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Efficacy of NKG2D CAR-T cells with IL-15/IL-15Rα signaling for treating Epstein-Barr virus-associated lymphoproliferative disorder

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Title: Efficacy of NKG2D CAR-T cells with IL-15/IL-15Rα signaling for treating Epstein-Barr virus-associated lymphoproliferative disorder
Authors: Qiusui Mai, Bailin He, Shikai Deng, Qing Zeng, Yanwen Xu, Cong Wang, Yunyi Pang, Sheng Zhang, Jinfeng Li, Jinfeng Zeng, Liqin Huang, Yongshui Fu, Chengyao Li, Tingting Li, Xiaojun Xu, Ling Zhang
Source: Experimental Hematology & Oncology, Vol 13, Iss 1, Pp 1-18 (2024)
Publisher Information: BMC, 2024.
Publication Year: 2024
Collection: LCC:Diseases of the blood and blood-forming organs
LCC:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Subject Terms: NKG2D, IL-15/IL-15Rα, CAR-T cells, EBV infection, Post-transplantation, Diseases of the blood and blood-forming organs, RC633-647.5, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
More Details: Abstract Epstein-Barr virus (EBV) related post-transplant lymphoproliferative disorder (EBV-PTLD) is a life-threatening complication after hematopoietic stem cell transplantation (HSCT) or solid organ transplantation (SOT), for which no standard therapeutic means have been developed. Significant increase expression of natural killer group 2 member D ligands (NKG2DLs) was observed on B-lymphoblastoid cells of EBV-PTLD, indicating NKG2DLs as potential therapeutic targets for treatment of EBV-PTLD. In this study, the recombinant constructs of NKG2D CAR and IL-15/IL-15Rα-NKG2D CAR were generated with a retroviral vector and then transduced to human T cells to produce NKG2D CAR-T and IL-15/IL-15Rα-NKG2D CAR-T cells, respectively. B-lymphoblastoid cell lines (B-LCLs) and the xenografted mouse models were established to evaluate the efficacy of these CAR-T cells. IL-15/IL-15Rα-NKG2D CAR-T cells exhibited superior proliferation and antigen-specific cytotoxic effect compared to NKG2D CAR-T, as IL-15/IL-15Rα signaling promoted the expansion of less differentiated central memory T cells (TCM) and increased expression of CD107a and IFN-γ. Moreover, EBV DNA load was dramatically reduced, and 80% B-LCL cells were eliminated by IL-15/IL-15Rα-NKG2D CAR-T cells after co-culturing. In-vivo study confirmed that IL-15/IL-15Rα-NKG2D CAR-T cell therapy significantly enhanced antiviral efficacy in mice, as the serum load of EBV after IL-15/IL-15Rα-NKG2D CAR-T cell infusion was 1500 times lower than the untreated control (P
Document Type: article
File Description: electronic resource
Language: English
ISSN: 2162-3619
Relation: https://doaj.org/toc/2162-3619
DOI: 10.1186/s40164-024-00553-z
Access URL: https://doaj.org/article/4f77cc45aa3f49358bfb6eacd3798041
Accession Number: edsdoj.4f77cc45aa3f49358bfb6eacd3798041
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  Data: Efficacy of NKG2D CAR-T cells with IL-15/IL-15Rα signaling for treating Epstein-Barr virus-associated lymphoproliferative disorder
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  Data: Experimental Hematology & Oncology, Vol 13, Iss 1, Pp 1-18 (2024)
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  Data: Abstract Epstein-Barr virus (EBV) related post-transplant lymphoproliferative disorder (EBV-PTLD) is a life-threatening complication after hematopoietic stem cell transplantation (HSCT) or solid organ transplantation (SOT), for which no standard therapeutic means have been developed. Significant increase expression of natural killer group 2 member D ligands (NKG2DLs) was observed on B-lymphoblastoid cells of EBV-PTLD, indicating NKG2DLs as potential therapeutic targets for treatment of EBV-PTLD. In this study, the recombinant constructs of NKG2D CAR and IL-15/IL-15Rα-NKG2D CAR were generated with a retroviral vector and then transduced to human T cells to produce NKG2D CAR-T and IL-15/IL-15Rα-NKG2D CAR-T cells, respectively. B-lymphoblastoid cell lines (B-LCLs) and the xenografted mouse models were established to evaluate the efficacy of these CAR-T cells. IL-15/IL-15Rα-NKG2D CAR-T cells exhibited superior proliferation and antigen-specific cytotoxic effect compared to NKG2D CAR-T, as IL-15/IL-15Rα signaling promoted the expansion of less differentiated central memory T cells (TCM) and increased expression of CD107a and IFN-γ. Moreover, EBV DNA load was dramatically reduced, and 80% B-LCL cells were eliminated by IL-15/IL-15Rα-NKG2D CAR-T cells after co-culturing. In-vivo study confirmed that IL-15/IL-15Rα-NKG2D CAR-T cell therapy significantly enhanced antiviral efficacy in mice, as the serum load of EBV after IL-15/IL-15Rα-NKG2D CAR-T cell infusion was 1500 times lower than the untreated control (P
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        Value: 10.1186/s40164-024-00553-z
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        Type: general
      – SubjectFull: IL-15/IL-15Rα
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      – SubjectFull: CAR-T cells
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      – TitleFull: Efficacy of NKG2D CAR-T cells with IL-15/IL-15Rα signaling for treating Epstein-Barr virus-associated lymphoproliferative disorder
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