To target high-risk neuroblastoma, which expresses surface GPC2 (tumor-exclusive, but downregulated under immune pressure) and GD2 (not tumor-exclusive) and is infiltrated by CD16a+ innate immune cells, Pascual-Pasto et al. developed GPC2-directed CAR T cells that secreted a bispecific innate immune cell engager (BiCE) targeting GD2 and CD16a. In vitro, these cells induced GPC2-dependent cytotoxicity and promoted GD2-dependent activation of innate immunity. In vivo, locally delivered GD2.BiCE increased NK cell retention in tumors. In patient-derived xenograft models, the secretion of GD2.BiCE improved antitumor efficacy over GPC2-targeting CAR T cells.
Contributed by Lauren Hitchings
ABSTRACT: Novel chimeric antigen receptor (CAR) T-cell approaches are needed to improve therapeutic efficacy in solid tumors. High-risk neuroblastoma is an aggressive pediatric solid tumor that expresses cell-surface GPC2 and GD2 with a tumor microenvironment infiltrated by CD16a-expressing innate immune cells. Here we engineer T-cells to express a GPC2-directed CAR and simultaneously secrete a bispecific innate immune cell engager (BiCE) targeting both GD2 and CD16a. In vitro, GPC2.CAR-GD2.BiCE T-cells induce GPC2-dependent cytotoxicity and secrete GD2.BiCE that promotes GD2-dependent activation of antitumor innate immunity. In vivo, GPC2.CAR-GD2.BiCE T-cells locally deliver GD2.BiCE and increase intratumor retention of NK-cells. In mice bearing neuroblastoma patient-derived xenografts and reconstituted with human CD16a-expressing immune cells, GD2.BiCEs enhance GPC2.CAR antitumor efficacy. A CAR.BiCE strategy should be considered for tumor histologies where antigen escape limits CAR efficacy, especially for solid tumors like neuroblastoma that are infiltrated by innate immune cells.
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 Childh
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) Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA. (4) Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. (5) Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, 19104, USA. Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, 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. Department of Biomedical and Health Informatics, 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. (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. New York University, Perlmutter Cancer Center, Grossman School of Medicine, New York, NY, 10016, USA. (13) Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. (14) Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. (15) Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. (16) Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. (17) Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. Department of Molecular Biology, University of Cantabria School of Medicine, Santander, Cantabria, 39011, Spain. (18) Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. (19) 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. (20) 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. (21) Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA. (22) Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA. (23) Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA. bossek@chop.edu. Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA. bossek@chop.edu.
