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.
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.
|Morshed, R A; Gutova, M; Juliano, J et al. (2015) Analysis of glioblastoma tumor coverage by oncolytic virus-loaded neural stem cells using MRI-based tracking and histological reconstruction. Cancer Gene Ther 22:55-61|
|Thaci, B; Ahmed, A U; Ulasov, I V et al. (2014) Depletion of myeloid-derived suppressor cells during interleukin-12 immunogene therapy does not confer a survival advantage in experimental malignant glioma. Cancer Gene Ther 21:38-44|
|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|
|Young, Jacob S; Kim, Julius W; Ahmed, Atique U et al. (2014) Therapeutic cell carriers: a potential road to cure glioma. Expert Rev Neurother 14:651-60|
|Balyasnikova, Irina V; Prasol, Melanie S; Ferguson, Sherise D et al. (2014) Intranasal delivery of mesenchymal stem cells significantly extends survival of irradiated mice with experimental brain tumors. Mol Ther 22:140-8|
|Young, Jacob S; Morshed, Ramin A; Kim, Julius W et al. (2014) Advances in stem cells, induced pluripotent stem cells, and engineered cells: delivery vehicles for anti-glioma therapy. Expert Opin Drug Deliv 11:1733-46|
|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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