VIRUS PRODUCTION CORE The primary objective of the Virus Production Core (VPC) is to continue to provide highly purified, high titer virus stocks, in support of studies outlined in each of the Projects and in the EGAM Core within this Program. Establishment of such stocks is essential to ensure consistency and reproducibility between experiments and laboratories for all of the Projects within this Program. Each lot is regularly tested for titer stability, foreign gene expression, and genotype stability. Additional functions of the VPC have included the following: (I) regular update of the Master Virus database as new viruses are produced, (ll) development of virus-specific standard operating protocols (SOPs) to achieve highest titers, and (III) maintenance of the Program website to report recent developments, including list of publications and upcoming meetings. However, translation of our novel vectors into the clinical setting has tjeen critically hampered by the inability to produce the vectors locally using Good Laboratory Practice (GLP) and current Good Manufacturing Practices (cGMP). Without this capability, production of novel vectors, like our IL-12 expressing candidate virus, M032, for the safety and toxicity studies required for investigational new drug (IND) applications and for the performance eariy stage clinical trials, had to be outsourced. Recently, to address this critical problem, the Comprehensive Cancer Center at UAB provided funds to renovate the existing Vaccine and Vector Production Facility (WPF) within the Special Building for Cancer Research to acquire the capability to produce GLP-quality therapeutic vectors. Additional financial support through the UAB Health Services Foundation General Endowment Fund was obtained in March, 2008. Thus, to accelerate the translation of novel vectors into the preclinical arena, additional objectives of the VPC are being incorporated into this renewal application. These include: (/) the adaptation of existing standard operating protocols (SOPs) for HSV production and the development of new SOPs that are specific for the WPF and our oncolytic HSV vectors, (If) the production of Master Cell Bank stocks of qualified Vero cells for the production of GLP-quality Working Cell Banks and Master Virus Stocks, (///) the completion of a series of certification tests to generate a certificate of analysis for each lot of virus prior to distribution to their respective Projects, or to the EGAM Core (Core B- Gillespie). The final objective of the VPC will be to produce and qualify the new cell line to be developed in Project 1.

Public Health Relevance

A Core facility for the production of highly purified, high titer virus stocks is essential to ensure consistency and reproducibility between experiments and laboratories, both In vitro and In vivo, for all of the Projects within this Program. Additionally, achieving the capability to translate our novel vectors into the clinical setting requires the use of Good Laboratory Practice (GLP) and current Good Manufacturing Practices (cGMP), as specified by the Food and Drug Administration (FDA). Local production of novel vectors, like our IL-12 expressing candidate virus, M032, would expedite the safety and toxicity studies that are required for submission of investigational new drug (IND) applications and to perform early stage clinical trials.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-GRB-S)
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University of Alabama Birmingham
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Friedman, G K; Nan, L; Haas, M C et al. (2015) ??34.5-deleted HSV-1-expressing human cytomegalovirus IRS1 gene kills human glioblastoma cells as efficiently as wild-type HSV-1 in normoxia or hypoxia. Gene Ther 22:348-55
Jackson, J D; McMorris, A M; Roth, J C et al. (2014) Assessment of oncolytic HSV efficacy following increased entry-receptor expression in malignant peripheral nerve sheath tumor cell lines. Gene Ther 21:984-90
Cody, James J; Markert, James M; Hurst, Douglas R (2014) Histone deacetylase inhibitors improve the replication of oncolytic herpes simplex virus in breast cancer cells. PLoS One 9:e92919
Roth, Justin C; Cassady, Kevin A; Cody, James J et al. (2014) Evaluation of the safety and biodistribution of M032, an attenuated herpes simplex virus type 1 expressing hIL-12, after intracerebral administration to aotus nonhuman primates. Hum Gene Ther Clin Dev 25:16-27
Widau, Ryan C; Parekh, Akash D; Ranck, Mark C et al. (2014) RIG-I-like receptor LGP2 protects tumor cells from ionizing radiation. Proc Natl Acad Sci U S A 111:E484-91
Smith, Tyrel T; Roth, Justin C; Friedman, Gregory K et al. (2014) Oncolytic viral therapy: targeting cancer stem cells. Oncolytic Virother 2014:21-33
Markert, James M; Razdan, Shantanu N; Kuo, Hui-Chien et al. (2014) A phase 1 trial of oncolytic HSV-1, G207, given in combination with radiation for recurrent GBM demonstrates safety and radiographic responses. Mol Ther 22:1048-55
Pressey, Joseph G; Haas, Marilyn C; Pressey, Christine S et al. (2013) CD133 marks a myogenically primitive subpopulation in rhabdomyosarcoma cell lines that are relatively chemoresistant but sensitive to mutant HSV. Pediatr Blood Cancer 60:45-52
Liauw, Stanley L; Connell, Philip P; Weichselbaum, Ralph R (2013) New paradigms and future challenges in radiation oncology: an update of biological targets and technology. Sci Transl Med 5:173sr2
Gillory, Lauren A; Megison, Michael L; Stewart, Jerry E et al. (2013) Preclinical evaluation of engineered oncolytic herpes simplex virus for the treatment of neuroblastoma. PLoS One 8:e77753

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