Class of 2017 Abstract / Objectives: Our working hypothesis is that patients who opt in to pharmacist counseling will have a higher medication possession ratio and longer length on therapy than patients who opt out of pharmacist counseling. Methods: Using data extracted from patient’s charts we retrospectively calculated medication possession ratio and length on therapy in relation to the patient receiving or not receiving counseling. Results: The patients analyzed were receiving 8 specific oral oncolytic medications provided by Avella Specialty Pharmacy in 2015. There were no significant differences found in MPR values for any of the 8 oral oncolytic medications included in the study. Iressa (p=0.826), Lonsurf (p=0.392), Stivarga (p=0.838), Zydelig (p=0.633), Zykadia (p=0.077), Tagrisso (p=0.060), Imbruvica (p=0.263) and Tarceva (p=0.326). No statistically significant differences were found in LOT values for any of the 8 oral oncolytic medications included in the study. Iressa (p=0.885), Lonsurf (p=0.868), Stivarga (p=0.326), Zydelig (p=0.502), Zykadia (p=0.212), Tagrisso (p=0.089), Imbruvica (p=0.540), Tarceva (p=0.129). Conclusions: Pharmacist counseling does not appear to affect MPR or LOT for patients taking oral oncolytic medications. Further research is warranted targeting other chronic disease states with complex oral regimens where medication adherence has not already been established from prior therapy options and adequate disease state knowledge.

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Everyone knows someone affected by cancer. It is a heterogeneous malignancy requiring different approaches depending on the source, aggressiveness, and stage of the disease. To this end, innovative cancer therapies are required to conquer the unique obstacles posed by each type of cancer. One emerging therapeutic avenue employs the use of oncolytic viruses. Oncolytic viruses are predominantly attenuated viruses that specifically replicate in cancerous cells, which often have defective anti-viral responses, while leaving normal tissue unaffected. The inability of certain cancers to counter viral infections stems from a defective interferon pathway utilized by the malignant cells for unregulated proliferation. This ingenious exploitation of the cancer’s double-edged attribute led to numerous oncolytic virus clinical trials presently culminating in an approved oncolytic virus therapy, Talimogene laherparepvec, for the treatment of advanced melanoma. Oncolytic measles virus is currently being evaluated in several pre-clinical and clinical cancer trials. This virus offers many advantages as a replicating cancer therapeutic such as an excellent safety profile, oncotropic traits, and permissiveness for enhancement via genetic engineering. Even so, further improvements of oncolytic measles virus may be required to overcome the various complexities that each type of cancer poses. Some concerns are also inherent to the use of measles virus itself, such as pre-existing neutralizing antibodies towards the virus from routine immunization. This thesis outlines three distinct projects which aim to improve oncolytic measles virus as a cancer therapeutic. Firstly, a novel pseudotyping platform for oncolytic measles virus is described as an efficient and robust system for viral envelope exchange for the purpose of evading neutralizing antibodies. Secondly, oncolytic measles virus armed with granzyme B displayed increased oncolytic and proinflammatory activity. Finally, synergizing oncolytic measles virus with viral sensitizers enhanced the replication and cancer cell killing ability of the virus in both human and murine cancer models. Each project uniquely demonstrated advances in improving oncolytic measles virus so it may surmount the current challenges facing it as a cancer therapeutic.

Cancer is the leading cause of death in Canada and one of the leading causes of death worldwide. Conventional cancer therapies such as chemotherapy often include severe side effects that can decrease the quality of life of patients undergoing treatment. Immunotherapy is designed to harness the host immune response and enhance its ability to seek out and kill cancer cells. Immunotherapy has gained traction in the past decade due to its improved safety and efficacy over conventional cancer therapies. However, there is room for improvement as most patients fail to respond to immunotherapy. The work described in this dissertation involves the development of therapeutic combination platforms that are designed to improve upon immunotherapy outcomes. Murine tumor models were used to develop a better understanding of biological processes associated with therapeutic efficacy. These findings can be used for the development of therapeutic strategies that can further improve the efficacy of cancer immunotherapy. / Cancer immunotherapy has demonstrated immense promise in the past decade. Immune checkpoint therapy has shown unprecedented responses in many cancers; however most patients fail to respond to checkpoint therapy. This highlights the need to develop a better understanding of factors in the tumor microenvironment that can influence therapeutic outcomes. In this body of work, we have utilized oncolytic viruses (OVs) to enhance immunogenicity in the tumor and study the cellular mechanisms that enable a therapeutic response. We utilize a combination of OVs and low dose chemotherapy to further sensitize murine models of mismatch repair-deficient colorectal cancer to checkpoint therapy. Using a Clariom S transcriptome assay we found that the combination induced gene signatures associated with the recruitment and activation of myeloid subsets. When we assessed tumor infiltrates, we found that the combination induced the chemoattraction of several myeloid subsets, including type I conventional DCs (cDC1s) which are known for their role in antigen presentation. Using Batf3-/- mice, we demonstrated that the therapeutic efficacy of our combination platform was dependent on the presence of cDC1s. In this dissertation, we also studied the role of OV-induced type I IFN (IFNI) in enabling or suppressing antitumor immunity. We found that OVs induced the upregulation of PD-L1 in an IFN-I-dependent manner in cancer cells and circulating immune cells. Inhibition of IFN-I signaling using an anti-IFNAR monoclonal antibody partially prevented OV-induced upregulation of PD-L1. Furthermore, the combination of OV and v | P a g e IFNAR blockade enhanced the effector functions of tumor-specific T cells and led to better tumor control compared to OV monotherapy. Altogether, these findings demonstrate that OVs can be an effective agent for enhancing immunogenicity in the tumor and promoting the infiltration of inflammatory myeloid subsets. By combining OVs with checkpoint or IFNAR inhibitors, we prevent the onset of immunosuppression and enable a favorable therapeutic response. / Thesis / Doctor of Philosophy (Medical Science)

