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Universal Protein Trans-Splicing-Based CAR System Enabling CAR-T Cells with Reduced Exhaustion and Enhanced Efficacy

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机构: [1]Laboratory of Human Diseases and Immunotherapy, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China. [2]Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu 610041, China. [3]Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China. [4]Cardiovascular Surgery Research Laboratory, West China Hospital, Sichuan University, Chengdu 610041, China.
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Adapter switches are commonly developed to control the activation process of CAR-T cells. However, these affinity-based adapter switches cannot control the exhaustion level of CAR-T cells, which leads to a reduction of antitumor activity. To overcome this hurdle, we developed a CAR system based on split intein-mediated protein trans-splicing. In this system, a split C-intein-mediated adapter switch (SIMAS) containing a CD19 antibody splices with an N-intein motif engineered on T-cell receptors to incorporate CD19 antibodies into T-cell receptors site-specifically, which generates protein trans-splicing-based integrated CAR-T (protinCAR-T) cells. Importantly, trans-splicing does not activate CAR-T cells, thus reducing exhaustion level. Only the binding of protinCAR-T cells to tumor cells and cell motility activate protinCAR-T cells, which have good antitumor activity in vivo. Generally, we developed a novel CAR system that enables tuning of CAR-T-cell activity, which provides solutions to address the safety and efficacy barriers of CAR-T-cell therapy.

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出版当年[2025]版:
大类 | 1 区 医学
小类 | 1 区 药物化学
最新[2025]版:
大类 | 1 区 医学
小类 | 1 区 药物化学
第一作者:
第一作者机构: [1]Laboratory of Human Diseases and Immunotherapy, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China. [2]Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu 610041, China. [3]Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China. [4]Cardiovascular Surgery Research Laboratory, West China Hospital, Sichuan University, Chengdu 610041, China.
通讯作者:
通讯机构: [1]Laboratory of Human Diseases and Immunotherapy, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China. [2]Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu 610041, China. [3]Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China. [4]Cardiovascular Surgery Research Laboratory, West China Hospital, Sichuan University, Chengdu 610041, China.
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