Neural tumors such as glioblastoma (GBM) remain amongst tlie most difficult to treat. We have been interested in using oncolytic viruses, based on herpes simplex virus type 1 (HSV-1), as a selective nervous system tumor-killing virus. Considerable effort in the vector development resulted in the engineering of oncolytic HSV vectors (oHSV) such rQNestin34.5 that are non-toxic for normal cells, yet capable of selective replication in GBM tumor cells. In order to effectively use oHSV in animal tumor models it is necessary to propagate and purify oHSV to high titers. Efforts in process development have resulted in scalable systems capable of manufacturing rQNestin34.5 and other oHSVs. My laboratory has spent considerable time developing refined and novel methodologies to improve virus production, purification and quality assessment to provide high quality vector stocks with dramatically reduced levels of protein and DNA contaminants (>99% removal) that can contribute to toxicity, immunity and biodistribution as well as confound in vivo efficacy studies. Our efforts in process development have resulted in scalable systems capable of manufacturing these vectors for pre-clinical efficacy and safety testing resulting in a 10 to 30-fold increase in overall virus yield and a corresponding 60-fold increase in concentration of the virus. The Core is in the unique position of being one of a few sites for oHSV virus vector production, purification and quality assessment testing. This extensive expertise along with our prior collaborative interaction with the projects (33 oHSV vector stocks produced and distributed since October 2007) supports the overall success ofthe current proposal. The primary goal of the oHSV Production Core is to provide large quantities of GLP-grade concentrated and purified oHSV vectors: (i) rQNestin34.5 for Aims 1 &3 of Project 2, Aim 1-3 of Project 3, and Aims 1-3 of Project 4;(ii) transductional retargeted/miR-regulated oHSV vectors engineered in Aims 1-3 of Project 1, or (iii) ChaseABC armed versions of rQNestin34.5 for Aims 1-3 of Project 3 or the ChaseABC-armed retargeted vector engineered in for Aim 2-3 of Project 3. The oHSV Production Core m work with the projects to provide optimal vector quantity and purity while providing the support necessary to,successfully exploit the available technology. We will continue to refine our production, purification and assessment systems. Should any of the engineered oHSV vectors tested in the projects prove efficacious, the Core would provide support to cGMP facilities for transfer of the production/purification technology of large-scale oHSV manufacture for possible Phase-1 human clinical trials.

Public Health Relevance

The ACS predicts there will be >12,000 deaths/yr from brain cancer. Oncolytic Herpes Simplex Virus (oHSV) therapy has shown some promise. The goal ofthe POl is to improve on this process. Doing so requires hightiter purified stocks, consistently grown and purified by one lab otherwise considerable variation in purity, stability, sterility and identity occurs. Core B will provide the projects with highly purified oHSV stocks based on the detailed protocols we have developed for oHSV production, purification and quality assessment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
1P01CA163205-01A1
Application #
8450343
Study Section
Special Emphasis Panel (ZCA1-RPRB-J (O1))
Project Start
Project End
Budget Start
2013-02-07
Budget End
2014-01-31
Support Year
1
Fiscal Year
2013
Total Cost
$134,980
Indirect Cost
$25,595
Name
Ohio State University
Department
Type
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Ouchi, Rie; Okabe, Sachiko; Migita, Toshiro et al. (2016) Senescence from glioma stem cell differentiation promotes tumor growth. Biochem Biophys Res Commun 470:275-81
Huang, Tianzhi; Alvarez, Angel A; Pangeni, Rajendra P et al. (2016) A regulatory circuit of miR-125b/miR-20b and Wnt signalling controls glioblastoma phenotypes through FZD6-modulated pathways. Nat Commun 7:12885
Chen, Xilin; Han, Jianfeng; Chu, Jianhong et al. (2016) A combinational therapy of EGFR-CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases. Oncotarget 7:27764-77
Cheng, Peng; Wang, Jia; Waghmare, Indrayani et al. (2016) FOXD1-ALDH1A3 Signaling Is a Determinant for the Self-Renewal and Tumorigenicity of Mesenchymal Glioma Stem Cells. Cancer Res 76:7219-7230
Ricklefs, Franz; Mineo, Marco; Rooj, Arun K et al. (2016) Extracellular Vesicles from High-Grade Glioma Exchange Diverse Pro-oncogenic Signals That Maintain Intratumoral Heterogeneity. Cancer Res 76:2876-81
Goins, William F; Hall, Bonnie; Cohen, Justus B et al. (2016) Retargeting of herpes simplex virus (HSV) vectors. Curr Opin Virol 21:93-101
Yoo, Ji Young; Jaime-Ramirez, Alena Cristina; Bolyard, Chelsea et al. (2016) Bortezomib Treatment Sensitizes Oncolytic HSV-1-Treated Tumors to NK Cell Immunotherapy. Clin Cancer Res 22:5265-5276
Freud, Aharon G; Keller, Karen A; Scoville, Steven D et al. (2016) NKp80 Defines a Critical Step during Human Natural Killer Cell Development. Cell Rep 16:379-91
Xiao, Run; Bergin, Stephen M; Huang, Wei et al. (2016) Environmental and Genetic Activation of Hypothalamic BDNF Modulates T-cell Immunity to Exert an Anticancer Phenotype. Cancer Immunol Res 4:488-97
Kim, Sung-Hak; Ezhilarasan, Ravesanker; Phillips, Emma et al. (2016) Serine/Threonine Kinase MLK4 Determines Mesenchymal Identity in Glioma Stem Cells in an NF-κB-dependent Manner. Cancer Cell 29:201-13

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