肿瘤细胞治疗研究
英文原题：De novo functional discovery of peptide-MHC restricted CARs from recombinase-constructed large-diversity monoclonal T cell libraries.
模拟T细胞受体（TCR）引发肽-主要组织相容性复合体（pMHC）特异性T细胞反应的嵌合抗原受体（CAR）在开发针对实体瘤、感染和自身免疫性疾病的免疫疗法方面具有巨大前景。
模拟T细胞受体（TCR）的嵌合抗原受体（CAR）能够诱导肽-主要组织相容性复合物（pMHC）特异性T细胞应答，有望用于开发治疗实体瘤、感染和自身免疫性疾病的免疫疗法。然而，TCR模拟（TCRm）CAR的广泛应用目前主要受限于缺乏简便有效的分离方法。本研究建立了一种从人初始抗体库从头发现TCRm CAR的高效流程，结合重组酶介导的高多样性单克隆文库构建与基于T细胞活化的正向及负向筛选。研究快速鉴定出多组功能强效的TCRm CAR，可特异性识别肽、交叉反应极低且基础性信号低，靶向受MHC限制的细胞内肿瘤相关抗原MAGE-A3、NY-ESO-1和MART-1。转导这些TCRm CAR的T细胞表现出pMHC特异性功能性亲合力、强效细胞因子释放，以及有效持久的细胞毒作用。所建立的方法可用于生成安全且强效的免疫疗法，靶向受MHC限制的抗原。
Chimeric antigen receptors (CAR) that mimic T cell receptors (TCR) on eliciting peptide-major histocompatibility complex (pMHC) specific T cell responses hold great promise in the development of immunotherapies against solid tumors, infections, and autoimmune diseases. However, broad applications of TCR-mimic (TCRm) CARs are hindered to date largely due to lack of a facile approach for the effective isolation of TCRm CARs. Here, we establish a highly efficient process for de novo discovery of TCRm CARs from human na ve antibody repertories by combining recombinase-mediated large-diversity monoclonal library construction with T cell activation-based positive and negative screenings. Panels of highly functional TCRm CARs with peptide-specific recognition, minimal cross-reactivity, and low tonic signaling were rapidly identified towards MHC-restricted intracellular tumor-associated antigens MAGE-A3, NY-ESO-1, and MART-1. Transduced TCRm CAR-T cells exhibited pMHC-specific functional avidity, potent cytokine release, and efficacious and persistent cytotoxicity. The developed approach could be used to generate safe and potent immunotherapies targeting MHC-restricted antigens.
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