Experimental Therapy of Human Triple Negative Breast Cancer Using Oncolytic Tanapoxvirus Recombinants Expressing Interleukin-2 And Monocyte Chemoattractant Protein-1

Date of Award

8-2017

Degree Name

Doctor of Philosophy

Department

Biological Sciences

First Advisor

Dr. Karim Essani

Second Advisor

Dr. Bruce Bejcek

Third Advisor

Dr. Rob Eversole

Fourth Advisor

Dr. Christopher Fisher

Keywords

Tanapoxvirus, human triple negative breast cancer, interleukin-2, MCP-l/CCL2, oncolytic virus, immunotherapy, codon usage

Abstract

Triple negative breast cancer (TNBC) is one of the most challenging breast cancer subtypes owing to its aggressive nature and the non-expression of therapeutic targets like estrogen, progesterone and human epidermal growth factor receptors. Standard therapeutics such as chemo and radiotherapies have a limited role in the treatment of TNBC due to the associated severe toxicity and development of resistance by cancer cells. Oncolytic viruses (OVs) are an emerging and promising treatment option for breast cancer with several viruses, including poxviruses under investigation in pre-clinical and clinical studies. Tanapoxvirus (TPV), a member of the genus Yatapoxvirus within the family poxviridae, naturally infects humans and has a large (144 kilo base pairs) genome that can be easily maneuvered and armed to potential oncolytic viruses. A distinct antigenicity among poxviruses with no cross-immunity with vaccinia virus and no reported direct human to human viral transmission are some of the desirable characteristics of TPV which make this virus a suitable OV candidate. Moreover, TPV causes a self-limiting, mild febrile illness in humans, and the morbidity of virus can be further enhanced by ablating virulence genes from the viral genome. This study describes the oncolytic potential of a panel of TPV recombinants, some of which express immune modulatory proteins, in human TNBC cells, both in vitro and in vivo. Most TPV recombinants showed comparable replicability and ability to induce cell death in human TNBC cells, in culture, TPV recombinants expressing mouse interleukin-2 [TPV/Δ66R/mIL-2] and mouse monocyte chemoattractant protein-1 (also known as CCL2) [TPV/Δ66R/mCCL2] regressed the MDA-MB-231 tumor xenografts in athymic nude mice significantly. Histological analyses of tumors showed that a predominantly mononuclear immune cell response was induced against tumors by TPV recombinants. The most striking effect in the form of deep infiltration of mononuclear cells into the tumor capsule was observed in tumors injected with TPV/Δ66R/mIL-2. In this study, the development of a computational tool “Quick Codon Count”, which not only allows analyses of large genome data sets for codon usage but also enables analyses of codon usage for each amino acid at the level of an open reading frame (ORF) has also been described. Development of the “Quick Codon Count” program is important as no currently available computational tool allows codon usage analyses at the level of each amino acid. Codon usage regulates the viral gene expression, hence understanding codon usage by pox and other viruses can guide the development of OVs.

Access Setting

Dissertation-Abstract Only

Restricted to Campus until

8-15-2027

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