Homogeneously high expression of CD32b makes it a potential target for CAR-T therapy for chronic lymphocytic leukemia

Springer Science and Business Media LLC - 2021
Guoling Wang1, Xiaolei Sun1, Shiyu Zuo1, Chuo Li1, Qing Niu1, Yuwei Xia1, Meng Yuan1, Min Liu1, Zihao Fang2, Xi Yang2, Yanyu Jiang3, Sheng Wang4, Hongwu Cui5, Huifang Huang6, Erlie Jiang1, Dongming Zhou7, Qi Deng3, Jing Pan8, Xiaoming Feng6
1State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300020, China
2Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China
3Department of Hematology, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, 300192, China
4Department of Thoracic Surgery, Hubei Cancer Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430079, China
5Department of Breast Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310000, China
6Central Laboratory, Fujian Medical University Union Hospital, Fuzhou, 350001, China
7Department of Pathogen Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
8State Key Laboratory of Experimental Hematology, Boren Clinical Translational Center, Department of Hematology, Beijing Boren Hospital, Beijing, 100070, China

Tóm tắt

AbstractCD19 chimeric antigen receptor (CAR)-T cells have been used to treat patients with refractory chronic lymphocytic leukemia (CLL). However, approximately 50% of patients do not respond to this therapy. To improve the clinical outcome of these patients, it is necessary to develop strategies with other optimal targets to enable secondary or combinational CAR-T cell therapy. By screening a panel of surface antigens, we found that CD32b (FcγRIIb) was homogeneously expressed at high site density on tumor cells from CLL patients. We then developed a second-generation CAR construct targeting CD32b, and T cells transduced with the CD32 CAR efficiently eliminated the CD32b+ Raji leukemic cell line in vitro and in a mouse xenograft model. Furthermore, CD32b CAR-T cells showed cytotoxicity against primary human CLL cells that were cultured in vitro or transplanted into immunodeficient mice. The efficacy of CD32b CAR T cells correlated with the CD32b density on CLL cells. CD32b is not significantly expressed by non-B hematopoietic cells. Our study thus identifies CD32b as a potential target of CAR-T cell therapy for CLL, although further modification of the CAR construct with a safety mechanism may be required to minimize off-target toxicity.

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