肿瘤细胞治疗研究
英文原题：Design optimization of antibody-ligand motifs to enhance CAR-T redirection activity against solid tumors.
抗原异质性和肿瘤微环境仍是有效CAR-T 细胞疗法的重大障碍，但结合肿瘤内多种抗原及其所处环境的天然配体提供了一种有前景的解决方案。
抗原异质性和肿瘤微环境仍是CAR-T治疗取得疗效的主要障碍，但能够同时结合肿瘤及其微环境中多种抗原的天然配体提供了有希望的解决思路。我们提出一种多靶点、可切换CAR-T（sCAR-T）策略：在T细胞上整合通用受体，并采用抗体-配体基序，将抗Her2单链可变片段（scFv，4D5）与剪接型VEGF-A（VEGF121）结合，从而靶向Her2、VEGFR1和VEGFR2。通过优化切换模块和CAR铰链区，保留了配体天然的二聚构象，增强抗原识别并促进免疫突触形成。在同系和异种移植模型中，与传统CAR-T相比，sCAR-T实现了更强的肿瘤清除和血管破坏，并克服了抗原异质性导致的免疫逃逸。我们还将该设计扩展至受体酪氨酸激酶样孤儿受体1（ROR1）。结果表明，基于抗体-配体基序的策略为复杂抗原靶向提供了多用途框架，有望提高免疫治疗的疗效和安全性，并拓宽其应用范围。
Antigenic heterogeneity and the tumor microenvironment remain major obstacles to effective chimeric antigen receptor T (CAR-T) therapy, but natural ligands engaging multiple antigens within tumors and their milieu offer a promising solution. Here, we present a multitarget switchable CAR-T (sCAR-T) strategy that integrates a universal receptor on T cells with an antibody-ligand motif, combining an anti-Her2 single-chain variable fragment (scFv) (4D5) and spliced VEGF-A (VEGF121) to target Her2, VEGFR1, and VEGFR2. Optimization of the switch and CAR hinge preserved the ligand's native dimeric conformation, enhancing antigen recognition and promoting immunological synapse formation. In syngeneic and xenograft models, sCAR-T achieves superior tumor eradication and vasculature disruption compared with conventional CAR-T, overcoming immune escape driven by antigenic heterogeneity. We further extend the sCAR-T design to target receptor tyrosine kinase-like orphan receptor 1 (ROR1), demonstrating that the antibody-ligand motif-based strategy provides a versatile framework for complex antigen targeting, with potential to improve efficacy and safety and enable broader application in immunotherapies targeting complex antigenic combinations.
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