Dataset Information

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

ABSTRACT: 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

DISEASE(S): Neuroblastoma

SUBMITTER: Hossein Fazelinia

LAB HEAD: Kristopher Bosse

PROVIDER: PXD067632 | Pride | 2026-01-29

REPOSITORIES: Pride

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Target antigen-displaying extracellular vesicles boost CAR T cell efficacy in cell and mouse models of neuroblastoma.

Giudice Anna Maria AM Matlaga Stephanie S Roth Sydney L SL Pascual-Pasto Guillem G Schürch Patrick M PM Rouin Geoffrey G McIntyre Brendan B Grothusen Grant P GP Cresswell-Clay Evan E Shraim Rawan R Groff David D Zecchino Vincent V Lombardi Simona S Martinez Daniel D Spruce Lynn A LA Brown Elizabeth M EM Fazelinia Hossein H Henrickson Sarah E SE Nance Jonas J Reynolds C Patrick CP Bosse Kristopher R KR

Science translational medicine 20251119 825

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 ...[more]

PMID: 41259537

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Project description:Anti-cancer immunotherapy approaches are increasingly coveted. Chimeric antigen receptor (CAR)-T cell therapy has been shown to be an effective treatment for hematological tumors, but the treatment of solid tumors still lacks effectiveness, due to lower intra-tumor infiltration of CAR-T cells and tumor-induced immunosuppression. Macrophages represent a very large proportion of the tumor environment, participate in many aspects to tumor development and therefore represent interesting therapeutic targets. Macrophages can infiltrate solid tumor tissue and interact with almost all cellular components in the tumor microenvironment. In addition, macrophages can also promote a direct anti-tumor response by phagocyting tumor cells. We have developed macrophages expressing a CAR receptor against the HER2 antigen. The CAR receptor possesses an intracellular domain CD3ζ having homology with the protein FcεRI-γ, which once activated by the recognition antibody-antigen, induces the phagocytic activity of macrophages. 72% of macrophages express the CAR after transduction. CAR-M can specifically phagocyte HER2 coated-beads in a much more effective way than WT macrophages. We have then confirmed the capacity of CAR-M to phagocyte HER2+ cancer cell lines. Co-culture of CAR-M with breast cancer tumoroids (HER2+ or HER2-) has also been performed demonstrating their efficacy in a more complex environment. However, in the tumor microenvironment, due to their plasticity, macrophages tend to adopt an anti-inflammatory phenotype losing their anti-tumor activities. We have therefore developed a combined strategy by inhibiting two proprotein convertases, Furin and PC1/3 in CAR-M. The inhibition of furin or PC1/3 induces an increase in pro-inflammatory markers and maintains macrophage activation in the presence of cancer cells. In addition, HER2+ CAR-M with shFurin or shPC1/3 greatly increases the phagocytic activity on Her2+ beads or Her2+ tumors. These enzymes are therefore phenotypic regulators of macrophages. Our strategy is therefore based on a double activation of tumor-infiltrating macrophages. The first one consists in boosting the phagocytic activity of macrophages by having them express a CAR receptor targeting a tumor antigen. The second allows their reprogramming towards a pro- inflammatory phenotype by the inhibition of Furin and/or PC1/3 proprotein convertases

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