Shang Kai, Huang Deyu, Liu Jun, Yu Zebin, Bian Wei, Chen Jiangqing, Zhao Yin, Liu Lina, Jiang Jie, Wang Yajie, Duan Yanting, Ge Jingyu, Zhang Shize, Zhou Chun, Han Yingli, Hu Yongxian, Zheng Weiyan, Sun Jie, Huang He, Pei Shanshan, Qian Pengxu, Sun Jie
Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou 310058, China; Liangzhu Laboratory, Zhejiang University, 1369 West Wenyi Road, Hangzhou 311121, China; Department of Cell Biology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou 310058, China; Institute of Hematology, Zhejiang University, Hangzhou 310058, China; Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou 310058, China.
Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou 310058, China; Liangzhu Laboratory, Zhejiang University, 1369 West Wenyi Road, Hangzhou 311121, China; Institute of Hematology, Zhejiang University, Hangzhou 310058, China; Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou 310058, China; Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou 310058, China.
Cell Rep Med. 2025 Jun 17;6(6):102148. doi: 10.1016/j.xcrm.2025.102148. Epub 2025 May 26.
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 CAR-T cells eliminate both AML cell lines and primary AML cells effectively while showing tolerable toxicity to HSPCs. Furthermore, we mutate the CD3ζ 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.
嵌合抗原受体（CAR）-T细胞疗法治疗急性髓系白血病（AML）受到缺乏合适肿瘤特异性抗原的阻碍。在此，我们提出CD97作为CAR-T细胞疗法治疗AML的潜在靶点，因为与正常造血干细胞和祖细胞（HSPCs）相比，其在AML细胞上的表达更广泛且更高。为了解决T细胞上CD97表达引起的自相残杀问题，我们使用CRISPR-Cas9在CAR-T细胞中敲除CD97。我们的CD97 CAR-T细胞能有效消除AML细胞系和原发性AML细胞，同时对HSPCs显示出可耐受的毒性。此外，我们对CAR的CD3ζ结构域进行突变，发现优化后的CD97 CAR-T细胞在体外和多个异种移植模型中均表现出持久的抗肿瘤活性。从机制上讲，转录谱显示优化后的CAR-T细胞延缓分化并抵抗耗竭。总体而言，我们的研究支持CD97作为CAR-T细胞疗法治疗AML的一个有前景的靶点。
