B7H3-targeting chimeric antigen receptor modification enhances antitumor effect of V9V2 T cells in glioblastoma

Background Glioblastoma (GBM) is a highly aggressive primary brain tumor with a poor prognosis. This study investigates the therapeutic potential of human V gamma 9V delta 2 T cells in GBM treatment. The sensitivity of different glioma specimens to V gamma 9V delta 2 T cell-mediated cytotoxicity is assessed using a patient-derived tumor cell clusters (PTCs) model.Methods The study evaluates the anti-tumor effect of V gamma 9V delta 2 T cells in 26 glioma cases through the PTCs model. Protein expression of BTN2A1 and BTN3A1, along with gene expression related to lipid metabolism and glioma inflammatory response pathways, is analyzed in matched tumor tissue samples. Additionally, the study explores two strategies to re-sensitize tumors in the weak anti-tumor effect (WAT) group: utilizing a BTN3A1 agonistic antibody or employing bisphosphonates to inhibit farnesyl diphosphate synthase (FPPS). Furthermore, the study investigates the efficacy of genetically engineered V gamma 9V delta 2 T cells expressing Car-B7H3 in targeting diverse GBM specimens.Results The results demonstrate that V gamma 9V delta 2 T cells display a stronger anti-tumor effect (SAT) in six glioma cases, while showing a weaker effect (WAT) in twenty cases. The SAT group exhibits elevated protein expression of BTN2A1 and BTN3A1, accompanied by differential gene expression related to lipid metabolism and glioma inflammatory response pathways. Importantly, the study reveals that the WAT group GBM can enhance V gamma 9V delta 2 T cell-mediated killing sensitivity by incorporating either a BTN3A1 agonistic antibody or bisphosphonates. Both approaches support TCR-BTN mediated tumor recognition, which is distinct from the conventional MHC-peptide recognition by alpha beta T cells. Furthermore, the study explores an alternative strategy by genetically engineering V gamma 9V delta 2 T cells with Car-B7H3, and both non-engineered and Car-B7H3 V gamma 9V delta 2 T cells demonstrate promising efficacy in vivo, underscoring the versatile potential of V gamma 9V delta 2 T cells for GBM treatment.Conclusions V gamma 9V delta 2 T cells demonstrate a robust anti-tumor effect in some glioma cases, while weaker in others. Elevated BTN2A1 and BTN3A1 expression correlates with improved response. WAT group tumors can be sensitized using a BTN3A1 agonistic antibody or bisphosphonates. Genetically engineered V gamma 9V delta 2 T cells, i.e., Car-B7H3, show promising efficacy. These results together highlight the versatility of V gamma 9V delta 2 T cells for GBM treatment.