IMMU-44. Identification of Therapeutic Target Antigens using patient derived glioblastoma and their clinical application to CAR-T cell therapy against glioblastoma

BACKGROUND Immune cell therapies, including CAR-T cell therapy, are gaining attention as novel cancer treatments. Although clinical trials of CAR-T cell therapy for glioblastoma have been reported, its effects are limited, and further improvements are necessary. We have attempted to identify tumor-specific antigens in glioblastoma, created CAR-T/NK cells targeting these antigens, verified their anti-tumor effects in vitro and in vivo. In this study, we describe our efforts in the therapeutic development of immune cell therapy for glioblastoma. METHODS Primary cell cultures were established from glioblastoma surgical specimens. B cells were extracted from the lymph nodes of mice immunized with these cultured cells. These B cells were fused with myeloma cells to create antibody-producing cells. Among these antibodies, we identified glioblastoma-specific antigens by selecting those that bind only to glioblastoma cells and not to normal brain cells. We created CAR-T/NK cells targeting the identified antigens and examined their anti-tumor effects in vitro and in vivo. RESULTS B7-H3 and PTGFRN were identified as tumor surface antigens specifically expressed in glioblastoma. We created CAR-T cells against these antigens and co-cultured it with GBM cells, which significantly increased the production of IL-2 and INF-γ. Furthermore, the CAR-T cells injected intracranial in an orthotopic xenograft model with patient-derived GBM cells, significantly reduced tumor growth. In addition, CAR-NK cells targeting B7-H3 also demonstrated anti-tumor effects in vitro and in vivo. CONCLUSION In this study, we identified B7-H3 and PTGFRN as tumor-specific surface antigens and confirmed their anti-tumor effects in vitro and in vivo. These results suggest that CAR-based immune cell therapy could be a novel treatment for glioblastoma. However, challenges remain, such as the blood-brain barrier and the immunosuppressive tumor microenvironment of glioblastoma. We are currently conducting research to overcome these issues, including the combined use of focused ultrasound.