Graduate Program in Molecular Medicine, Faculty of Science, Mahidol University, Bangkok, Thailand; Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; School of Cardiovascular and Medical Health, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, UK.
Biomed Pharmacother. 2024 Jun;175:116718. doi: 10.1016/j.biopha.2024.116718. Epub 2024 May 13.
Advanced cholangiocarcinoma (CCA) presents a clinical challenge due to limited treatment options, necessitating exploration of innovative therapeutic approaches. Bispecific T cell engager (BTE)-armed T cell therapy shows promise in hematological and solid malignancies, offering potential advantages in safety over continuous BTE infusion. In this context, we developed a novel BTE, targeting CD3 on T cells and integrin αvβ6, an antigen elevated in various epithelial malignancies, on cancer cells. The novel BTE was generated by fusing an integrin αvβ6-binding peptide (A20) to an anti-CD3 (OKT3) single-chain variable fragment (scFv) through a GS peptide linker (A20/αCD3 BTE). T cells were then armed with A20/αCD3 BTE (A20/αCD3-armed T cells) and assessed for antitumor activity. Our results highlight the specific binding of A20/αCD3 BTE to CD3 on T cells and integrin αvβ6 on target cells, effectively redirecting T cells towards these targets. After co-culture, A20/αCD3-armed T cells exhibited significantly heightened cytotoxicity against integrin αvβ6-expressing target cells compared to unarmed T cells in both KKU-213A cells and A375.β6 cells. Moreover, in a five-day co-culture, A20/αCD3-armed T cells demonstrated superior cytotoxicity against KKU-213A spheroids compared to unarmed T cells. Importantly, A20/αCD3-armed T cells exhibited an increased proportion of the effector memory T cell (Tem) subset, upregulation of T cell activation markers, enhanced T cell proliferation, and increased cytolytic molecule/cytokine production, when compared to unarmed T cells in an integrin αvβ6-dependent manner. These findings support the potential of A20/αCD3-armed T cells as a novel therapeutic approach for integrin αvβ6-expressing cancers.
晚期胆管癌（CCA）由于治疗选择有限，给临床带来挑战，需要探索创新的治疗方法。双特异性 T 细胞衔接器（BTE）武装的 T 细胞疗法在血液系统和实体恶性肿瘤中显示出前景，与连续 BTE 输注相比，在安全性方面具有潜在优势。在这种情况下，我们开发了一种新型 BTE，该 BTE 靶向 T 细胞上的 CD3 和癌细胞上的整合素 αvβ6，后者在各种上皮恶性肿瘤中升高。新型 BTE 通过将整合素 αvβ6 结合肽（A20）融合到抗-CD3（OKT3）单链可变片段（scFv）上，通过 GS 肽接头（A20/αCD3 BTE）来产生。然后用 A20/αCD3 BTE 武装 T 细胞（A20/αCD3-武装 T 细胞），并评估其抗肿瘤活性。我们的结果突出了 A20/αCD3 BTE 与 T 细胞上的 CD3 和靶细胞上的整合素 αvβ6 的特异性结合，有效地将 T 细胞重新导向这些靶标。共培养后，与未武装的 T 细胞相比，A20/αCD3-武装 T 细胞对表达整合素 αvβ6 的靶细胞的细胞毒性明显增强，无论是在 KKU-213A 细胞还是 A375.β6 细胞中。此外，在为期五天的共培养中，与未武装的 T 细胞相比，A20/αCD3-武装 T 细胞对 KKU-213A 球体的细胞毒性更强。重要的是，与未武装的 T 细胞相比，A20/αCD3-武装 T 细胞以整合素 αvβ6 依赖的方式表现出效应记忆 T 细胞（Tem）亚群比例增加、T 细胞激活标志物上调、T 细胞增殖增强以及细胞溶解分子/细胞因子产生增加。这些发现支持 A20/αCD3-武装 T 细胞作为表达整合素 αvβ6 的癌症的一种新的治疗方法的潜力。
