Construction and characterization of chimeric FcγR T cells for universal T cell therapy
Abstract Background Several approaches are being explored for engineering off-the-shelf chimeric antigen receptor (CAR) T cells. In this study, we engineered chimeric Fcγ receptor (FcγR) T cells and tested their potential as a versatile platform for universal T cell therapy. Methods Chimeric FcγR (C...
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BMC
2025-01-01
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| Series: | Experimental Hematology & Oncology |
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| Online Access: | https://doi.org/10.1186/s40164-025-00595-x |
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| author | Juanjuan Zhao Manling Chen Xudong Li Zhaoqi Chen Wei Li Rongqun Guo Min Wang Zhongxing Jiang Yongping Song Jianxiang Wang Delong Liu |
| author_facet | Juanjuan Zhao Manling Chen Xudong Li Zhaoqi Chen Wei Li Rongqun Guo Min Wang Zhongxing Jiang Yongping Song Jianxiang Wang Delong Liu |
| author_sort | Juanjuan Zhao |
| collection | DOAJ |
| description | Abstract Background Several approaches are being explored for engineering off-the-shelf chimeric antigen receptor (CAR) T cells. In this study, we engineered chimeric Fcγ receptor (FcγR) T cells and tested their potential as a versatile platform for universal T cell therapy. Methods Chimeric FcγR (CFR) constructs were generated using three distinct forms of FcγR, namely CD16A, CD32A, and CD64. The functionality of CFR T cells was evaluated through degranulation assays, specific target lysis experiments, in vitro cytokine production analysis, and assessment of tumor xenograft destruction specificity in mouse models using different monoclonal antibodies (MoAbs). Results Three types of CFR T cells were engineered, 16s3, 32-8a, 64-8a CFR T cells. In the presence of rituximab (RTX), cytotoxicity of all three types of CFR T cells against CD20+ Raji-wt, K562-CD20+, and primary tumor cells was significantly higher than that of the mock T cells (P < 0.001). When herceptin was used, all three types of CFR T cells exhibited significant cytotoxicity against HER2+ cell lines of SK-BR-3, SK-OV-3, and HCC1954 (P < 0.001). The cytotoxicity of 64-8a CFR T cells was significantly inhibited by free human IgG at a physiological dose (P < 0.001), which was not observed in 16s3, 32-8a CFR T cells. Compared to 32-8a CFR T cells, 16s3 CFR T cells exhibited more prolonged cytotoxicity than 32-8a CFR T cells (P < 0.01). In in vivo assays using xenograft models, 16s3 CFR T cells significantly prolonged the survival of mice xenografted with Raji-wt cells in the presence of RTX (P < 0.001), and effectively reduced tumor burden in mice xenografted with SK-OV-3 cells in the presence of herceptin (P < 0.05). No significant non-specific cytotoxicity of CFR T cells was found in vivo. Conclusion The anti-tumor effects of the CFR T cells in vitro and in xenograft mouse models are mediated by specific MoAbs such as RTX and herceptin. The CFR T cells therefore have the features of universal T cells with specificity directed by MoAbs. 16s3 CFR T cells are chosen for clinical trials. |
| format | Article |
| id | doaj-art-b70765606ca5454c920c525030eac085 |
| institution | Kabale University |
| issn | 2162-3619 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Experimental Hematology & Oncology |