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<p> Oncolytic viruses are able to selectively replicate in tumour cells and are an attractive new avenue of cancer therapy that lacks the toxic side effects of current treatment modalities. HSV-1 mutants lacking ICPO are promising oncolytic vectors, however, the mechanisms behind viral oncolysis remain unclear. Since PML contributes to the repression of HSV-1 and also is downregulated in various types of cancer, but particularly in prostate cancer, PML has been implicated as a factor influencing the permissiveness of tumour cells to I CPO-null HSV-1 oncolysis. By screening a series of immortalized patient matched normal and tumour prostate epithelial cells for sensitivity to ICPO-null HSV-1 oncolysis and evaluating the levels of PML in each cell line, we were unable to establish a link between PML status and permissiveness to ICPO-null HSV-1 oncolytic vectors. Also, since a large proportion of the population possesses pre-existing immunity to HSV -1, which may hinder systemic administration of HSV-1 vectors, we sought to determine if BHV-1 could be an alternative oncolytic herpesvirus. BHV-1 was cytotoxic to various human immortalized and transformed cell lines in vitro, but was generally more restricted from normal human cells, suggesting that BHV -1 may have potential as an oncolytic virus. However, the sensitivity of human cells to BHV -1 infection did not correlate with type I IFN signaling, as has been demonstrated for other oncolytic viruses. Furthermore, neutralizing antibodies against HSV-1 were unable to cross-react with BHV -1 in vitro suggesting that pre-existing immunity to HSV -1 in humans may not hinder BHV -1 infection. It is hoped that these results will contribute to the understanding of viral mediated oncolysis and also provide some evidence that BHV-1 may be a new alternative oncolytic herpesvirus, however, in vivo studies are necessary to evaluate the oncolytic efficacy of BHV -1. </p> / Thesis / Master of Science (MSc)

The adoptive transfer of cancer-specific T-cells has demonstrated success as a novel treatment strategy in some hematological malignancies but this approach has not yet achieved widespread curative potential in the majority of tumors. To circumvent many of the limitations currently facing adoptive cell therapies, our lab has recently developed a combination therapy involving the in vivo boosting of adoptively transferred tumor-specific memory T-cells with an oncolytic viral vaccine. While this represents a demonstrably powerful approach in preclinical models of cancer it is limited by its targeting of a single antigen. Therapeutic resistance is a common concern when targeting a single antigen or pathway and an ideal therapy would include built-in mechanisms to address the heterogeneity and mutability that is inherent to cancer. Thus the focus of this research involved the development of a strategy to target therapeutic resistance in the context of the adoptive cell transfer with oncolytic viral boost regimen. In order to address the single antigen limitations, the engineering of tumor-specific T-cells with a targeting capacity for a second antigen is described. In addition to their endogenous tumor target it is shown that these cells have specificity for and can kill cells expressing ligands for the natural killer group 2 member D receptor which are commonly upregulated on both cancer cells and components of the tumor microenvironment. Indeed it is demonstrated in an in vivo model of relapse that T-cells capable of targeting both antigens produce more consistent and prolonged remissions than those with only their endogenous targeting capacity. Furthermore pharmacological strategies for the enhancement of engineered T cell survival and efficacy are also described. Finally the early development of a chimeric tumor model to further characterize the potential of dual-specific T-cells to address tumor heterogeneity is presented. / Thesis / Master of Science (MSc)