Cyclosporine A-resistant CAR-T cells mediate antitumour immunity in the presence of allogeneic cells.

Autor: Zhang Y; State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.; Research Units of Infectious disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, 310003, China., Fang H; State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.; Research Units of Infectious disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, 310003, China., Wang G; State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.; Research Units of Infectious disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, 310003, China., Yuan G; State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.; Research Units of Infectious disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, 310003, China., Dong R; Department of Hematology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China., Luo J; State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.; Research Units of Infectious disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, 310003, China., Lyu Y; Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, International Campus, Zhejiang University, Hangzhou, 310058, China., Wang Y; Bone Marrow Transplantation Center of the First Affiliated Hospital and Department of Cell Biology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, 310058, China.; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China., Li P; Puluoting Health Technology Co., Ltd, Hangzhou, 310003, China., Zhou C; School of Public Health & Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China., Yin W; Key Laboratory for Biomedical Engineering of the Ministry of Education, College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou, 310058, China.; Department of Thoracic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China., Xiao H; Department of Hematology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China. haowenxiaoxiao@zju.edu.cn., Sun J; Bone Marrow Transplantation Center of the First Affiliated Hospital and Department of Cell Biology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, 310058, China. sunj4@zju.edu.cn.; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China. sunj4@zju.edu.cn., Zeng X; State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China. xunzeng@zju.edu.cn.; Research Units of Infectious disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, 310003, China. xunzeng@zju.edu.cn.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Dec 20; Vol. 14 (1), pp. 8491. Date of Electronic Publication: 2023 Dec 20.
DOI: 10.1038/s41467-023-44176-0
Abstrakt: Chimeric antigen receptor (CAR)-T therapy requires autologous T lymphocytes from cancer patients, a process that is both costly and complex. Universal CAR-T cell treatment from allogeneic sources can overcome this limitation but is impeded by graft-versus-host disease (GvHD) and host versus-graft rejection (HvGR). Here, we introduce a mutated calcineurin subunit A (CNA) and a CD19-specific CAR into the T cell receptor α constant (TRAC) locus to generate cells that are resistant to the widely used immunosuppressant, cyclosporine A (CsA). These immunosuppressant-resistant universal (IRU) CAR-T cells display improved effector function in vitro and anti-tumour efficacy in a leukemia xenograft mouse model in the presence of CsA, compared with CAR-T cells carrying wild-type CNA. Moreover, IRU CAR-T cells retain effector function in vitro and in vivo in the presence of both allogeneic T cells and CsA. Lastly, CsA withdrawal restores HvGR, acting as a safety switch that can eliminate IRU CAR-T cells. These findings demonstrate the efficacy of CsA-resistant CAR-T cells as a universal, 'off-the-shelf' treatment option.
(© 2023. The Author(s).)
Databáze: MEDLINE
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