Glioblastoma multiforme (GBM) represents the most common form of primary brain cancer with a two- year survival rate of ~ 26% following the best therapy. The capacity to advance the course of this disease therefore very much depends on our abilities to design and test novel therapies. Our group has been focused on the development of conditionally replicative adenoviruses (CRAds). CRAds are engineered to selectively replicate within and kill tumor cells through the use of transductional modifications t enhance viral infectivity and tumor-selective promoter elements that transcriptionally restrict expression of genes essential for viral replication. The potential success of adenoviral-based virotherapy has, however, been limited in practice. Preclinical work suggests that oncolytic viruses promote immune responses, which outweigh direct oncolysis in mediating anti-tumor efficacy. In fact, the major challenge of oncolytics lies in the difficult task of understanding ho to stimulate profitable anti-tumor immunity in the context of preexisting antiviral immunity. Present clinical data support preclinical observations that anti-tumor immune responses are important to long- term oncolytic virotherapy efficacy. Consequently, elucidating the mechanisms which drive the balance between anti-viral immunity vs. anti-tumor immunity in the central nervous system (CNS) will be key in mediating successful oncolytic virotherapy against GBM. As we look into the next phase of our project, we face several important questions with fundamental implications for the field of brain tumor virotherapy: (1) is it desirable to overcome anti-viral immunity? (2) is anti-tumor immunity more important than oncolysis? and (3) can one quantify this and consistently manipulate the host immune response against intracranial tumors? These three problems serve as the basis for our renewal application and for our three specific aims that together test the central hypothesis "Regulatory T cell inhibition promotes vira oncolysis and long-term anti-tumor response in the context of oncolytic virotherapy of GBM".

Public Health Relevance

Glioblastoma multiforme (GBM) is the most common primary malignant tumor of the adult central nervous system (CNS). Although oncolytic virotherapy represents an attractive therapy for this cancer, one of the major limitations of this approach entails immune response to viral vectors. This proposal seeks to evaluate the role of regulatory T cells in anti-viral and anti-tumoral immunity in the setting of oncolytic virotherapy of brain tumors in order to advance this strategy to the clinical setting.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BDCN-M (02))
Program Officer
Yovandich, Jason L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Chicago
Schools of Medicine
United States
Zip Code
Thaci, B; Ahmed, A U; Ulasov, I V et al. (2014) Depletion of myeloid-derived suppressor cells during interleukin-12 immunogene therapy does not confer a survival advantage in experimental malignant glioma. Cancer Gene Ther 21:38-44
Lewis, Travis B; Glasgow, Joel N; Harms, Ashley S et al. (2014) Fiber-modified adenovirus for central nervous system Parkinson's disease gene therapy. Viruses 6:3293-310
Dreixler, John C; Poston, Jacqueline N; Balyasnikova, Irina et al. (2014) Delayed administration of bone marrow mesenchymal stem cell conditioned medium significantly improves outcome after retinal ischemia in rats. Invest Ophthalmol Vis Sci 55:3785-96
Wainwright, Derek A; Chang, Alan L; Dey, Mahua et al. (2014) Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4, and PD-L1 in mice with brain tumors. Clin Cancer Res 20:5290-301
Auffinger, B; Tobias, A L; Han, Y et al. (2014) Conversion of differentiated cancer cells into cancer stem-like cells in a glioblastoma model after primary chemotherapy. Cell Death Differ 21:1119-31
Young, Jacob S; Kim, Julius W; Ahmed, Atique U et al. (2014) Therapeutic cell carriers: a potential road to cure glioma. Expert Rev Neurother 14:651-60
Balyasnikova, Irina V; Prasol, Melanie S; Ferguson, Sherise D et al. (2014) Intranasal delivery of mesenchymal stem cells significantly extends survival of irradiated mice with experimental brain tumors. Mol Ther 22:140-8
Young, Jacob S; Morshed, Ramin A; Kim, Julius W et al. (2014) Advances in stem cells, induced pluripotent stem cells, and engineered cells: delivery vehicles for anti-glioma therapy. Expert Opin Drug Deliv 11:1733-46
Auffinger, B; Thaci, B; Ahmed, A et al. (2013) MicroRNA targeting as a therapeutic strategy against glioma. Curr Mol Med 13:535-42
Kim, Chung Kwon; Ahmed, Atique U; Auffinger, Brenda et al. (2013) N-acetylcysteine amide augments the therapeutic effect of neural stem cell-based antiglioma oncolytic virotherapy. Mol Ther 21:2063-73

Showing the most recent 10 out of 54 publications