Antitumor Responses in the Absence of Toxicity in Solid Tumors by Targeting B7-H3 Via Chimeric Antigen Receptor T Cells

The cell surface expression of B7-H3 across multiple tumor subtypes and its restricted expression in normal tissues make it an attractive target for cancer immunotherapy. We generated chimeric antigen receptor (CAR) T cells targeting B7-H3 (B7-H3.CAR-Ts), and tested them in pancreatic ductal adenocarcinoma (PDAC), ovarian cancer (OC) and neuroblastoma (NB) models in vitro and in vivo. The results showed that B7-H3.CAR-Ts effectively controlled the growth of PDAC, OC and NB tumor cells in vitro and in orthotopic, metastatic and patient-derived xenograft (PDX) mouse models. In addition, we found that 4-1BB costimulation promotes lower PD1 expression in B7-H3.CAR-Ts, and thus have superior antitumor activity when targeting PD-L1 constitutively expressing tumor cells. Finally, taking the advantage of the cross-reactivity of B7-H3.CAR with murine B7-H3 (mB7-H3), we investigated the antitumor efficacy and safety of B7-H3.CAR-Ts in a syngeneic pancreatic orthotopic tumor model in immunocompetent mouse. The mB7-H3.CAR-Ts significantly controlled the tumor growth in immunocompetent mice tumor model without decreasing the hematopoietic or immune cell numbers, and no tissue damage in any analyzed organs was observed, these findings further support the safety and efficacy of B7-H3.CAR-Ts for clinical application.