 2019; Wang et al., 2019). In fact, TMB as a marker for
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