A PD-L1/CD3 BISPECIFIC ANTIBODY ENHANCES THE ANTI-TUMOR EFFECTS OF REGORAFENIB AGAINST COLON CANCER.

IF 5.3 2区 医学 Q1 ONCOLOGY
Izuchukwu F Okpalanwaka, Elizabeth A Daugherity, Amanda L McCormick, Trevor S Anderson, Savanna L Smith, Caryn Lawrence, Duke Appiah, Devin B Lowe
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Abstract

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.

pd-l1 / cd3双特异性抗体增强瑞非尼对结肠癌的抗肿瘤作用。
结直肠癌(CRC)是全球癌症相关死亡的主要原因。目前患者的标准治疗可能包括手术、化疗和免疫检查点抑制剂(ICIs),但这些方法通常不能确保对晚期疾病的持久反应。Regorafenib (REG)是一种fda批准的酪氨酸激酶抑制剂,具有免疫调节特性,适用于标准治疗进展的结直肠癌患者,但单独使用该药物的个体的5年相对生存率较低。我们假设REG可能更适合与免疫治疗剂一起使用,特异性刺激肿瘤微环境(TME)内T细胞的浸润和激活。我们设计了一种PD-L1/CD3双特异性抗体(bsAb),可以同时结合表达PD-L1的CRC细胞并刺激活化的T细胞,以研究在CRC临床前模型中与REG的联合策略。REG + 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1型易发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小鼠相比,来自REG + 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bsAb配对,bsAb锚定在CRC细胞上,减少免疫抑制(通过PD-L1阻断),并激活/维持TME内抗原特异性CD8+ T细胞。我们新描述的REG + bsAb方案在临床前改善了抗肿瘤结果,可能代表了CRC患者未来的一种有希望的方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
11.20
自引率
1.80%
发文量
331
审稿时长
3 months
期刊介绍: Molecular Cancer Therapeutics will focus on basic research that has implications for cancer therapeutics in the following areas: Experimental Cancer Therapeutics, Identification of Molecular Targets, Targets for Chemoprevention, New Models, Cancer Chemistry and Drug Discovery, Molecular and Cellular Pharmacology, Molecular Classification of Tumors, and Bioinformatics and Computational Molecular Biology. The journal provides a publication forum for these emerging disciplines that is focused specifically on cancer research. Papers are stringently reviewed and only those that report results of novel, timely, and significant research and meet high standards of scientific merit will be accepted for publication.
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