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 #
5U01NS069997-03
Application #
8315730
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
2012-07-01
Budget End
2013-06-30
Support Year
3
Fiscal Year
2012
Total Cost
$1,353,977
Indirect Cost
$271,251
Name
University of Chicago
Department
Surgery
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
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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
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Chung, Eun Ji; Cheng, Yu; Morshed, Ramin et al. (2014) Fibrin-binding, peptide amphiphile micelles for targeting glioblastoma. Biomaterials 35:1249-56
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
Ahmed, Atique U; Auffinger, Brenda; Lesniak, Maciej S (2013) Understanding glioma stem cells: rationale, clinical relevance and therapeutic strategies. Expert Rev Neurother 13:545-55

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