The major aim of this U01 (NINDS Cooperative Program in Translation Research) application is to develop a highly novel approach for the treatment of malignant brain tumors. Our strategy entails the use of neural stem cells (NSC) as carriers of an oncolytic adenovirus which directly targets glioma stem cells. Since one of the major limitations of virotherapy is poor spread following injection, we have recently shown that NSCs can more effectively migrate and deliver an oncolytic adenovirus to intracranial glioma than local injection of the virus alone. This form of carrier mediated delivery leads to enhanced viral replication in the tumor, decreased anti-adenoviral immune response, and a much more potent anti-tumor response than local injection of the virus alone. In order to translate our work into the clinical setting, we have held a pre-IND meeting with the Food and Drug Administration (FDA). We have completed some of the preliminary FDA directed studies, and now propose to develop a clinical trial in which a novel oncolytic adenovirus will be delivered via NSCs. We hypothesize that an adenoviral vector targeted to GBM, when rendered selectively replicative via transcriptional/transductional modification and delivered via NSCs, will demonstrate superior specificity required for human clinical trials and thereby allow full realization of the potential benefits of virotherapy for malignant glioma. To achieve this goal, we would like to utilize the U01 mechanism to complete the following specific aims which will ultimately culminate in securing an IND for a phase I clinical trial: Milestone/Aim 1: Validate the therapeutic efficacy of CRAd-Survivin-pk7 loaded NSCs in vitro and in animal models of glioma. Milestone/Aim 2: Evaluate the therapeutic efficacy and safety monitoring with CRAd-Survivin-pk7 loaded NSCs in the presence of temozolomide-based chemotherapy and radiotherapy. Milestone/Aim 3: Determine the migration, engraftment, and long-term fate of CRAd-Survivin-pk7 loaded NSCs in vitro and in animal models of glioma with MRI. Milestone/Aim 4: Perform a toxicology and biodistribution study with NSC-loaded cGMP-grade clinical lot virus. Milestone/Aim 5: Conduct RAC and FDA preparation meetings and assemble documents for filing Investigational New Drug (IND) application for neural stem cell based virotherapy in malignant glioma.

Public Health Relevance

Malignant brain tumors remain an incurable disease and therefore represent a significant public health care problem. The proposed studies are designed to advance a novel therapy toward a clinical trial that may improve the outcome of this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01NS069997-05
Application #
8737319
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Mcgavern, Linda
Project Start
2010-07-01
Project End
2015-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
5
Fiscal Year
2014
Total Cost
$1,151,530
Indirect Cost
$205,658
Name
University of Chicago
Department
Surgery
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Dey, Mahua; Yu, Dou; Kanojia, Deepak et al. (2016) Intranasal Oncolytic Virotherapy with CXCR4-Enhanced Stem Cells Extends Survival in Mouse Model of Glioma. Stem Cell Reports 7:471-82
Kim, Julius Woongki; Auffinger, Brenda; Spencer, Drew A et al. (2016) Single dose GLP toxicity and biodistribution study of a conditionally replicative adenovirus vector, CRAd-S-pk7, administered by intracerebral injection to Syrian hamsters. J Transl Med 14:134
Muroski, Megan E; Morshed, Ramin A; Cheng, Yu et al. (2016) Controlled Payload Release by Magnetic Field Triggered Neural Stem Cell Destruction for Malignant Glioma Treatment. PLoS One 11:e0145129
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
Kanojia, Deepak; Morshed, Ramin A; Zhang, Lingjiao et al. (2015) βIII-Tubulin Regulates Breast Cancer Metastases to the Brain. Mol Cancer Ther 14:1152-61
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
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
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
Kim, Julius W; Kane, J Robert; Young, Jacob S et al. (2015) Neural stem cell-mediated delivery of oncolytic adenovirus. Curr Protoc Hum Genet 85:13.11.1-9
Zhai, Lijie; Lauing, Kristen L; Chang, Alan L et al. (2015) The role of IDO in brain tumor immunotherapy. J Neurooncol 123:395-403

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