Abstract A024: CAR T cells locally delivered in porcine decellularized matrix hydrogels enhance survival in post-resection glioblastoma

Abstract Glioblastoma (GBM) is the most common malignant primary brain tumor in adults, with a median overall survival of 12-15 months, despite maximal surgical resection, radiation, and temozolomide. While chimeric antigen receptor (CAR) T cell therapy has demonstrated remarkable efficacy against hematologic malignancies, its activity in GBM has been limited by the immunosuppressive tumor microenvironment (TME), adaptive resistance from the tumor, poor trafficking of CAR T cells after peripheral administration, limited diffusion across the blood-brain- and blood-tumor-barriers, and lack of CAR T cell persistence. Because GBM recurrence is predominantly local, we hypothesize that regional delivery of CAR T cells directly into the post-resection cavity can overcome the immunosuppressive TME and improve the duration and magnitude of antitumor activity. To test this, we developed a biomaterials-based approach to encapsulate CAR T cells within a decellularized porcine brain extracellular matrix (dECM) hydrogel that transforms from a viscous pre-gel solution into a self-supporting scaffold at physiologic temperatures. dECM hydrogels were characterized for DNA and protein content, gelation kinetics, macrostructure and pore size, and CAR T cell viability and release kinetics. Encapsulated and released CAR T cells retained full cytotoxic function in vitro, demonstrating tumor-killing activity equivalent to freshly manufactured CAR T cells within impedance assays. We developed an orthotopic NSG mouse model of recurrent U87MG-EGFRvIII+ GBM, in which resection surgery alone does not improve survival compared to untreated mice, in order to evaluate the therapeutic impact of local delivery of CAR T cells during the post-resection window. The local implantation of on-target EGFRvIII-CAR T cells within dECM hydrogels, after resection, produced durable tumor control and significantly prolonged survival when compared to resection alone or dECM loaded with off-target CAR T cells. Additionally, a single locoregional dose of CAR-loaded dECM significantly extended survival and suppressed tumor recurrence comparably to multiple doses administered intravenously. Notably, local delivery of CAR-loaded dECM gels achieved durable tumor control at one-tenth the systemic CAR T cell dose and conferred survival benefits comparable to repeated intravenous infusions of the same CAR T cell product. These studies demonstrate that biomaterials-guided local delivery of CAR T cells enables potent and durable immunotherapy for GBM, allowing for treatment at an early opportunity time window that overcomes key biological and delivery barriers plaguing systemic delivery of immunotherapies. Citation Format: Meghan Logun, Kelly Hicks, Lois Park, Logan Zhang, Zev Binder, Donald M. O'Rourke. CAR T cells locally delivered in porcine decellularized matrix hydrogels enhance survival in post-resection glioblastoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr A024.