We have previously designed and implemented a variety of oncolytic vectors based on vaccinia virus, developing a panel of gene-deleted and tumor-targeting strains that have displayed promising pre- clinical and early clinical results. We have also pioneered the use of cell-based carrier vehicles to more efficiently deliver oncolytic virus strains to their tumor targets. In particular we demonstrated that Cytokine Induced Killer (CIK) cells could not only act as effective delivery vehicles for vaccinia strains, but could also synergize with the virus to increase their anti-tumor effects. Despite these recent advances, these therapies have still not reached their full potential. In this proposal we have identified key limitations to the future development of these biological therapies, including the requirement to overcome anti-viral immune responses in order to efficiently repeat treat with the same therapy;and the need for both added potency and improved safety within these vectors. We look to address these in three main aims: in the first two aims we will focus on improving the systemic delivery of the viral vector to the tumor, especially in pre-immunized animal models and look to implement strategies to even take advantage of the anti-viral immune response;in the final aim we will examine the advantages of placing different transgene or essential viral gene products under the control of externally regulated protein stability domains. A total of three complimentary approaches will be applied to enhance viral delivery in the face of an anti-viral immune response, focusing on evading circulating neutralizing antibody;(i) epitope swapping or epitope removal will be used to reduce antibody recognition, (ii) binding of viral particles to targeted microbubbles, followed by ultrasound mediated release within the tumor environment and (iii) use of cell carriers to deliver virus to the tumor, particularly incorporating viral strains with mutations that increase the levels of the 'stealth'or enveloped form of the virus produced in situ. In the final aim we will further define and incorporate previously demonstrated advantages of externally regulating the function of different therapeutic transgenes expressed from the viral vectors. Alternatively, we will regulate essential viral gene expression, so providing a shut-off switch within the vector. The overall objectives of this proposal are therefore to overcome some of the major limitations of oncolytic viral therapy, so improving its clinical potential and providing realistic alternative treatment options for patients with some of the hardest to treat cancers, including relapsed, drug-resistant and disseminated disease. Data produced in this proposal will be directly applied to the protocol design of clinical trials under development at the University of Pittsburgh, and so we expect it to directly lead to patient benefits.

Public Health Relevance

This overall aim of this proposal is to enhance the application of oncolytic (replication selective) viruses. This will primarily involve improving the systemic delivery of these vectors, both in naove and previously immunized hosts. In addition we will incorporate regulated transgene function to improve the effectiveness of these therapies and we will look to integrate the oncolytic viruses with immune cell therapies. The focus of this proposal will not only be on improving the biological agents as single therapies, but also on how to combine them such that the natural interactions between viruses and immune cell therapies can be utilized to enhance the therapeutic outcome.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Study Section
Gene and Drug Delivery Systems Study Section (GDD)
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Welch, Anthony R
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University of Pittsburgh
Schools of Medicine
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Rojas, Juan J; Sampath, Padma; Bonilla, Braulio et al. (2016) Manipulating TLR Signaling Increases the Anti-tumor T Cell Response Induced by Viral Cancer Therapies. Cell Rep 15:264-73
Hou, Weizhou; Sampath, Padma; Rojas, Juan J et al. (2016) Oncolytic Virus-Mediated Targeting of PGE2 in the Tumor Alters the Immune Status and Sensitizes Established and Resistant Tumors to Immunotherapy. Cancer Cell 30:108-119
Rojas, Juan J; Sampath, Padma; Hou, Weizhou et al. (2015) Defining Effective Combinations of Immune Checkpoint Blockade and Oncolytic Virotherapy. Clin Cancer Res 21:5543-51
Hou, Weizhou; Chen, Hannah; Rojas, Juan et al. (2014) Oncolytic vaccinia virus demonstrates antiangiogenic effects mediated by targeting of VEGF. Int J Cancer 135:1238-46
Zou, Y; Li, F; Hou, W et al. (2014) Manipulating the expression of chemokine receptors enhances delivery and activity of cytokine-induced killer cells. Br J Cancer 110:1992-9
Tang, H; Sampath, P; Yan, X et al. (2013) Potential for enhanced therapeutic activity of biological cancer therapies with doxycycline combination. Gene Ther 20:770-8
Sampath, Padma; Li, Jun; Hou, Weizhou et al. (2013) Crosstalk between immune cell and oncolytic vaccinia therapy enhances tumor trafficking and antitumor effects. Mol Ther 21:620-8
Chen, Hannah; Sampath, Padma; Hou, Weizhou et al. (2013) Regulating cytokine function enhances safety and activity of genetic cancer therapies. Mol Ther 21:167-74
Li, Jun; O'Malley, Mark; Sampath, Padma et al. (2012) Expression of CCL19 from oncolytic vaccinia enhances immunotherapeutic potential while maintaining oncolytic activity. Neoplasia 14:1115-21
Rojas, Juan J; Thorne, Steve H (2012) Theranostic potential of oncolytic vaccinia virus. Theranostics 2:363-73

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