RP1 ABSTRACT Glioblastoma (GBM), the most common primary brain tumor, is notoriously resistant to current treatments. Its prognosis is grim, with a median survival of only 12-15 months after standard treatment, which typically involves surgical resection followed by radiation and chemotherapy. Despite these efforts, GBM often recurs. New therapeutic approaches are urgently needed. One avenue being explored is immunotherapy, which aims to harness the body’s immune system to fight cancer. Among these, chimeric antigen receptor (CAR)-T cell therapy has shown promise. CAR T cells, initially transformative for blood cancers, are now being evaluated for solid tumors like GBM. In our research proposal, we intend to utilize B7-H3 as a specific target for CAR T cells. B7- H3 (also known as CD276) belongs to the B7 family and holds significant promise for cancer treatment. Its overexpression in various tumors, including GBM, makes it an attractive candidate. Dr. Dotti (RP3) has recently initiated a clinical trial involving B7-H3 CAR T cells for GBM (ClinicalTrials.gov identifier: NCT06158139). Furthermore, due to B7-H3’s consistent overexpression in GBM cells compared to healthy tissue, both in vitro and in vivo studies demonstrate the potential of CAR T cells to effectively target GBM. To enhance CAR therapy for GBM, we propose utilizing immunomodulators released through controlled release scaffolds. Notably, microglia and macrophages are the predominant immune cells infiltrating GBM, and this population expresses substantial levels of toll-like receptors (TLRs). Further, both TLR and STING agonists have been shown to enhance CAR T cell activity. Our approach involves evaluating the delivery rate of the TLR7/8 agonist resiquimod (Resi), TLR 9 agonist CpG, TLR 4 agonist MPLA, or STING agonist cGAMP, which will be administered locally to the tumor resection cavity. Agonists will be formulated within nanofibrous polymer scaffolds with varying degradation rates. The goal is to f