title: Local convection-enhanced delivery of an anti-CD40 agonistic monoclonal antibody induces antitumor effects in mouse glioma models.
abstract: Glioblastoma is one of the most malignant brain tumors in adults and has a dismal prognosis. In a previous report, we reported that CD40, a TNF-R-related cell surface receptor, and its ligand CD40L were associated with glioma outcomes. Here we attempted to activate CD40 signaling in the tumor and determine if it exerted therapeutic efficacy.
  
  
  
  CD40 expression was examined in 3 mouse glioma cell lines (GL261, NSCL61, and bRiTs-G3) and 5 human glioma cell lines (U87, U251, U373, T98, and A172). NSCL61 and bRiTs-G3, as glioma stem cells, also expressed the glioma stem cell markers MELK and CD44. In vitro, we demonstrated direct antitumor effects of an anti-CD40 agonistic monoclonal antibody (FGK45) against the cell lines. The efficacy of FGK45 was examined by local convection-enhanced delivery of the monoclonal antibody against each glioma model.
  
  
  
  CD40 was expressed in all mouse and human cell lines tested and was found at the cell membrane of each of the 3 mouse cell lines. FGK45 administration induced significant, direct antitumor effects in vitro. The local delivery of FGK45 significantly prolonged survival compared with controls in the NSCL61 and bRiTs-G3 models, but the effect was not significant in the GL261 model. Increases in apoptosis and CD4(+) and CD8(+) T cell infiltration were observed in the bRiTs-G3 model after FGK45 treatment.
  
  
  
  Local delivery of FGK45 significantly prolonged survival in glioma stem cell models. Thus, local delivery of this monoclonal antibody is promising for immunotherapy against gliomas.
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan (T.S., R.S., M.C., I.S., A.S., M.K., Y.S., T.T.);Department of Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan (N.I.)Division of Stem Cell Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido 060-0815, Japan (T.K.).
authors.forename: Takuhiro
authors.initials: T
authors.lastname: Shoji
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan (T.S., R.S., M.C., I.S., A.S., M.K., Y.S., T.T.);Department of Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan (N.I.)Division of Stem Cell Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido 060-0815, Japan (T.K.).
authors.forename: Ryuta
authors.initials: R
authors.lastname: Saito
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan (T.S., R.S., M.C., I.S., A.S., M.K., Y.S., T.T.);Department of Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan (N.I.)Division of Stem Cell Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido 060-0815, Japan (T.K.).
authors.forename: Masashi
authors.initials: M
authors.lastname: Chonan
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan (T.S., R.S., M.C., I.S., A.S., M.K., Y.S., T.T.);Department of Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan (N.I.)Division of Stem Cell Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido 060-0815, Japan (T.K.).
authors.forename: Ichiyo
authors.initials: I
authors.lastname: Shibahara
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan (T.S., R.S., M.C., I.S., A.S., M.K., Y.S., T.T.);Department of Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan (N.I.)Division of Stem Cell Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido 060-0815, Japan (T.K.).
authors.forename: Aya
authors.initials: A
authors.lastname: Sato
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan (T.S., R.S., M.C., I.S., A.S., M.K., Y.S., T.T.);Department of Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan (N.I.)Division of Stem Cell Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido 060-0815, Japan (T.K.).
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kanamori
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan (T.S., R.S., M.C., I.S., A.S., M.K., Y.S., T.T.);Department of Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan (N.I.)Division of Stem Cell Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido 060-0815, Japan (T.K.).
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Sonoda
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan (T.S., R.S., M.C., I.S., A.S., M.K., Y.S., T.T.);Department of Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan (N.I.)Division of Stem Cell Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido 060-0815, Japan (T.K.).
authors.forename: Toru
authors.initials: T
authors.lastname: Kondo
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan (T.S., R.S., M.C., I.S., A.S., M.K., Y.S., T.T.);Department of Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan (N.I.)Division of Stem Cell Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido 060-0815, Japan (T.K.).
authors.forename: Naoto
authors.initials: N
authors.lastname: Ishii
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan (T.S., R.S., M.C., I.S., A.S., M.K., Y.S., T.T.);Department of Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan (N.I.)Division of Stem Cell Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido 060-0815, Japan (T.K.).
authors.forename: Teiji
authors.initials: T
authors.lastname: Tominaga
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000819:agonists* / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use; D045744:Cell Line, Tumor; D018481:Convection; D004195:Disease Models, Animal; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D016019:Survival Analysis; D014611:Vaccination / Q000379:methods
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D019013:CD40 Antigens; C000622230:FGK45 monoclonal antibody
keywords: CD40; convection-enhanced delivery; glioma; immunotherapy