• Kunkun Han, Xuan Wang, Guodong Chen, Wenyue Liu, Xiao Mei, Yili Yang, and Xin Xu.
• China Regional Research Center, International Center for Genetic Engineering and Biotechnology, Taizhou, Jiangsu, P. R. China.
• J. Investig. Med. 2025 Jan 1; 73 (1): 455345-53.

AbstractNKG2D 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.

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