| spelling | doaj-art-b70765606ca5454c920c525030eac0852025-01-19T12:13:00ZengBMCExperimental Hematology & Oncology2162-36192025-01-0114111610.1186/s40164-025-00595-xConstruction and characterization of chimeric FcγR T cells for universal T cell therapyJuanjuan Zhao0Manling Chen1Xudong Li2Zhaoqi Chen3Wei Li4Rongqun Guo5Min Wang6Zhongxing Jiang7Yongping Song8Jianxiang Wang9Delong Liu10Department of Hematology, The First Affiliated Hospital of Zhengzhou UniversityState Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical CollegeDepartment of Hematology, The First Affiliated Hospital of Zhengzhou UniversityState Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical CollegeDepartment of Hematology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Hematology, The First Affiliated Hospital of Zhengzhou UniversityState Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical CollegeDepartment of Hematology, The First Affiliated Hospital of Zhengzhou UniversityDepartment of Hematology, The First Affiliated Hospital of Zhengzhou UniversityState Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical CollegeDepartment of Hematology, The First Affiliated Hospital of Zhengzhou UniversityAbstract Background Several approaches are being explored for engineering off-the-shelf chimeric antigen receptor (CAR) T cells. In this study, we engineered chimeric Fcγ receptor (FcγR) T cells and tested their potential as a versatile platform for universal T cell therapy. Methods Chimeric FcγR (CFR) constructs were generated using three distinct forms of FcγR, namely CD16A, CD32A, and CD64. The functionality of CFR T cells was evaluated through degranulation assays, specific target lysis experiments, in vitro cytokine production analysis, and assessment of tumor xenograft destruction specificity in mouse models using different monoclonal antibodies (MoAbs). Results Three types of CFR T cells were engineered, 16s3, 32-8a, 64-8a CFR T cells. In the presence of rituximab (RTX), cytotoxicity of all three types of CFR T cells against CD20+ Raji-wt, K562-CD20+, and primary tumor cells was significantly higher than that of the mock T cells (P < 0.001). When herceptin was used, all three types of CFR T cells exhibited significant cytotoxicity against HER2+ cell lines of SK-BR-3, SK-OV-3, and HCC1954 (P < 0.001). The cytotoxicity of 64-8a CFR T cells was significantly inhibited by free human IgG at a physiological dose (P < 0.001), which was not observed in 16s3, 32-8a CFR T cells. Compared to 32-8a CFR T cells, 16s3 CFR T cells exhibited more prolonged cytotoxicity than 32-8a CFR T cells (P < 0.01). In in vivo assays using xenograft models, 16s3 CFR T cells significantly prolonged the survival of mice xenografted with Raji-wt cells in the presence of RTX (P < 0.001), and effectively reduced tumor burden in mice xenografted with SK-OV-3 cells in the presence of herceptin (P < 0.05). No significant non-specific cytotoxicity of CFR T cells was found in vivo. Conclusion The anti-tumor effects of the CFR T cells in vitro and in xenograft mouse models are mediated by specific MoAbs such as RTX and herceptin. The CFR T cells therefore have the features of universal T cells with specificity directed by MoAbs. 16s3 CFR T cells are chosen for clinical trials.https://doi.org/10.1186/s40164-025-00595-xFcγRUniversal CAR TOff-the-shelf CAR TRituximabHerceptinLymphoma |
| spellingShingle | Juanjuan Zhao Manling Chen Xudong Li Zhaoqi Chen Wei Li Rongqun Guo Min Wang Zhongxing Jiang Yongping Song Jianxiang Wang Delong Liu Construction and characterization of chimeric FcγR T cells for universal T cell therapy Experimental Hematology & Oncology FcγR Universal CAR T Off-the-shelf CAR T Rituximab Herceptin Lymphoma |
| title | Construction and characterization of chimeric FcγR T cells for universal T cell therapy |
| title_full | Construction and characterization of chimeric FcγR T cells for universal T cell therapy |
| title_fullStr | Construction and characterization of chimeric FcγR T cells for universal T cell therapy |
| title_full_unstemmed | Construction and characterization of chimeric FcγR T cells for universal T cell therapy |
| title_short | Construction and characterization of chimeric FcγR T cells for universal T cell therapy |
| title_sort | construction and characterization of chimeric fcγr t cells for universal t cell therapy |
| topic | FcγR Universal CAR T Off-the-shelf CAR T Rituximab Herceptin Lymphoma |
| url | https://doi.org/10.1186/s40164-025-00595-x |
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