327 B7-H3 Chimeric Antigen Receptor Modified T Cells Show Potent Anti-Tumor Activity in a Preclinical Model of Glioblastoma

Abstract

Abstract INTRODUCTION While initial phase I data suggest efficacy of local delivery of chimeric antigen receptor (CAR) modified T cells against glioblastoma (GBM), their activity remains limited in part by the intensity of antigen expression. Targeting more robust tumor associated antigens (TAAs) may help to improve anti-tumor responses. B7-H3 (CD276), a transmembrane glycoprotein which is overexpressed on many solid cancers including GBM, is a promising target. Here we generate CAR T cells specific for B7-H3 and characterize their function in a preclinical model of glioblastoma. METHODS B7-H3 CAR T cells were generated by retroviral transduction of healthy donor peripheral blood mononuclear cells (PBMCs) using a vector designed by our lab. The CAR modified T cells were tested in vitro for their ability to produce proinflammatory cytokines and kill B7-H3 positive glioma cell lines. In vivo activity of B7-H3 CAR T cells was tested using an orthotopic GBM xenograft mouse model. RESULTS >B7-H3 CAR T cells produced the proinflammatory cytokines interferon-gamma (IFN-g), interleukin-2 (IL-2), and tumor necrosis factor-alpha (TNF-a) when cocultured with B7-H3 positive glioma cell lines. B7-H3 CAR T cells also killed B7-H3 positive glioma cells in an in vitro cytotoxicity assay. Finally, B7-H3 CAR T cells demonstrated potent anti-tumor activity in vivo, producing tumor regression in our mouse model of GBM and significantly improving survival. CONCLUSION B7-H3 CAR T cells effectively target GBM and demonstrate significant anti-tumor activity in our preclinical studies. Efforts to translate this CAR for clinical use are warranted and will add to the armamentarium for treating patients with GBM and other solid cancers.