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Development of a Mathematical Model to Understand, Design & Improve Development of a Mathematical Model to Understand, Design & Improve Oncolytic Virus Therapies Cory Batenchuk Thesis submitted to the Faculty of Graduate and Postdoctoral Studies in partial fulfillment of the requirementas for the Doctorate in Philosophy degree in Biochemistry, Microbiology & Immunology with a specialization in human and molecular genetics. Department of Biochemistry, Microbiology & Immunology Faculty of Medicine, University of Ottawa © Cory Batenchuk, Ottawa, Canada, 2014 Abstract Oncolytic viruses (OVs) are emerging as a potent therapeutic platform for the treatment of malignant disease. The tumor cells inability to induce antiviral defences in response to a small cytokine known as interferon (IFN) is a common defect exploited by OVs. Heterogeneity in IFN signalling across tumors is therefore a pillar element of resistance to these therapies. I have generated a mathematical model and simulation platform to study the impact of IFN on OV dynamics in normal and cancerous tissues. In the first part of my thesis, I used this model to identify novel OV engineering strategies which could be implemented to overcome IFN based resistance in tumor tissues. From these simulations, it appears that a positive feedback loop, established by virus-mediated expression of an interferon-binding decoy receptor, could increase tumor cytotoxicity without compromising normal cells. The predictions set forth by this model have been validated both qualitatively and quantitatively in in-vitro and in-vivo models using two independent OV strains. This model has subsequently been used to investigate OV attenuation mechanisms, the impact of tumor cell heterogeneity, as well as drug-OV interactions. Following these results, it became apparent that selectivity should equally be observed when overwhelming the cell with a non replicating virus. While normal tissues will clear this pseudo- infection rapidly, owing to their high baseline in antiviral products at the onset of infection, tumor cells with defective anti-viral pathways should not have readily available biomachinery required to degrade this pro-apoptotic signal. Recapitulated by the mathematical model, non- replicating virus-derived particles generated by means of UV irradiation selectively kill tumor cells in cultured cell lines and patient samples, leading to long term cures in murine models. Taken together, this thesis uses a novel mathematical model and simulation platform to understand, design & improve oncolytic virus-based therapeutics. Table of Contents Table of Contents ........................................................................................................................... i List of Figures ................................................................................................................................ v List of Abbreviations ................................................................................................................. viii List of Symbols ........................................................................................................................... xiv Acknowledgements .................................................................................................................... xvi Chapter I. General Introduction ................................................................................................. 1 1.1 The Process of Tumorigenesis .............................................................................................. 1 1.2 Impact of the Tumor Microenvironment ............................................................................... 5 1.3 Oncogenic viruses are a Factor Involved in the Onset of Tumorigenesis ............................. 8 1.4 The Role of Type-I Interfrons (IFNs) in Cancer Progression ............................................... 9 1.5 The History of Chemotherapies and the Emergence of Viruses-based Therapies .............. 11 1.5 The Development of Oncolytic Viruses (OVs) as Anti-Cancer Platforms ......................... 14 1.6 The Mechanisms of resistance to OV therapies .................................................................. 18 1.7 Overcoming resistance to OV therapies .............................................................................. 20 1.8 Modelling OV dynamics ..................................................................................................... 22 1.8 Hypothesis ........................................................................................................................... 24 i | P a g e 1.9 Objectives ............................................................................................................................ 25 Chapter II. Model-based rational design of an oncolytic virus with improved therapeutic potential ....................................................................................................................................... 26 Chapter Synopsis ....................................................................................................................... 27 Abstract ..................................................................................................................................... 29 Introduction ............................................................................................................................... 30 Results ....................................................................................................................................... 33 Discussion ................................................................................................................................. 44 Methods ..................................................................................................................................... 45 Chapter III. Microtubule Destabilizers Disrupt Interferon Production and Sensitize to Rhabdovirus Bystander Killing ................................................................................................. 51 Chapter Synopsis ....................................................................................................................... 52 Abstract ..................................................................................................................................... 54 Introduction ............................................................................................................................... 55 Results ....................................................................................................................................... 57 Discussion ................................................................................................................................. 81 Methods ..................................................................................................................................... 84 ii | P a g e Chapter IV. Reciprocal cellular cross-talk within the tumour microenvironment enhances oncolytic virus activity ................................................................................................................ 95 Chapter Synopsis ....................................................................................................................... 96 Abstract ..................................................................................................................................... 99 Introduction ............................................................................................................................... 99 Results ..................................................................................................................................... 100 Conclusion ............................................................................................................................... 121 Acknowledgments ................................................................................................................... 122 Methods ................................................................................................................................... 123 Chapter V. Non-replicating rhabdovirus-derived particles (NRRPs) eradicate acute leukemia by direct cytolysis and induction of anti-tumor immunity ................................... 134 Chapter Synopsis ..................................................................................................................... 135 Abstract ................................................................................................................................... 137 Introduction ............................................................................................................................. 138 Results ..................................................................................................................................... 139 Discussion ............................................................................................................................... 151 Methods ................................................................................................................................... 153 iii | P a g e 5. General Discussion ................................................................................................................ 158 5.1 Insight from modelling the mechanism of action of virus sensitizers ............................... 158 5.2 Positive-feedback - a key process to achieve tumor selective cytotoxicity ...................... 159 5.4 Sensitization of stroma
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