title: CD40/CD40L expression correlates with the survival of patients with glioblastomas and an augmentation in CD40 signaling enhances the efficacy of vaccinations against glioma models.
abstract: BACKGROUND
  The prognosis of glioblastoma (GBM) remains poor; therefore, effective therapeutic strategies need to be developed. CD40 is a costimulatory molecule whose agonistic antibody has been shown to activate antitumor effects. Recently, CD40 has been extensively targeted for immunotherapeutic purposes.
  
  
  METHODS
  Expressions of CD40/CD40L mRNAs were examined in 86 cases of World Health Organization grade IV GBM and 36 cases of grade III gliomas and correlated with outcomes. CD40 signaling was employed to augment the efficacy of immunotherapy against gliomas. The efficacy of FGK45, an agonistic antibody for CD40, was examined by adding it to a tumor lysate-based subcutaneous vaccination against a GL261 glioma model and an NSCL61 glioma-initiating cell-like cell tumor model.
  
  
  RESULTS
  We demonstrated for the first time using quantitative PCR that grade III gliomas express higher levels of CD40/CD40L than does grade IV GBM. The higher expression of CD40/CD40L was associated with good prognoses in patients with GBM. Addition of FGK45 to the subcutaneous tumor cell lysate-based vaccination significantly prolonged survival in both tumor models. However, the efficacy was modest in NSCL61-model mice. Therefore, we established combination immunotherapeutic strategies using FGK45 and OX86, an agonistic antibody for OX40. Combination immunotherapy significantly prolonged survival with synergistic effects. Apoptosis increased and proliferation decreased in tumors treated with combination immunotherapy.
  
  
  CONCLUSIONS
  The high expression of CD40/CD40L can be used as a biomarker for better prognoses in patients with gliomas. Immunotherapy using FGK45 significantly prolonged survival and represents a potential therapeutic strategy for gliomas including glioma-initiating cells.
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan (M.C., R.S., T.S., I.S., M.K., Y.S., T.T.); Pathological Division, Tohoku University Hospital, Sendai, Japan (M.W.); Departments of Respiratory Oncology and Molecular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (T.K.); Department of Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan (N.I.).
authors.forename: Masashi
authors.initials: M
authors.lastname: Chonan
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan (M.C., R.S., T.S., I.S., M.K., Y.S., T.T.); Pathological Division, Tohoku University Hospital, Sendai, Japan (M.W.); Departments of Respiratory Oncology and Molecular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (T.K.); Department of Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan (N.I.).
authors.forename: Ryuta
authors.initials: R
authors.lastname: Saito
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan (M.C., R.S., T.S., I.S., M.K., Y.S., T.T.); Pathological Division, Tohoku University Hospital, Sendai, Japan (M.W.); Departments of Respiratory Oncology and Molecular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (T.K.); Department of Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan (N.I.).
authors.forename: Takuhiro
authors.initials: T
authors.lastname: Shoji
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan (M.C., R.S., T.S., I.S., M.K., Y.S., T.T.); Pathological Division, Tohoku University Hospital, Sendai, Japan (M.W.); Departments of Respiratory Oncology and Molecular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (T.K.); Department of Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan (N.I.).
authors.forename: Ichiyo
authors.initials: I
authors.lastname: Shibahara
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan (M.C., R.S., T.S., I.S., M.K., Y.S., T.T.); Pathological Division, Tohoku University Hospital, Sendai, Japan (M.W.); Departments of Respiratory Oncology and Molecular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (T.K.); Department of Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan (N.I.).
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kanamori
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan (M.C., R.S., T.S., I.S., M.K., Y.S., T.T.); Pathological Division, Tohoku University Hospital, Sendai, Japan (M.W.); Departments of Respiratory Oncology and Molecular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (T.K.); Department of Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan (N.I.).
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Sonoda
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan (M.C., R.S., T.S., I.S., M.K., Y.S., T.T.); Pathological Division, Tohoku University Hospital, Sendai, Japan (M.W.); Departments of Respiratory Oncology and Molecular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (T.K.); Department of Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan (N.I.).
authors.forename: Mika
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan (M.C., R.S., T.S., I.S., M.K., Y.S., T.T.); Pathological Division, Tohoku University Hospital, Sendai, Japan (M.W.); Departments of Respiratory Oncology and Molecular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (T.K.); Department of Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan (N.I.).
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kikuchi
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan (M.C., R.S., T.S., I.S., M.K., Y.S., T.T.); Pathological Division, Tohoku University Hospital, Sendai, Japan (M.W.); Departments of Respiratory Oncology and Molecular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (T.K.); Department of Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan (N.I.).
authors.forename: Naoto
authors.initials: N
authors.lastname: Ishii
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan (M.C., R.S., T.S., I.S., M.K., Y.S., T.T.); Pathological Division, Tohoku University Hospital, Sendai, Japan (M.W.); Departments of Respiratory Oncology and Molecular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan (T.K.); Department of Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan (N.I.).
authors.forename: Teiji
authors.initials: T
authors.lastname: Tominaga
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis; D001932:Brain Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000628:therapy; D019013:CD40 Antigens / Q000819:agonists / Q000096:biosynthesis*; D023201:CD40 Ligand / Q000096:biosynthesis*; D019496:Cancer Vaccines / Q000494:pharmacology*; D002648:Child; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005909:Glioblastoma / Q000378:metabolism* / Q000401:mortality / Q000628:therapy; D006801:Humans; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D053262:Receptors, OX40 / Q000819:agonists; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D019013:CD40 Antigens; D019496:Cancer Vaccines; D053262:Receptors, OX40; D023201:CD40 Ligand
keywords: CD40; CD40 ligand; glioma; immunotherapy; prognosis