CAR-T（CAR-T）细胞疗法在非肿瘤性疾病中的应用
Chimeric antigen receptor T (CAR-T) cell therapy in non-oncological diseases.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
携带 IL-15/IL-15Rα 信号的 NKG2D CAR-T 细胞治疗 EB 病毒相关淋巴增殖性疾病的疗效
英文原题：Efficacy of NKG2D CAR-T cells with IL-15/IL-15Rα signaling for treating Epstein-Barr virus-associated lymphoproliferative disorder.
查看英文原题
Efficacy of NKG2D CAR-T cells with IL-15/IL-15Rα signaling for treating Epstein-Barr virus-associated lymphoproliferative disorder.
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中文摘要
EB病毒（EBV）相关移植后淋巴增殖性疾病（EBV-PTLD）是造血干细胞移植（HSCT）或实体器官移植（SOT）后的致命性并发症，目前尚无标准治疗方法。EBV-PTLD的B淋巴母细胞样细胞中NK 细胞组2成员D配体（NKG2DL）表达显著增加，提示其可能成为EBV-PTLD治疗靶点。
本研究利用逆转录病毒载体构建NKG2D CAR及IL-15/IL-15R-NKG2D CAR，并转导人T细胞，分别制备NKG2D CAR-T 和IL-15/IL-15R-NKG2D CAR-T 细胞。研究建立B淋巴母细胞样细胞系（B-LCL）及异种移植小鼠模型，评估CAR-T 疗效。IL-15/IL-15R-NKG2D CAR-T 细胞较NKG2D CAR-T 增殖能力更强、抗原特异性细胞毒作用更佳；IL-15/IL-15R信号促进分化程度较低的中央记忆T细胞（TCM）扩增，并提高CD107a和IFN-γ表达。共培养后，IL-15/IL-15R-NKG2D CAR-T 细胞使EBV DNA载量大幅降低，并清除80%的B-LCL细胞。体内研究证实，该疗法显著增强小鼠抗病毒效果；输注IL-15/IL-15R-NKG2D CAR-T 后，血清EBV载量比未治疗对照低1500倍（P<0.001）。其疗效增强可能源自IL-15/IL-15R信号改善NKG2D CAR-T 细胞体内归巢和持续性，并增加IFN-γ、穿孔素及颗粒溶素产生。
总之，共表达IL-15/IL-15R的NKG2D CAR-T 细胞促进中央记忆CAR-T 细胞增殖并改善其体内归巢和持续性，从而增强对EBV-PTLD的抗肿瘤和抗病毒作用。
展开英文摘要原文
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-15R -NKG2D CAR were generated with a retroviral vector and then transduced to human T cells to produce NKG2D CAR-T and IL-15/IL-15R -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-15R -NKG2D CAR-T cells exhibited superior proliferation and antigen-specific cytotoxic effect compared to NKG2D CAR-T, as IL-15/IL-15R signaling promoted the expansion of less differentiated central memory T cells (T CM ) and increased expression of CD107a and IFN- .
Moreover, EBV DNA load was dramatically reduced, and 80% B-LCL cells were eliminated by IL-15/IL-15R -NKG2D CAR-T cells after co-culturing. In-vivo study confirmed that IL-15/IL-15R -NKG2D CAR-T cell therapy significantly enhanced antiviral efficacy in mice, as the serum load of EBV after IL-15/IL-15R -NKG2D CAR-T cell infusion was 1500 times lower than the untreated control (P < 0.
001). The enhanced efficacy of IL-15/IL-15R -NKG2D CAR T cells was probably due to the IL-15/IL-15R signaling improved homing and persistence of NKG2D CAR-T cells in vivo, and increased the production of IFN- , Perforin, and Granulysin.
In conclusion, NKG2D CAR-T cells co-expressing IL-15/IL-15R promoted the central memory CAR T cell proliferation and improved the homing and persistence of CAR T cells in vivo, resulting in enhanced anti-tumor and anti-viral effects in treating EBV-PTLD.
论文信息
- 作者
- Mai Q、He B、Deng S、Zeng Q、Xu Y、Wang C、Pang Y、Zhang S
- 第一作者单位
- Department of Blood Transfusion, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China.China
- 通讯作者单位
- Department of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, 510515, China. zhangling1982@163.com.China
- 期刊
- Experimental hematology & oncology2024 Aug 19
- 原文标识
- PubMed 39160631 · DOI 10.1186/s40164-024-00553-z
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