Glioblastoma multiforme (GBM) represents the most common primary malignant tumor of the adult central nervous system. The median survival after surgical intervention alone is approximately six months and the addition of radio-/chemotherapy can extend this time up to twelve months. Failed therapy is most often associated with local recurrence in the proximity of the original tumor. Consequently, efforts aimed at developing new therapies have focused on treatment strategies that target the tumor environment but spare normal and healthy surrounding brain cells. Oncolytic viruses (CRAds) that are replication competent in tumor but not in normal cells represent a novel approach for treating neoplastic diseases. To bypass the dependence on CAR for adenoviral entry and replication, we created a new generation of novel adenoviral vectors which selectively bind to receptors which are over-expressed by GBMs. First, we substituted the receptor binding domain of Ad5 with either (a) integrin binding sequence, RGD, (b) the receptor binding domain of serotype Ad3, or (c) a heparan sulfate binding proteoglycan (HSPG), pk7. Second, we tested a variety of tumor specific promoters (TSP) and identified survivin as the optimal TSP for transcriptional control of E1a. Survivin expression in gliomas is associated with poor prognosis, increased rates of recurrence, and resistance to chemo- and radiotherapy. Finally, in an effort to create a novel viral imaging modality that would provide a signal correlating with viral replication and progeny production, we developed an approach to incorporate an imageable substrate directly into the adenovirus capsid for subsequent imaging of viral replication and spread with PET. Based on the above considerations, we then created three conditionally replicative vectors: CRAd-S-RGD, CRAd-S-5/3, and CRAd- S-pk7. Our hypothesis is that such transcriptional/transductional modifications of Ad5 will show superior tumor selectivity and a high oncolytic efficacy against malignant glioma, with minimal toxicity to normal brain. Preliminary studies suggest that of the three vectors, CRAd-S-pk7 is the optimal virus for further preclinical development. In this application, we will focus on CRAd-S-pk7 and examine the mechanism by which this novel virus mediates enhanced glioma oncolysis in vitro and in vivo by pursuing the following specific aims: (1) characterize the infectivity, replication, and gene expression profile of CRAd-S-pk7 in primary glioblastoma multiforme in vitro;(2) determine if CRAd-S-pk7 exhibits enhanced oncolysis efficacy in vivo;(3) compare the toxicity, blood clearance, biodistribution, and immune profile of CRAd-S-pk7 between a fully permissive and semi-permissive animal model in vivo;and (4) determine whether CRAd-S-pk7 labeled with HSV-TK can be used for assessing viral replication and response to oncolytic virotherapy with PET in vivo. Malignant brain tumors remain highly resistant to conventional therapy and new and novel treatments are urgently needed to make an impact on this devastating disease.
The aim of this proposal is to complete the preclinical studies of a novel oncolytic adenovirus with the aim of rapidly translating the results into a phase I/II clinical trial.

Public Health Relevance

Malignant brain tumors remain highly resistant to conventional therapy and new and novel treatments are urgently needed to make an impact on this devastating disease. The aim of this proposal is to complete the preclinical studies of a novel oncolytic adenovirus with the aim of rapidly translating the results into a phase I/II clinical trial.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA122930-03
Application #
7749964
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Yovandich, Jason L
Project Start
2008-01-09
Project End
2012-12-31
Budget Start
2010-01-01
Budget End
2010-12-31
Support Year
3
Fiscal Year
2010
Total Cost
$312,391
Indirect Cost
Name
University of Chicago
Department
Surgery
Type
Schools of Medicine
DUNS #
005421136
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
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
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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