IMMU-20. Effective CAR-T cell medulloblastoma therapy in an immunocompetent mouse model

Immunotherapy with chimeric antibody receptor (CAR) T cells is effective for previously incurable hematologic cancers and may transform treatment for refractory brain tumors. However, CAR-T cell therapy for solid tumors has not yet been as successful as for leukemias, and animal models are needed to improve implementation. At present, preclinical studies of CAR-T cell therapy for brain tumors have typically used exogenous tumors, xenografted into immunocompromised mice, because primary mouse brain tumors do not express antigens that match brain tumor-specific antigens in humans. To advance preclinical development of CAR-T brain tumor therapy, we engineered mice to develop medulloblastomas that express B7-H3, an antigen specifically expressed on human medulloblastomas and other pediatric brain tumors. We show that treating these tumors with B7-H3-directed CAR-T cells provokes anti-tumor responses both in vitro and in vivo. Administering B7-H3 CAR-T cells by intracranial injection increased the event-free survival time of mice with medulloblastoma, in a dose-dependent manner. CAR-T cell treatment was not curative as an isolated intervention, suggesting that cure will require pairing with surgical resection and additional adjuvant therapy. Our model presents new opportunities to study the mechanisms of CAR-T cell efficacy and recurrence in an immunocompetent host with intact vasculature and blood-brain barrier. Our ongoing studies using scRNA-seq will allow us to define therapy-induced changes in tumor cells, CAR-T cells and cells of the tumor microenvironment and to test new T-cell modifications and combinations of therapeutic modalities, toward a goal of optimizing CAR-T cell therapy for pediatric brain tumors.