CNSC-02. BORN TO KILL: NEURODEVELOPMENTAL CELLS AS RENEWABLE TARGETS IN T CELL THERAPY FOR GLIOBLASTOMA

Abstract Glioblastoma (GBM) is a highly aggressive brain cancer with limited treatment options and poor long-term survival. Adoptive cellular therapy (ACT) has shown promise in targeting GBM, but current strategies often rely on tumor-derived antigens, limiting their applicability in patients with inoperable tumors. Moreover, GBM recurrence is driven by tumor heterogeneity and glioma stem cells (GSCs) that evade standard therapies. Radial glial cells (RGCs), neurodevelopmental progenitors with transcriptional similarity to GSCs, express developmental antigens (DAs) also found in GBM, suggesting their potential as a tumor-independent, renewable antigen source. To explore this, we used single-cell RNA sequencing to profile RGCs from postnatal day 4 murine cortices and identified a subset of antigens shared with tumors from the KR158B GBM model. Using our O.R.A.N. antigen prediction platform, we screened these for immunogenicity and developed an RGC-derived cDNA antigen library for use in ACT. Polyclonal T cells generated from dendritic cells pulsed with RGC RNA showed robust IFNγ and TNFα release in response to cognate antigen and selectively lysed tumor cells in vitro. Further, RGC T cells were significantly better than total tumor RNA (ttRNA) T cells at killing CD133-enriched tumor cells, indicating a preference of RGC T cells for stemness markers. In GBM-bearing mice, ACT using RGC T cells significantly improved survival (p = 0.0058), achieving outcomes comparable to ttRNA ACT, without overt neurotoxicity or systemic inflammation. In parallel human studies, RGC-derived antigens were tested against patient-derived GBM xenografts. Although RGC T cells targeted a smaller fraction of tumor cells compared to ttRNA T cells, they showed enriched recognition of GSC-like populations in 3D bioprinted immune-tumor assays. These findings support the utility of RGCs as a tumor-independent antigen source capable of driving anti-GBM responses. This renewable library enables ACT even in cases where tumor resection is not possible and provides a strategy for targeting treatment-resistant GSC subpopulations early in disease progression.