CD40/CD40L expression correlates with the survival of patients with glioblastomas and an augmentation in CD40 signaling enhances the efficacy of vaccinations and prolongs survival in intracranial glioma- and glioma-initiating cell-isografted tumor models

The neurotrophic hepatocyte growth factor attenuates CD8+ cytotoxic T-lymphocyte activity BENKHOUCHA, Mahdia, et al. BENKHOUCHA, Mahdia, et al. The neurotrophic hepatocyte growth factor attenuates CD8+ cytotoxic T-lymphocyte activity. CD40/CD40L expression correlates with the survival of patients with glioblastomas and an augmentation in CD40 signaling enhances the efficacy of vaccinations and prolongs survival in intracranial glioma-and glioma-initiating cell-isografted tumor models Full Title: CD40/CD40L expression correlates with the survival of patients with glioblastomas and an augmentation in CD40 signaling enhances the efficacy of vaccinations and prolongs survival in intracranial glioma-and glioma-initiating cell-isografted tumor models Article Type: Basic and Translational Investigations Abstract: Background: The prognosis of glioblastomas remains poor; therefore, effective therapeutic strategies need to be developed. An agonistic CD40 antibody was shown to activate anti-tumor effects and has been extensively targeted for immunotherapeutic purposes. Methods: The expression of CD40 and CD40L mRNAs were examined in 86 cases of WHO grade IV glioblastomas 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 NSCL61 glioma-initiating cell-like cell tumor model. Results: We demonstrated for the first time using quantitative PCR that grade III gliomas expressed higher levels of CD40 and CD40L than grade IV glioblastomas. The higher expression of CD40 and CD40L was associated with good prognoses in patients with glioblastomas. The addition of FGK45 to the subcutaneous vaccination significantly prolonged survival over that with the control vaccination in both tumor models. The efficacy of this treatment was limited to the NSCL61 model; therefore, we established combination immunotherapeutic strategies using FGK45 and OX86, an agonistic antibody for OX40. Combination immunotherapy significantly prolonged survival with synergistic effects. Apoptosis was 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. 1 CD40/CD40L expression correlates with the survival of patients with glioblastomas and an augmentation in CD40 signaling enhances the efficacy of vaccinations and prolongs survival in intracranial glioma-and glioma-initiating cell-isografted tumor models The authors have no conflict of interest associated with this manuscript.