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.
Conclusions: 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.
Patient Care: Our preclinical study shows that B7-H3 CAR T cells have potent anti-GBM activity. B7-H3 is a validated tumor antigen for GBM, DIPG, and a number of solid tumors. Thus this research provides the foundation for testing B7-H3 CAR T cells in a GBM clinical trial, hopefully improving outcomes for patients with this devastating disease.
Learning Objectives: By the conclusion of this session, participants should be able to: 1) Describe the role of T cell immunotherapy for patients with GBM; 2) Identify some limitations of current experimental GBM immunotherapies; 3) Discuss alternatives to improving therapy, and the potential benefit of targeting B7-H3