The critical role of the host endogenous immune compartment after intracerebroventricular CAR T cell therapy in recurrent GBM

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, with a median survival of under 15 months and no effective treatment after recurrence. A recent phase I trial of intracerebroventricular (ICV) bivalent CAR T cells in recurrent GBM showed promising responses, including tumor reduction and prolonged survival. However, relapse remains common. We performed in-depth profiling of longitudinal CSF and tumor samples from responders and non-responders to characterize immune dynamics following infusion. Our study reveals that while CAR T cells activate post-infusion across all patients, outcomes were defined by divergent remodeling of the endogenous immune landscape. Cytotoxic NK cell expansion characterized responders, whereas regulatory T cell expansion and abundant baseline immunosuppressive myeloid cells characterized non-responders. These findings indicate that host immune cells play a critical role in ICV CAR T cell therapy for GBM, suggesting that combinatorial strategies modulating the endogenous immune compartment could improve next-generation treatments.