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

Autor:	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
Jazyk:	angličtina
Rok vydání:	2024
Předmět:	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
Zdroj:	Experimental Hematology & Oncology, Vol 13, Iss 1, Pp 1-18 (2024)
Druh dokumentu:	article
ISSN:	2162-3619
DOI:	10.1186/s40164-024-00553-z
Popis:	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
Databáze:	Directory of Open Access Journals
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