B7-H3–Targeted CAR-Vδ1T Cells Exhibit Potent Broad-Spectrum Activity against Solid Tumors
Licui Jiang, Fengtao You, Hai Wu, Changsong Qi, Shufen Xiang, Ping Zhang, Huimin Meng, Min Wang, Jiequn Huang, Yafen Li, Dan Chen, Gangli An, Nan Yang, Bozhen Zhang, Lin Shen, Lin Yang
Abstract
Vδ1T cells, a rare subset of γδT cells, hold promise for treating solid tumors. Unlike conventional T cells, they recognize tumor antigens independently of the MHC antigen presentation pathway, making them a potential "off-the-shelf" cell therapy product. However, isolation and activation of Vδ1T cells is challenging, which has limited their clinical investigation. Here, we developed a large-scale clinical-grade manufacturing process for Vδ1T cells and validated the therapeutic potential of B7-H3 chimeric antigen receptor (CAR)-modified Vδ1T cells in treating solid tumors. Coexpression of IL2 with the B7-H3-CAR led to durable antitumor activity of Vδ1T cells in vitro and in vivo. In multiple subcutaneous and orthotopic mouse xenograft tumor models, a single intravenous administration of the CAR-Vδ1T cells resulted in complete tumor regression. These modified cells demonstrated significant in vivo expansion and robust homing ability to tumors, akin to natural tissue-resident immune cells. Additionally, the B7-H3-CAR-Vδ1T cells exhibited a favorable safety profile. In conclusion, B7-H3-CAR-modified Vδ1T cells represent a promising strategy for treating solid tumors. Significance: A clinical-grade expansion protocol enabled generation of B7-H3-targeted CAR-Vδ1T cells with robust anticancer activity and a favorable safety profile, supporting the potential of CAR-Vδ1T cells as an "off-the-shelf" therapy for solid tumors.