title: CAR-Engineered NK Cells Targeting Wild-Type EGFR and EGFRvIII Enhance Killing of Glioblastoma and Patient-Derived Glioblastoma Stem Cells.
abstract: Glioblastoma (GB) remains the most aggressive primary brain malignancy. Adoptive transfer of chimeric antigen receptor (CAR)-modified immune cells has emerged as a promising anti-cancer approach, yet the potential utility of CAR-engineered natural killer (NK) cells to treat GB has not been explored. Tumors from approximately 50% of GB patients express wild-type EGFR (wtEGFR) and in fewer cases express both wtEGFR and the mutant form EGFRvIII; however, previously reported CAR T cell studies only focus on targeting EGFRvIII. Here we explore whether both wtEGFR and EGFRvIII can be effectively targeted by CAR-redirected NK cells to treat GB. We transduced human NK cell lines NK-92 and NKL, and primary NK cells with a lentiviral construct harboring a second generation CAR targeting both wtEGFR and EGFRvIII and evaluated the anti-GB efficacy of EGFR-CAR-modified NK cells. EGFR-CAR-engineered NK cells displayed enhanced cytolytic capability and IFN-γ production when co-cultured with GB cells or patient-derived GB stem cells in an EGFR-dependent manner. In two orthotopic GB xenograft mouse models, intracranial administration of NK-92-EGFR-CAR cells resulted in efficient suppression of tumor growth and significantly prolonged the tumor-bearing mice survival. These findings support intracranial administration of NK-92-EGFR-CAR cells represents a promising clinical strategy to treat GB.
authors.affiliation: Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA.|The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Han
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA.
authors.forename: Jianhong
authors.initials: J
authors.lastname: Chu
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA.
authors.forename: Wing
authors.initials: W
authors.lastname: Keung Chan
authors.affiliation: Center for Biostatistics, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Jianying
authors.initials: J
authors.lastname: Zhang
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA.
authors.forename: Youwei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219 USA.
authors.forename: Justus B
authors.initials: JB
authors.lastname: Cohen
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Victor
authors.affiliation: Department of Neurological Surgery, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Walter H
authors.initials: WH
authors.lastname: Meisen
authors.affiliation: Department of Neurological Surgery, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Sung-Hak
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219 USA.
authors.forename: Paola
authors.initials: P
authors.lastname: Grandi
authors.affiliation: Department of Radiology, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Qi-En
authors.initials: QE
authors.lastname: Wang
authors.affiliation: Department of Biomedical Engineering, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Neurological Surgery, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Nakano
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: E Antonio
authors.initials: EA
authors.lastname: Chiocca
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219 USA.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Glorioso Iii
authors.affiliation: Department of Neurological Surgery, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Balveen
authors.initials: B
authors.lastname: Kaur
authors.affiliation: Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA.|The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.affiliation: Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA.|The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yu
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015870:Gene Expression; D005909:Glioblastoma / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D014411:Neoplastic Stem Cells / Q000276:immunology* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; C410723:epidermal growth factor receptor VIII; D007371:Interferon-gamma; D066246:ErbB Receptors