Kunkun Han, Xuan Wang, Guodong Chen, Wenyue Liu, Xiao Mei, Yili Yang, Xin Xu
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The CAR expression on CAR-T cells was assessed by flow cytometry, and the killing effects of CAR-T cells on MM were assessed by the cytotoxicity assay and ELISA assay. Moreover, xenograft models were also established to evaluate the ability of IL21-NKG2D-CAR-T cells to eliminate MM in vivo. Our results indicated that NKG2D CAR-T cells had dramatic cytotoxicity on MM cells in vitro, and co-expression of IL-21 significantly increased the cytotoxicity of NKG2D CAR-T cells on MM cells. Remarkably, we found that dexamethasone enhanced the cytotoxicity of IL21-NKG2D CAR-T cells on MM cells. Furthermore, IL21-NKG2D CAR-T cells also displayed significant anti-myeloma activity in vivo. In conclusion, IL21-NKG2D CAR-T cells had dramatic cytotoxicity on MM cells in vitro and in vivo, and a system to apply IL21-NKG2D CAR-T cells and low dosage of dexamethasone for the future study of the targeted therapy for MM has been established.</p>","PeriodicalId":16112,"journal":{"name":"Journal of Investigative Medicine","volume":" ","pages":"45-53"},"PeriodicalIF":2.5000,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Targeted therapy of multiple myeloma by IL21-NKG2D CAR-T cells.\",\"authors\":\"Kunkun Han, Xuan Wang, Guodong Chen, Wenyue Liu, Xiao Mei, Yili Yang, Xin Xu\",\"doi\":\"10.1177/10815589241291846\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>NKG2D chimeric antigen receptor (CAR)-modified T cells (NKG2D CAR-T cells) have been reported to be preclinically efficient in several tumors, but little is known whether NKG2D CAR-T cells co-expressing IL21 (IL21-NKG2D CAR-T cells) display greater antitumor activity in multiple myeloma (MM). 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引用次数: 0
摘要
据报道,NKG2D嵌合抗原受体(CAR)修饰的T细胞(NKG2D CAR-T细胞)在多种肿瘤的临床前研究中都很有效,但对于联合表达IL21的NKG2D CAR-T细胞(IL21-NKG2D CAR-T细胞)是否在多发性骨髓瘤(MM)中显示出更强的抗肿瘤活性却知之甚少。本研究制备了慢病毒,用于表达与细胞外NKG2D序列相连的IL21序列,其信号肽通过CD8α铰链-跨膜结构域与融合了CD3-ζ链信号结构域的4-1BB分子相连,并构建了工程化的IL21-NKG2D-CAR T细胞和NKG2D-CAR T细胞。通过流式细胞术评估了CAR-T细胞上的CAR表达,并通过细胞毒性试验和ELISA试验评估了CAR-T细胞对MM的杀伤作用。此外,还建立了异种移植模型,以评估IL21-NKG2D-CAR T细胞在体内消灭MM的能力。我们的研究结果表明,NKG2D CAR-T细胞在体外对MM细胞具有显著的细胞毒性,而共同表达IL-21能显著提高NKG2D-CAR T细胞对MM细胞的细胞毒性。值得注意的是,我们发现地塞米松能增强 IL21-NKG2D-CAR T 细胞对 MM 细胞的细胞毒性。此外,IL21-NKG2D-CAR T 细胞在体内也显示出显著的抗骨髓瘤活性。总之,IL21-NKG2D-CAR T细胞对MM细胞具有显著的体外和体内细胞毒性,并建立了应用IL21-NKG2D-CAR T细胞和低剂量地塞米松进行MM靶向治疗研究的体系。
Targeted therapy of multiple myeloma by IL21-NKG2D CAR-T cells.
NKG2D chimeric antigen receptor (CAR)-modified T cells (NKG2D CAR-T cells) have been reported to be preclinically efficient in several tumors, but little is known whether NKG2D CAR-T cells co-expressing IL21 (IL21-NKG2D CAR-T cells) display greater antitumor activity in multiple myeloma (MM). In this study, the lentivirus has been produced for expression of the IL21 sequence linked to the extracellular NKG2D sequence with the signal peptide linked through the CD8α hinge-transmembrane domain to the 4-1BB molecule fused with the CD3-ζ chain signaling domain, and the engineered IL21-NKG2D CAR-T cells and NKG2D CAR-T cells were constructed. The CAR expression on CAR-T cells was assessed by flow cytometry, and the killing effects of CAR-T cells on MM were assessed by the cytotoxicity assay and ELISA assay. Moreover, xenograft models were also established to evaluate the ability of IL21-NKG2D-CAR-T cells to eliminate MM in vivo. Our results indicated that NKG2D CAR-T cells had dramatic cytotoxicity on MM cells in vitro, and co-expression of IL-21 significantly increased the cytotoxicity of NKG2D CAR-T cells on MM cells. Remarkably, we found that dexamethasone enhanced the cytotoxicity of IL21-NKG2D CAR-T cells on MM cells. Furthermore, IL21-NKG2D CAR-T cells also displayed significant anti-myeloma activity in vivo. In conclusion, IL21-NKG2D CAR-T cells had dramatic cytotoxicity on MM cells in vitro and in vivo, and a system to apply IL21-NKG2D CAR-T cells and low dosage of dexamethasone for the future study of the targeted therapy for MM has been established.
期刊介绍:
Journal of Investigative Medicine (JIM) is the official publication of the American Federation for Medical Research. The journal is peer-reviewed and publishes high-quality original articles and reviews in the areas of basic, clinical, and translational medical research.
JIM publishes on all topics and specialty areas that are critical to the conduct of the entire spectrum of biomedical research: from the translation of clinical observations at the bedside, to basic and animal research to clinical research and the implementation of innovative medical care.