Title

Oncolytic Tanapoxvirus Variants Expressing mIL-2 And mCCL-2 Regress Human Pancreatic Cancer Xenografts In Immunocompromised And Immunocompetent CAnN.Cg-Foxn1nu/Crl Nude Mice

Date of Award

6-2022

Degree Name

Doctor of Philosophy

Department

Biological Sciences

First Advisor

Karim Essani, Ph.D.

Second Advisor

John Spitsbergen, Ph.D.

Third Advisor

Rob Eversole, Ph.D.

Fourth Advisor

Jack Hoppin, Ph.D.

Keywords

Oncolytic virus, pancreatic cancer, PET/CT imaging, tanapox virus, tumor volume, virotherapy

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the fifth leading cause of cancer-related death in Western countries. The incidence of PDAC has increased over the last 40 years and is projected to be the second leading cause of cancer death by 2030. Despite aggressive treatment regimens, prognosis for patients diagnosed with PDAC is very poor; PDAC has the lowest 5-year survival rate for any form of cancer in the United States (US). PDAC cases are rarely detected in early stage when surgical resection can be performed and few, approximately 20%, are suitable for surgical resection which remains the only curative treatment when combined with adjuvant chemotherapy. Treatment regimens excluding surgical intervention, such as chemotherapeutic treatments, are associated with adverse effects and genetherapy strategies also struggle with lack of specificity and/or efficacy. The lack of effective treatments for this disease highlights the necessity for innovation in treatment options for patients diagnosed with early- to late-phase PDAC. Immuno-oncolytic viruses (OVs) have been of particular interest as a potential treatment option for PDAC, with differing OVs under assessment through ongoing clinical trials. In this study we assess the oncolytic potential of tanapoxvirus (TPV) recombinants expressing mouse monocyte chemoattractant protein (mMCP)-1, also known as mCCL2, and mouse interleukin (mIL)-2, in human pancreatic cancer cells (Bx Pc-3), via in vitro and in vivo assays using immunocompromised and immunocompetent murine test systems. Both the wild type (wt) TPV (TPV/eGFP) and the TPV recombinants demonstrated efficient replicability and viral plaque formation in BxPc-3 cells. Intratumoral treatment with TPV/Δ66R/mCCL2 and TPV/Δ66R/mIL-2, expressing mCCL2 and mIL-2 respectively, resulted in regression of growth of BxPc-3 tumor xenografts in nude mice as compared to the control, mock injected tumors in immunocompromised subjects; mCCL-2 expressing TPV OV resulted in significant difference from control at p<0.05. Histological analysis of immunocompromised subjects treated with TPV/Δ66R/mCCL2 or TPV/Δ66R/mIL-2 demonstrated presence of caspase positive adenocarcinomas at the transplant site, moderate increase in staining for CD3 and CD4 in TPV/Δ66R/mCCL2 treated subjects, relative equivalent staining for CD8 and CD68 and increased severity of chronic, active inflammation as compared to mock treated controls. In conclusion, TPV recombinants expressing mCCL2 and mIL-2 demonstrated a therapeutic effect in regression of Bx Pc-3 tumor xenografts in immunocompromised nude mice; mnCCL-2 significantly different at p<0.05. Considering the enhanced oncolytic potency of TPV recombinants expressing mCCL2 and mIL-2 in an experimental nude mouse model, further investigation as alternative or combination treatment option for human PDAC may be warranted.

Access Setting

Dissertation-Abstract Only

Restricted to Campus until

6-1-2023

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