Abdelfattah Nouran S, Kula Tomasz, Elledge Stephen J
Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women's Hospital, Howard Hughes Medical Institute, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women's Hospital, Howard Hughes Medical Institute, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Immunity. 2024 Dec 10;57(12):2945-2958.e5. doi: 10.1016/j.immuni.2024.11.009. Epub 2024 Dec 3.
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.
过继性T细胞疗法（ACT）的许多有前景的靶点都是自身抗原，但自身反应性T细胞通常在胸腺选择过程中被清除或转变为调节性表型。为了绕过T细胞耐受性并获得有效且安全的T细胞疗法，我们开发了T-Switch，这是一种体外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。然后通过肽结合区域的定向进化来修饰TCR的精细特异性，以将其特异性切换为感兴趣的自身抗原。我们应用T-Switch工程化对肿瘤相关自身抗原有反应的合成TCR，验证了该方法的安全性和有效性，并且针对人类蛋白质组检测未发现脱靶识别。因此，T-Switch代表了一种用于创建基于T细胞免疫疗法的高灵敏度合成TCR文库的资源。
