Target antigen–displaying extracellular vesicles boost CAR T cell efficacy in cell and mouse models of neuroblastoma
Menée à l'aide de lignées cellulaires et de modèles murins de neuroblastome, cette étude met en évidence l'intérêt de vésicules extracellulaires synthétiques présentant des antigènes tumoraux cibles pour améliorer l'efficacité des lymphocytes CAR-T
Glypican-2 (GPC2) and the disialoganglioside GD2 are validated CAR T cell targets in neuroblastoma, but durable clinical responses remain limited. This modest chimeric antigen receptor T cell (CAR T cell) efficacy is in part due to suboptimal T cell persistence, antigen down-regulation, and a hostile tumor microenvironment, which includes immune cell–modulating extracellular vesicles (EVs). Neuroblastoma-derived EVs may contain CAR targets or other immunoregulatory elements that can modulate CAR T cell antitumor activity. Thus, we first profiled the surfaceome of neuroblastoma EVs and assessed their impact on both GPC2 and GD2 CAR T cell function. Neuroblastoma EVs displayed GPC2 and GD2, with minimal expression of programmed death-ligand 1 (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 nontumor-derived GPC2+ synthetic EVs (SyntEVs) as CAR T cell enhancers and armored them with either albumin-binding domains or GD2-binding domains. In mice harboring human neuroblastoma cell line–derived or patient-derived xenografts, serial infusion of armored SyntEVs after 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 down-regulation. This SyntEV platform offers a versatile system to address the therapeutic limitations of CAR T cells in solid tumors. Vaccination with antigen-displaying SyntEVs enhances GPC2 CAR T cell persistence and antitumor efficacy in models of neuroblastoma. The effectiveness of CAR T cell therapy for solid tumors has been limited by poor persistence due to immunosuppressive tumor microenvironments, among other factors. Here, Giudice et al. show that neuroblastoma cells released extracellular vesicles (EVs) carrying the tumor antigens glypican-2 (GPC2) and the disialoganglioside GD2. These EVs activated CAR T cells targeting these antigens. Tumor-derived and synthetic EVs carrying GPC2 boosted CAR T cell persistence and tumor control in mouse models of neuroblastoma, suggesting a potential avenue to overcome some of the hurdles that limit the efficacy of CAR T cell therapy for solid tumors. —Daniela Neuhofer
Science Translational Medicine , article en libre accès, 2025