Engineered CRO-CD7 CAR-NK cells derived from pluripotent stem cells avoid fratricide and efficiently suppress human T-cell malignancies

作者：Yunqing Lin, Ziyun Xiao, Fangxiao Hu, Xiujuan Zheng, Chenyuan Zhang, Yao Wang, Yanhong Liu, Dehao Huang, Zhiqian Wang, Chengxiang Xia, Qitong Weng, Leqiang Zhang, Yaoqin Zhao, Hanmeng Qi, Yiyuan Shen, Yi Chen, Fan Zhang, Jiaxin Wu, Pengcheng Liu, Jiacheng Xu, Lijuan Liu, Yanping Zhu, Jingliao Zhang, Wenbin Qian, Aibin Liang, Xiaofan Zhu, Tongjie Wang, Mengyun Zhang, Jinyong Wang · 发表于：Journal of Hematology & Oncology · 年份：2025 · DOI：10.1186/s13045-025-01712-3 · 被引用次数：13 · 研究领域：CAR-T cell therapy research、Immune Cell Function and Interaction、Immunotherapy and Immune Responses

T-cell malignancies are highly aggressive hematological tumors with limited effective treatment options. CAR-NK cell therapy targeting CD7 has emerged as a promising approach for treating T-cell malignancies. However, conventional CAR-NK cell therapy faces the challenges of cell fratricide due to CD7 expression on both malignant cells and normal NK cells. Additionally, engineering CARs into human tissue-derived NK cells demonstrates heterogeneity, low transduction efficiency, and high manufacturing costs. The human pluripotent stem cells (hPSCs) were genetically modified by knocking out the CD7 gene and introducing the CD7 CAR expression cassette to generate CD7 KO-CD7 CAR-hPSCs. These modified hPSCs were subsequently differentiated into CD7 KO-CD7 CAR-iNK cells using an efficient organoid induction method. The cytotoxicity of CD7 KO-CD7 CAR-iNK cells against CD7 + tumor cells was evaluated. Furthermore, we overexpressed the CXCR4 gene in CD7 KO-CD7 CAR-hPSCs and derived CXCR4-expressing CD7 KO-CD7 CAR-iNK (CRO-CD7 CAR-iNK) cells. The dynamics of CRO-CD7 CAR-iNK cells in vivo were tracked, and their therapeutic efficacy was assessed using human T-cell acute lymphoblastic leukemia (T-ALL) xenograft models. The CD7 KO-CD7 CAR-iNK cells derived from CD7 KO-CD7 CAR-hPSCs effectively avoided fratricide, demonstrated normal expansion, and exhibited potent and specific anti-tumor activity against CD7 + T-cell tumor cell lines and primary T-ALL cells. CXCR4 overexpression in CRO-CD7 ...