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.

Public Health Relevance

The proposed studies address the use of oncolytic adenoviruses and immunotherapy as a combined treatment option for glioblastoma. The research is relevant to public health because patients with glioblastoma only have a 5% 5-year survival rate after conventional treatment. Understanding the biology and immunology of how these tumors respond to this combination treatment will allow for better treatment options to extend the life expectancy of patients diagnosed with glioblastoma.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31CA228207-01A1
Application #
9683275
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Radaev, Sergey
Project Start
2019-01-01
Project End
2021-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Hospitals
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030