Project Summary/Abstract With current treatment options, the five year survival rate of patients with glioblastoma (GB) is only 5%. Thus, different therapies should be developed. One promising alternative therapy is the use of the oncolytic virus, Delta-24-RGD, which has resulted in complete responses in up to 15% of GB patients. Delta-24-RGD causes death by cancer cell lysis and immunogenic cell death. Our preliminary data show that mice with GB can be cured with treatment of the armed oncolytic adenoviruses, named Delta-24-RGDOX, which expresses immune agonist, OX40L. The OX40 signaling pathway can enhance effector T-cell responses against cancer cells. Conversely, the tumor microenvironment of GB can employ immunosuppressive and anergic mechanisms to halt immune responses directed against the tumor. For example, the activation of indoleamine-2,3-dioxygenase (IDO), which has been reported to be upregulated in GB, can activate immunosuppressive regulatory T-cells. Thus, we hypothesize that the combination treatment of Delta-24-RGDOX and IDO inhibitors will immunomodulate the tumor microenvironment towards a more cytotoxic and less immunosuppressive nature and be effective in the treatment of GB. To test this hypothesis, we aim to 1) Compare the therapeutic efficacy of using Delta-24-RGDOX with and without IDO inhibitors in murine GB and 2) Analyze the effectiveness of Delta-24-RGDOX in combination with IDO inhibitors to overcome T-cell anergy in mouse models of GB. Completing this study will provide a greater understanding of the immune tumor evasion mechanisms that occur after treatment with Delta-24-RGDOX and/or IDO inhibitors leading to better therapeutic targets for GB.