Imps-05cd40/cd40l expression correlates with the survival of patients with glioblastomas and an augmentation in cd40 signaling prolongs survival in intracranial glioma- and glioma-initiating cell-isografted tumor models

BACKGROUND: The prognosis of glioblastomas remains poor; therefore, effective therapeutic strategies need to be developed. CD40 is a costimulatory molecule and its agonistic antibody have been shown to activate anti-tumor effects. Recently, CD40 has been extensively targeted for immunotherapeutic purposes. METHODS: The expression of CD40 and CD40L mRNAs were examined in 86 cases of 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, dendritic cells, and OX86; an agonistic antibody for OX40 were examined by adding it to a tumor lysate-based subcutaneous vaccination against GL261 glioma model or 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. 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, dendritic cells, and OX86. We initially used a FGK45 and dendritic cells-based vaccination. The effects of the combination immunotherapy were not significantly different from those of the FGK45 immunotherapy. We then used a combination of FGK45 and OX86. Combination immunotherapy significantly prolonged survival with synergistic effects. Apoptosis increased and proliferation decreased in tumors treated with combination immunotherapy, especially when CD40 was stimulated. CONCLUSIONS: The high expression of CD40 and CD40L can be used as a biomarker for better prognoses in patients with gliomas. Immunotherapy using FGK45, dendritic cells, and OX86 significantly prolonged survival and represents a potential therapeutic strategy for gliomas including glioma-initiating cells.