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.

中文翻译：

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T-Switch：基于特异性的工程平台，用于开发安全有效的 T 细胞疗法


过继性 T 细胞疗法 （ACT） 的许多有前途的靶点是自身抗原，但自反应性 T 细胞通常在胸腺选择过程中被消除或转移到调节表型。为了绕过 T 细胞耐受性并获得有效且安全的 T 细胞疗法，我们开发了 T-Switch，这是一个 体外 T 细胞受体 （TCR） 工程平台，用于创建、修饰和全面分析可靶向自身抗原的 TCR。T-Switch 首先扩增识别与自身抗原密切相关的“外来”肽的 T 细胞。然后通过肽结合区的定向进化来修饰 TCR 的精细特异性，以将其特异性转换为感兴趣的自身抗原。我们应用 T-Switch 来设计对肿瘤相关自身抗原反应的合成 TCR，验证了这种方法的安全性和有效性，并且没有检测到针对人类蛋白质组测量的脱靶识别。因此，T-Switch 代表了为基于 T 细胞的免疫疗法创建高灵敏度合成 TCR 集合的资源。