Investigating neuroblastoma, Giudice et al. found that in both mice and patient samples, tumor-derived extracellular vesicles (EVs) displayed CAR T cell target antigens GPC2 and GD2, with minimal expression of PD-L1, and could activate respective CAR T cells. To utilize this therapeutically, the researchers engineered GPC2+ synthetic EVs as CAR T cell enhancers, and armed them with either albumin-binding domains or GD2-binding domains. Serial infusion of these SyntEVs coated GPC2lo tumor cells with GPC2 (circumventing antigen downregulation), enhanced CAR T cell persistence, and increased tumor control.
Contributed by Lauren Hitchings
ABSTRACT: 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.
Author Info: (1) Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. (2) Division of Oncology and Center for Childho
Author Info: (1) Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. (2) Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. (3) Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. (4) Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. (5) Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. (6) Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. (7) Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. (8) Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. (9) Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. (10) Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. (11) Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. (12) Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. (13) Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. (14) Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. (15) Proteomics Core Facility, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. (16) Proteomics Core Facility, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. (17) Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Proteomics Core Facility, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. (18) Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. (19) Pediatric Cancer Research Center and Department of Pediatrics, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA. (20) Pediatric Cancer Research Center and Department of Pediatrics, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA. (21) Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
