Date of Defense

6-28-2018

Date of Graduation

12-2017

Department

Biological Sciences

First Advisor

Karim Essani

Second Advisor

Silvia Rossbach

Abstract

The National Cancer Institute defines cancer as a group of related diseases characterized by unimpeded cell division with metastatic abilities. Cells frequently mutate and potentially become cancerous, but generally these cells are cleared by the immune system. The disease state of cancer arises when the mutated cells evade the immune clearance, which indicates medical intervention is required. Current therapies most commonly utilize chemotherapy, radiation, or a combination of the two, however, alternative therapies are being developed such as immunotherapies and oncolytic viruses (OVs). OVs cause a viral infection, clearing cancerous cells through viral replication mechanisms, such as viral cytolysis, while simultaneously priming the adaptive immune system to better recognize and clear infected cancer cells. OVs are also capable of facilitating changes to the tumor microenvironment (TME), optimizing the immune response. Certain characteristics are required of OVs, such as a large population immunologically naïve to the infection, inability to cause serious disease in humans, and preferential replication in cancerous cells. Tanapoxvirus (TPV) is currently being investigated as an effective OV. Most of the world is immunologically naïve to the virus, which is isolated to the Tana River Valley in Kenya. The infection is defined as self-limiting, and resolves approximately six weeks post-infection independent of treatment. Preferential replication in cancerous cells is not innate to TPV; however, it can be induced by ablation of the thymidine kinase gene. The therapeutic benefits of TPV have been observed in in vivo nude mouse models utilizing colorectal cancer, triple negative breast cancer (TNBC), as well as melanoma. The TPV/∆66R/fliC viral recombinant was effective in regression of induced colorectal cancer in a nude mouse model. The 66R ablation is the thymidine kinase gene, which increases preferential replication within cancerous cells, and the fliC insertion will stimulate the innate immune response through interactions with Toll-like receptor 5. In TNBC both the TPV/∆66R/CCL-2 and the TPV/∆66R/m-IL2 recombinants showed significant regression in induced TNBC tumors on the nude mouse model. These mechanisms function by recruiting macrophages at the site of infection and priming the T cells for increased cancer cell recognition respectively. Finally the TPV/∆15L recombinant was able to show regression in melanoma tumors in the nude mouse model by preventing the production of interferon-¡1 (INF-¡1). An in vitro cell assay was conducted and indicated that INF-¡1 asserts a greater antiproliferative effect than the type one INFs, so by preventing the production of this cytokine an increase efficiency of viral replication will be observed. Finally, the TPV infection is influenced by the TME through interactions with matrix metalloproteinase-9 (MMP-9). Interactions with MMP-9 prevents viral replication from occurring by an unknown mechanism, and preventing this interaction will increase the therapeutic effects TPV can assert. Future studies will observe the effects of TPV in an immunocompetent mouse model, as well as the potential of TPV as a treatment for pancreatic cancer. This research indicated that TPV has immense potential as an OV for treatment of multiple different types of cancers, and it’s therapeutic effects should continue to be investigated.

Access Setting

Honors Thesis-Open Access

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