CAR T cell therapy is transformative in hematologic malignancies but has produced limited and transient benefit in glioblastoma and other high-grade gliomas, in part because the tumor microenvironment is highly immunosuppressive and CAR T cell behavior in situ remains poorly characterized. Most clinical monitoring relies on blood-based measurements, leaving fundamental questions unresolved about how many CAR T cells enter brain tumors, where they localize, whether they remain migratory and cytotoxic, and how they interact with endogenous immune cells and stromal niches. This ASPIRE Award seeks to define the spatial tumor–immune features that enable or restrict CAR T activity, an essential step toward improving response rates and durability for patients with recurrent disease.
The team will integrate clinically annotated human specimens from an IL13Rα2-CAR T trial with complementary syngeneic mouse glioma models that are responsive or resistant to CAR T therapy. Using matched spatial proteomics and transcriptomic imaging approaches, they will map CAR T cells and host immune populations, quantify activation and exhaustion states, and relate these to tumor and microenvironmental characteristics implicated in resistance. Longitudinal profiling in mice will provide temporal resolution of CAR T niches and microenvironmental remodeling, and comparative analyses across treatment conditions will highlight actionable mechanisms. By generating a high-resolution, multimodal atlas of CAR T–tumor interactions in glioma, this project is poised to guide next-generation CAR T engineering and biomarker-driven trial design, improving the likelihood that patients benefit from cellular immunotherapy.