Combination Immunotherapy for Glioblastoma Multiforme With the Combination of GVAX and PD-1 Blockade, Using Anti-PD1 Antibody

Abstract

Glioblastoma Multiforme (GBM), also known as grade IV astrocytoma, is generally found in the cerebral hemispheres but can be found anywhere else in the brain or the spinal cord. Even after surgery and chemotherapy, GBM has a high rate of recurrence. Median survival after diagnosis is 12 months, with less than 3 to 5% people surviving greater than 5 years. Without treatment, average survival is about 3 months. Immune checkpoint inhibition is a recent addition to the regimen of treatment of cancers and has shown some promising results in Melanoma and lung cancer. The primary research goal of this thesis was to study if treatment with a combination of GVAX and PD-1 blockade leads to improved survival in comparison to PD-1 treatment alone in a mouse glioma model. If a combination treatment of GVAX and PD-1 leads to improved survival as compared to PD-1 treatment alone, a secondary goal of my research was to identify the underlying immune mechanisms that were responsible for this survival advantage. Finally, a third goal of my research was to examine survival advantage, if any, from treatment with GVAX and PD-1 can be enhanced further with the addition of a second immune checkpoint molecule. Data from this study is presented which shows that combination immunotherapy with GVAX and Anti-PD1 does provide survival advantage by increasing tumor infiltration of Cd8+ T-cells into the tumor and by increasing Cd8+ T-cells to Treg cell ratio. The survival advantages conferred by the combination of GVAX and Anti-PD1 was further enhanced by the addition of second immune checkpoint molecule OX40.Triple combination treated mice also developed immune memory towards the tumor and long-term survivors rejected a tumor challenge with three times more cells than the initial tumor challenge. These results confirm the initial hypothesis that combination immunotherapy with GVAX and immune checkpoint molecules can be an efficacious treatment for patients with GBM.