STEM-10. TARGETING EPH FAMILY OF RECEPTORS: ADVANCED PRECISION THERAPY FOR GBM

Abstract Targeting Eph Family of Receptors: Advanced Precision Therapy for GBM Abstract* (MAX 300 WORDS) Glioblastoma (GBM) is an aggressive brain cancer and is associated with very poor prognosis. Standard treatment involves surgical resection, post-operative radiation and TMZ chemotherapy. Further research into new therapeutic approaches which target chemo-resistant tumor propagating cells, are urgently required. The EphA receptor family of proteins are frequently elevated and functional in GBM. Our data in GBM tissue shows that tumor cells expressing EphA, can be efficiently targeted using antibody drug conjugate (ADC) approaches. EphA3 CAR T cells demonstrated curative efficacy in an orthotopic xenograft model of glioblastoma. EphA3 CAR T cells were equally effective in targeting patient-derived neurospheres and infiltrate, disaggregate, and induce apoptosis in GBM-derived explant organoids. Using spatial and single cell transcriptomics approaches we have identified Eph family members that are expressed on distinct tumor cell compartments. Over-expression of these Eph family members in primary GBM lines led to a reduction in neurosphere formation, Ki67 staining and growth rates. Using GBM explant organoid models, we demonstrate efficient killing using combinatorial ADC approaches. We thus provide evidence supporting the therapeutic potential of EphA3 CAR T-cell and ADC therapy in glioblastoma by targeting EphA3 associated with brain cancer stem cells and the tumor vasculature. As an extension we propose that multi-targeting of EphA family members might better capture GBM tumor heterogeneity and lead to an extension GBM patient survival.