美国霍华德休斯医学研究院Stephen J. Elledge团队开发出一种基于特异性的工程平台T-Switch，可用于开发安全有效的T细胞治疗。该研究于2024年12月3日在线发表于国际一流学术期刊《免疫》。

据了解，许多有前景的过继性T细胞治疗（ACT）靶点是自体抗原，但自反应性T细胞通常在胸腺选择过程中被消除，或转化为调节性表型。

为了绕过T细胞耐受性并获得有效且安全的T细胞治疗，研究人员开发了T-Switch。这是一个体外T细胞受体（TCR）工程平台，可用于创建、修改和全面分析能够靶向自体抗原的TCR。T-Switch首先扩增能够识别与自体抗原密切相关的“外源”肽的T细胞。

然后，通过对肽结合区域的定向进化，修改TCR的精细特异性，使其特异性转向目标自体抗原。

研究人员将T-Switch应用于工程合成TCR，使其对肿瘤相关的自体抗原产生反应，并验证了这种方法的安全性和有效性，且在与人类蛋白质组的检测中未发现脱靶识别。因此，T-Switch为创建高灵敏度的合成TCR库提供了一个资源，可用于T细胞免疫治疗。

附：英文原文

Title: T-Switch: A specificity-based engineering platform for developing safe and effective T cell therapeutics

Author: Nouran S. Abdelfattah, Tomasz Kula, Stephen J. Elledge

Issue&Volume: 2024-12-03

Abstract: Many promising targets for adoptive T cell therapy (ACT) are self-antigens, but self-reactive T cells are generally eliminated during thymic selection or diverted to regulatory phenotypes. To bypass T cell tolerance and obtain potent and safe T cell therapeutics, we developed T-Switch, an in vitro T cell receptor (TCR) engineering platform for the creation, modification, and comprehensive profiling of TCRs that can target self-antigens. T-Switch first expands T cells that recognize a “foreign” peptide closely related to a self-antigen. The fine specificity of the TCR is then modified by directed evolution of the peptide binding region to switch its specificity to the self-antigen of interest. We applied T-Switch to engineer synthetic TCRs reactive to a tumor-associated self-antigen, validated the safety and efficacy of this approach, and detected no off-target recognition as measured against the human proteome. Thus, T-Switch represents a resource for the creation of collections of highly sensitive synthetic TCRs for T cell-based immunotherapies.

DOI: 10.1016/j.immuni.2024.11.009

Source: https://www.cell.com/immunity/abstract/S1074-7613(24)00524-7