B7-H3-Targeted CAR-Vd1T Cells Exhibit Potent Broad-Spectrum Activity Against Solid Tumors

Vd1T cells, a rare subset of ?dT 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 Vd1T cells is challenging, which has limited their clinical investigation. Here, we developed a large-scale clinical-grade manufacturing process for Vd1T cells and validated the therapeutic potential of B7-H3-CAR-modified Vd1T cells in treating solid tumors. Co-expression of interleukin-2 with the B7-H3-CAR led to durable anti-tumor activity of Vd1T cells in vitro and in vivo. In multiple subcutaneous and orthotopic mouse xenograft tumor models, a single intravenous administration of the CAR-Vd1T 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-Vd1T cells exhibited a favorable safety profile. In conclusion, B7-H3-CAR-modified Vd1T cells represent a promising strategy for treating solid tumors. Overall design: To investigate the molecular mechanisms underlying the superior efficacy of IL-2-expressing AQ-CAR-IL2-Vd1T cells compared to AG-CAR-Vd1T cells, we performed single-cell RNA sequencing on cells after repeated antigen stimulation with Raji-B7-H3 cells in vitro for four consecutive days.