Immunotherapy against malignant brain tumors - of mice and men

Abstract: Glioblastoma Multiforme (GBM) is the most abundant and most aggressive primary brain tumor in adults. Due to the infiltrative growth of the tumor, surgery will never be radical. Radiation and chemotherapy only marginally improve the poor prognosis due to the ability of the GBM to develop resistance towards these treatments. Therefore it is of great importance to find new efficient treatment modalities. The aim with this thesis was to develop and evaluate a cytokine based immunotherapy as treatment for GBM in both an experimental mouse glioma model as well as in patients suffering from GBM. In paper I we demonstrate the establishment of a GM-CSF and IFNγ based immunotherapy in the mouse glioma model, GL261. Mice with intracranial gliomas were immunized intraperitoneally with GL261 cell genetically modified to produce GM-CSF combined with recombinant IFNγ. This combination synergistically enhanced survival to 90%. In paper II-III we investigated the immune responses elicited by these immunizations both systemically as well as locally in the tumor. We found that the immunizations with GM-CSF and IFNγ were highly dependent on T-cells for mediating survival of the mice. In paper IV we monitored the immune responses elicited in GBM patients receiving IFNγ based immunotherapy using ELIspot and CBA. Immunotherapy enhances the patient’s own antitumoral immune responses otherwise suppressed by the tumor. We believe that this treatment, in combination with conventional treatments such as surgery, radiotherapy and chemotherapy, has a great promise for the future treatment of patients with GBM.