Target antigen-displaying extracellular vesicles boost CAR T cell efficacy in neuroblastoma

GPC2 and GD2 are validated CAR T cell targets in neuroblastoma, but durable responses remain limited. We profiled the surfaceome of neuroblastoma-derived extracellular vesicles (EVs) and assessed their impact on CAR T cell function. Neuroblastoma EVs displayed GPC2 and GD2, with minimal PD-L1, and were detected in blood from tumor-bearing mice and patients. These EVs directly activated paired CAR T cells, suggesting a role for a peripheral source of CAR antigen. To exploit this therapeutically, we engineered non-tumor-derived GPC2+ synthetic EVs (SyntEVs) as CAR T cell enhancers and armored them with either albumin- or GD2-binding domains. In mice harboring human neuroblastomas, serial infusion of armored SyntEVs following GPC2 CAR T cells enhanced tumor control by boosting peripheral CAR T cell persistence. Moreover, GD2-targeting SyntEVs decorated low-antigen tumor cells with GPC2, circumventing antigen downregulation. This SyntEV platform offers a versatile system to address the therapeutic limitations of CAR T cells in solid tumors.