Okpalanwaka Izuchukwu F, Daugherity Elizabeth A, McCormick Amanda L, Anderson Trevor S, Smith Savanna L, Lawrence Caryn, Appiah Duke, Lowe Devin B
Texas Tech University Health Sciences Center, Abilene, TX, United States.
Texas Tech University Health Sciences Center, Abilene, Texas, United States.
Mol Cancer Ther. 2025 Apr 9. doi: 10.1158/1535-7163.MCT-24-1015.
Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. The current standard of care for patients may involve surgery, chemotherapy, and immune checkpoint inhibitors (ICIs), but these approaches typically fail to secure durable responses against late-stage disease. Regorafenib (REG) is an FDA-approved tyrosine kinase inhibitor with immunomodulating properties for CRC patients who progress on standard care, but 5-year relative survival rates for individuals dosed with the drug as a monotherapy are poor. We hypothesize that REG may be more appropriately leveraged alongside immunotherapeutic agents that specifically stimulate T cell infiltration and activation within the tumor microenvironment (TME). We engineered a PD-L1/CD3 bispecific antibody (bsAb) that simultaneously binds PD-L1-expressing CRC cells and stimulates activated T cells in order to investigate combination strategies with REG in pre-clinical models of CRC. Combined REG + bsAb therapy safely initiated and sustained inhibition against MC38 and CT26 progression in vivo, and these effects correlated to improved CD8+ T cell infiltration and activity within a Type-1-prone TME. Additionally, cytotoxic CD8+ T cells from REG + bsAb-sensitized mice exhibited heightened tumor cell reactivity compared to animals treated with either agent alone. Therefore, the immunomodulatory benefits of REG can be effectively paired with a bsAb that anchors to CRC cells, diminishes immunosuppression (through PD-L1 blockade), and activates/sustains antigen-specific CD8+ T cells within the TME. Our newly described REG + bsAb regimen led to improved anti-tumor outcomes pre-clinically and may represent a promising future approach for CRC patients.
结直肠癌（CRC）是全球癌症相关死亡的主要原因。目前针对患者的标准治疗方案可能包括手术、化疗和免疫检查点抑制剂（ICI），但这些方法通常无法确保对晚期疾病产生持久反应。瑞戈非尼（REG）是一种经美国食品药品监督管理局（FDA）批准的酪氨酸激酶抑制剂，对接受标准治疗后病情进展的CRC患者具有免疫调节特性，但作为单一疗法给药的个体的5年相对生存率较低。我们假设，REG与特异性刺激肿瘤微环境（TME）内T细胞浸润和激活的免疫治疗药物联合使用可能更为合适。我们设计了一种PD-L1/CD3双特异性抗体（bsAb），它能同时结合表达PD-L1的CRC细胞并刺激活化的T细胞，以便在CRC临床前模型中研究与REG的联合策略。REG与bsAb联合治疗在体内安全启动并持续抑制MC38和CT26的进展，这些作用与在倾向于1型的TME中CD8+T细胞浸润和活性的改善相关。此外，与单独使用任何一种药物治疗的动物相比，来自REG与bsAb致敏小鼠的细胞毒性CD8+T细胞表现出更高的肿瘤细胞反应性。因此，REG的免疫调节益处可以有效地与一种锚定在CRC细胞上、减少免疫抑制（通过阻断PD-L1）并在TME内激活/维持抗原特异性CD8+T细胞的bsAb配对。我们新描述的REG与bsAb方案在临床前改善了抗肿瘤效果，可能代表了一种有前景的CRC患者未来治疗方法。
