Cyclosporine A-resistant CAR-T cells mediate antitumour immunity in the presence of allogeneic cells
Abstract 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...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-44176-0 |
| _version_ | 1797376896592248832 |
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| author | Yixi Zhang Hongyu Fang Guocan Wang Guangxun Yuan Ruoyu Dong Jijun Luo Yu Lyu Yajie Wang Peng Li Chun Zhou Weiwei Yin Haowen Xiao Jie Sun Xun Zeng |
| author_facet | Yixi Zhang Hongyu Fang Guocan Wang Guangxun Yuan Ruoyu Dong Jijun Luo Yu Lyu Yajie Wang Peng Li Chun Zhou Weiwei Yin Haowen Xiao Jie Sun Xun Zeng |
| author_sort | Yixi Zhang |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-08T19:45:11Z |
| format | Article |
| id | doaj.art-2b27d29c26a64f5ea0f9eb0cf1c7b524 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-08T19:45:11Z |
| publishDate | 2023-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-2b27d29c26a64f5ea0f9eb0cf1c7b5242023-12-24T12:22:48ZengNature PortfolioNature Communications2041-17232023-12-0114111310.1038/s41467-023-44176-0Cyclosporine A-resistant CAR-T cells mediate antitumour immunity in the presence of allogeneic cellsYixi Zhang0Hongyu Fang1Guocan Wang2Guangxun Yuan3Ruoyu Dong4Jijun Luo5Yu Lyu6Yajie Wang7Peng Li8Chun Zhou9Weiwei Yin10Haowen Xiao11Jie Sun12Xun Zeng13State 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 MedicineState 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 MedicineState 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 MedicineState 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 MedicineDepartment of Hematology, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineState 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 MedicineZhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, International Campus, Zhejiang UniversityBone Marrow Transplantation Center of the First Affiliated Hospital and Department of Cell Biology, Zhejiang University School of MedicinePuluoting Health Technology Co., LtdSchool of Public Health & Sir Run Run Shaw Hospital, Zhejiang University School of MedicineKey Laboratory for Biomedical Engineering of the Ministry of Education, College of Biomedical Engineering and Instrument Science, Zhejiang UniversityDepartment of Hematology, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineBone Marrow Transplantation Center of the First Affiliated Hospital and Department of Cell Biology, Zhejiang University School of MedicineState 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 MedicineAbstract 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.https://doi.org/10.1038/s41467-023-44176-0 |
| spellingShingle | Yixi Zhang Hongyu Fang Guocan Wang Guangxun Yuan Ruoyu Dong Jijun Luo Yu Lyu Yajie Wang Peng Li Chun Zhou Weiwei Yin Haowen Xiao Jie Sun Xun Zeng Cyclosporine A-resistant CAR-T cells mediate antitumour immunity in the presence of allogeneic cells Nature Communications |
| title | Cyclosporine A-resistant CAR-T cells mediate antitumour immunity in the presence of allogeneic cells |
| title_full | Cyclosporine A-resistant CAR-T cells mediate antitumour immunity in the presence of allogeneic cells |
| title_fullStr | Cyclosporine A-resistant CAR-T cells mediate antitumour immunity in the presence of allogeneic cells |
| title_full_unstemmed | Cyclosporine A-resistant CAR-T cells mediate antitumour immunity in the presence of allogeneic cells |
| title_short | Cyclosporine A-resistant CAR-T cells mediate antitumour immunity in the presence of allogeneic cells |
| title_sort | cyclosporine a resistant car t cells mediate antitumour immunity in the presence of allogeneic cells |
| url | https://doi.org/10.1038/s41467-023-44176-0 |
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