DDDR-39. PI3 KINASE AND CHECKPOINT INHIBITION: A POTENTIALLY NOVEL THERAPEUTIC STRATEGY FOR GLIOBLASTOMA (GBM)

Abstract Glioblastoma is the most common and aggressive malignant brain tumor with a median survival of less than 2 years, highlighting the need for more effective therapeutics. Dual pathway synergism between PI3K inhibitors and check-point inhibitors is a promising therapeutic avenue that has not been explored. Based on this possibility, we hypothesized that the combination of PI3K and checkpoint inhibitors will improve survival in our native glioblastoma mouse model. Treatment with GCT-007, a small molecule PI3K inhibitor, induces growth arrest of GBM cells that is accompanied by increases in the cell surface expression of molecules targeted by the immune system and immunotherapy drugs, including MHC Class II and PD-L1. Treatment of mouse GL261 and human U251 GBM cell lines with GCT-007 caused growth arrest, increased the cell surface expression of PD-L1 and MHC class II, and synergized with radiation to cause growth arrest and cell death. We compared GCT-007 to Paxalisib in our in vitro studies and observed that GCT-007 outperformed Paxalisib at increasing MHC class II and PD-L1 expression on the tumor cells at equivalent doses. We then performed in vivo animal studies using our native mouse GBM model. We treated mice orally with GCT-007 and observed a significantly prolonged survival compared to placebo. Mice treated with anti-PD1 resulted in a sexually dimorphic response consisting of prolonged remission of all female mice, now surviving beyond 1 year, but no improvement in the survival of male mice compared to placebo. Adding GCT-007 to anti-PD1 did not alter the prolonged remission outcome in female mice, it did result in prolonged remission of 25% of the male mice, now beyond 1 year. In conclusion, these results indicate that GCT-007 treatment alone improves survival in our native GBM mouse model and it may also improve the response to immune checkpoint inhibitor therapy in at least a fraction of GBM tumors. These data warrant further investigation as a potentially novel therapeutic approach to GBM.