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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA122930-07
Application #
8685898
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Yovandich, Jason L
Project Start
2006-07-01
Project End
2018-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Chicago
Department
Surgery
Type
Schools of Medicine
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
60637
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
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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
Zhai, Lijie; Lauing, Kristen L; Chang, Alan L et al. (2015) The role of IDO in brain tumor immunotherapy. J Neurooncol 123:395-403
Kanojia, Deepak; Balyasnikova, Irina V; Morshed, Ramin A et al. (2015) Neural Stem Cells Secreting Anti-HER2 Antibody Improve Survival in a Preclinical Model of HER2 Overexpressing Breast Cancer Brain Metastases. Stem Cells 33:2985-94
Auffinger, Brenda; Spencer, Drew; Pytel, Peter et al. (2015) The role of glioma stem cells in chemotherapy resistance and glioblastoma multiforme recurrence. Expert Rev Neurother 15:741-52
Dey, Mahua; Ahmed, Atique U; Lesniak, Maciej S (2015) Cytomegalovirus and glioma: putting the cart before the horse. J Neurol Neurosurg Psychiatry 86:191-9
Spencer, Drew A; Young, Jacob S; Kanojia, Deepak et al. (2015) Unlocking the promise of oncolytic virotherapy in glioma: combination with chemotherapy to enhance efficacy. Ther Deliv 6:453-68

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