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)
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
Li, Gina; Bonamici, Nicolas; Dey, Mahua et al. (2018) Intranasal delivery of stem cell-based therapies for the treatment of brain malignancies. Expert Opin Drug Deliv 15:163-172
Panek, Wojciech K; Pituch, Katarzyna C; Miska, Jason et al. (2018) Local Application of Autologous Platelet-Rich Fibrin Patch (PRF-P) Suppresses Regulatory T Cell Recruitment in a Murine Glioma Model. Mol Neurobiol :
Panek, Wojciech K; Kane, J Robert; Young, Jacob S et al. (2017) Hitting the nail on the head: combining oncolytic adenovirus-mediated virotherapy and immunomodulation for the treatment of glioma. Oncotarget 8:89391-89405
Kim, Julius W; Miska, Jason; Young, Jacob S et al. (2017) A Comparative Study of Replication-Incompetent and -Competent Adenoviral Therapy-Mediated Immune Response in a Murine Glioma Model. Mol Ther Oncolytics 5:97-104
Chang, Alan L; Miska, Jason; Wainwright, Derek A et al. (2016) CCL2 Produced by the Glioma Microenvironment Is Essential for the Recruitment of Regulatory T Cells and Myeloid-Derived Suppressor Cells. Cancer Res 76:5671-5682
Miska, Jason; Rashidi, Aida; Chang, Alan L et al. (2016) Anti-GITR therapy promotes immunity against malignant glioma in a murine model. Cancer Immunol Immunother 65:1555-1567
Roth, Steven; Dreixler, John C; Mathew, Biji et al. (2016) Hypoxic-Preconditioned Bone Marrow Stem Cell Medium Significantly Improves Outcome After Retinal Ischemia in Rats. Invest Ophthalmol Vis Sci 57:3522-32
Lukas, Rimas V; Mehta, Minesh P; Lesniak, Maciej S (2015) Society for Neuro-Oncology 2014 annual meeting updates on central nervous system metastases. Neurooncol Pract 2:57-61
Kim, Julius W; Kane, J Robert; Young, Jacob S et al. (2015) A Genetically Modified Adenoviral Vector with a Phage Display-Derived Peptide Incorporated into Fiber Fibritin Chimera Prolongs Survival in Experimental Glioma. Hum Gene Ther 26:635-46
Dey, Mahua; Chang, Alan L; Miska, Jason et al. (2015) Dendritic Cell-Based Vaccines that Utilize Myeloid Rather than Plasmacytoid Cells Offer a Superior Survival Advantage in Malignant Glioma. J Immunol 195:367-76

Showing the most recent 10 out of 77 publications