title: CAR T Cells Targeting Podoplanin Reduce Orthotopic Glioblastomas in Mouse Brains.
abstract: Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor in adults with a 5-year overall survival rate of less than 10%. Podoplanin (PDPN) is a type I transmembrane mucin-like glycoprotein, expressed in the lymphatic endothelium. Several solid tumors overexpress PDPN, including the mesenchymal type of GBM, which has been reported to present the worst prognosis among GBM subtypes. Chimeric antigen receptor (CAR)-transduced T cells can recognize predefined tumor surface antigens independent of MHC restriction, which is often downregulated in gliomas. We constructed a lentiviral vector expressing a third-generation CAR comprising a PDPN-specific antibody (NZ-1-based single-chain variable fragment) with CD28, 4-1BB, and CD3ζ intracellular domains. CAR-transduced peripheral blood monocytes were immunologically evaluated by calcein-mediated cytotoxic assay, ELISA, tumor size, and overall survival. The generated CAR T cells were specific and effective against PDPN-positive GBM cells in vitro. Systemic injection of the CAR T cells into an immunodeficient mouse model inhibited the growth of intracranial glioma xenografts in vivo. CAR T-cell therapy that targets PDPN would be a promising adoptive immunotherapy to treat mesenchymal GBM.
authors.affiliation: Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shiina
authors.affiliation: Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Japan. Division of Neurosurgery, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
authors.forename: Masasuke
authors.initials: M
authors.lastname: Ohno
authors.affiliation: Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Japan.
authors.forename: Fumiharu
authors.initials: F
authors.lastname: Ohka
authors.affiliation: Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Japan. Division of Neurosurgery, Koujunkai Daido Hospital, Nagoya, Japan.
authors.forename: Shunichiro
authors.initials: S
authors.lastname: Kuramitsu
authors.affiliation: Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Japan.
authors.forename: Akane
authors.initials: A
authors.lastname: Yamamichi
authors.affiliation: Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Kato
authors.affiliation: Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Motomura
authors.affiliation: Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Japan.
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Tanahashi
authors.affiliation: Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Division of Diagnostic Pathology, Shizuoka Cancer Center, Shizuoka, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Watanabe
authors.affiliation: Division of Diagnostic Pathology, Shizuoka Cancer Center, Shizuoka, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Ito
authors.affiliation: Division of Cancer Biology, Nagoya University School of Medicine, Nagoya, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Senga
authors.affiliation: Division of Cancer Biology, Nagoya University School of Medicine, Nagoya, Japan.
authors.forename: Michinari
authors.initials: M
authors.lastname: Hamaguchi
authors.affiliation: Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Wakabayashi
authors.affiliation: Department of Regional Innovation, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Mika K
authors.initials: MK
authors.lastname: Kaneko
authors.affiliation: Department of Regional Innovation, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Yukinari
authors.initials: Y
authors.lastname: Kato
authors.affiliation: Preston Robert Tisch Brain Tumor Center at Duke and Department of Pathology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Vidyalakshmi
authors.initials: V
authors.lastname: Chandramohan
authors.affiliation: Preston Robert Tisch Brain Tumor Center at Duke and Department of Pathology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.affiliation: Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Japan. anatsume@med.nagoya-u.ac.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Natsume
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000628:therapy*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D005260:Female; D005909:Glioblastoma / Q000378:metabolism / Q000628:therapy*; D006801:Humans; D016219:Immunotherapy, Adoptive; D008562:Membrane Glycoproteins / Q000276:immunology* / Q000378:metabolism; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011946:Receptors, Antigen / Q000378:metabolism* / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*; D000098853:Podoplanin
chemical_list: D008562:Membrane Glycoproteins; D011946:Receptors, Antigen; D011993:Recombinant Fusion Proteins; C117468:PDPN protein, human; D000098853:Podoplanin