Abstract 1498: Nanobody-based CAR T cells targeting B7-H3 in pancreatic cancer

Abstract Pancreatic cancer is a common cause of cancer-related mortality worldwide with a poor 5-year survival rate. Adoptive transfer of T cells engineered with chimeric antigen receptors (CAR T cells) have shown promising potency in hematological malignancies, but it is more challenging to apply CAR T cells in the treatment of solid tumors. One of the major barriers is the lack of appropriate therapeutic targets. B7-H3 (CD276) is an emerging and promising pan-cancer target that is overexpressed in multiple solid tumors including pancreatic ductal adenocarcinoma (PDAC) and neuroblastoma (NB) but limited in normal tissues. Interestingly, it is highly expressed in not only tumor cells but also tumor-associated myeloid cells in the tumor microenvironment. In this study, we isolated a panel of novel B7-H3 specific nanobodies from our camel VHH single domain phage libraries. These nanobodies bind to human B7-H3-expressing tumor cell lines and cross-react with B7-H3 of different species. Notably, three nanobody-based CAR T cells (B12, C4 and G8) demonstrate potent cytolytic effects on B7-H3 positive PDAC and NB cell lines in vitro. In particular, CAR T cells have been tested in a metastatic PDAC model and a NB model in mice, showing that C4 and B12 nanobody-based CAR T cells have potent antitumor efficacy without evident side effects. Therefore, we conclude that our new B7-H3 targeted nanobody-based CAR T cells, in particular C4 and B12 derived CAR T cells, are promising for treating solid tumors such as pancreatic cancer and other deadly solid tumors. Citation Format: Dan Li, RuiXue Wang, Tianyuzhou Liang, Brad St. Croix, Mitchell Ho. Nanobody-based CAR T cells targeting B7-H3 in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1498.