肿瘤细胞治疗研究
英文原题：CD97-directed CAR-T cells with enhanced persistence eradicate acute myeloid leukemia in diverse xenograft models.
我们的研究支持将 CD97 作为抗 AML 的 CAR-T 治疗的有前景靶点。
急性髓系白血病（AML）CAR-T疗法受阻于缺乏合适的肿瘤特异性抗原。本研究提出CD97可能是AML CAR-T治疗靶点，因为其在AML细胞中的表达范围更广、水平更高，而在正常造血干细胞和祖细胞（HSPC）中较低。为解决T细胞表达CD97造成的自相残杀问题，我们利用CRISPR-Cas9敲除CAR-T细胞中的CD97。CD97敲除CAR-T细胞可有效清除AML细胞系和原代AML细胞，同时对HSPC的毒性可耐受。此外，我们对CAR的CD3结构域进行突变，发现优化后的CD97 CAR-T细胞在体外及多个异种移植模型中均具有持久抗肿瘤活性。机制上，转录谱显示优化后的CAR-T细胞可延缓分化并抵抗耗竭。综上，本研究支持CD97作为治疗AML的有前景CAR-T靶点。
Chimeric antigen receptor (CAR)-T therapy on acute myeloid leukemia (AML) is hindered by the absence of a suitable tumor-specific antigen. Here, we propose CD97 as a potential target for CAR-T therapy against AML based on its broader and higher expression on AML cells compared to normal hematopoietic stem and progenitor cells (HSPCs). To resolve the fratricide problem caused by CD97 expression on T cells, we knock out CD97 in CAR-T cells using CRISPR-Cas9. Our CD97 KO CAR-T cells eliminate both AML cell lines and primary AML cells effectively while showing tolerable toxicity to HSPCs. Furthermore, we mutate the CD3 domain of the CAR and find that the optimized CD97 CAR-T cells exhibit persistent anti-tumor activity both in vitro and in multiple xenograft models. Mechanistically, transcriptional profiles reveal that the optimized CAR-T cells delay differentiation and resist exhaustion. Collectively, our study supports CD97 as a promising target for CAR-T therapy against AML.
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