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Enhancing Cancer Immunotherapies Using Cell-Based or Viral Vectored Vaccines

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Title: Enhancing Cancer Immunotherapies Using Cell-Based or Viral Vectored Vaccines
Author: Mould, Robert
Department: Department of Pathobiology
Program: Pathobiology
Advisor: Bridle, Byram
Abstract: Over the past decade there has been a dramatic increase of interest in cancer immunotherapy due to a variety of advantages over conventional methods and promising results. Cancer immunotherapy is a collection of treatment modalities used to treat cancer by taking advantage of the potency and specificity of the immune system. While immunotherapy, as a whole, can encompass many facets of the immune system, a primary focus is the generation or enhancement of a tumour-specific immune response. Herein, we describe several methods that enhance tumor-specific immunity by exploiting the potent immunogenicity of viral vectored, or dendritic cell (DC)-based vaccines. Viral vectors are a useful vaccine vehicle due to their innate ability to provide an antigen source in the form of a recombinant transgene, while in an immunogenic context. The generation of anti-tumor immunity in this context relies on endogenous antigen-presenting cells, of which DCs are the most potent. DCs have a superior capacity to engage naïve T cells to facilitate a clonal expansion of a tumour-specific repertoire. As such DCs are thought to be an ideal candidate for a cell-based cancer vaccine. Unfortunately, both viral vector and DC-based vaccines have many obstacles that need to be carefully avoided in order to generate efficacious results. To this end we have described several methods of overcoming some of these obstacles that have led to enhanced therapeutic benefits. Firstly, we described how multi-site injections, where a vaccine dose is spread between two or more limbs, can enhance the magnitude of a global vaccine response when compared to a single bolus. We also characterized a novel method of epitope mapping that can uncover epitopes for even poorly immunogenic proteins using a heterologous virus-based prime-boost strategy. Finally, we performed an in-depth analysis of the various subsets contained within murine bone marrow-derived DC cultures. We demonstrated that true DCs make up a minority of a heterogenous population of cells and are exclusively responsible for generating T cell immunity. Taken together our results demonstrated several means of enhancing cancer immunotherapies.
URI: http://hdl.handle.net/10214/18033
Date: 2020-06
Rights: Attribution-NonCommercial-NoDerivatives 4.0 International
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Attribution-NonCommercial-NoDerivatives 4.0 International Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivatives 4.0 International