Anti-Tumor Effects of MAPK-Dependent Tumor-Selective Oncolytic Vaccinia Virus Armed with CD/UPRT against Pancreatic Ductal Adenocarcinoma in Mice

Hajime Kurosaki,Masato Yamane,Motomu Nakatake,Kenta Ishii,Teruhisa Sakamoto,Nozomi Kuwano,Yoshiyuki Fujiwara,Takafumi Nakamura

doi:10.3390/cells10050985

Hajime Kurosaki, Masato Yamane + Show 6 more

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https://doi.org/10.3390/cells10050985

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Journal: Cells	Publication Date: Apr 23, 2021
Citations: 9	License type: CC BY 4.0

Affiliation: Tottori University

Abstract

Engineered vaccinia virus serves as an oncolytic virus for cancer virotherapy. We evaluated the oncolytic characteristics of VGF- and O1-deleted recombinant mitogen-activated protein kinase (MAPK)-dependent vaccinia virus (MDRVV). We found that compared with viruses with the deletion of either gene alone, MDRVV is more attenuated in normal cells and can replicate in cancer cells that exhibit constitutive ERK1/2 activation in the MAPK pathway. We armed MDRVV with a bifunctional fusion gene encoding cytosine deaminase and uracil phosphoribosyltransferase (CD/UPRT), which converts 5-fluorocytosine (5-FC) into chemotherapeutic agents, and evaluated its oncolytic activity alone or in combination with 5-FC in human pancreatic cancer cell lines, tumor mouse models of peritoneal dissemination and liver metastasis, and ex vivo-infected live pancreatic cancer patient-derived tissues. CD/UPRT-armed MDRVV alone could efficiently eliminate pancreatic cancers, and its antitumor effects were partially enhanced in combination with 5-FC in vitro and in vivo. Moreover, the replication of MDRVV was detected in tumor cells of patient-derived, surgically resected tissues, which showed enlarged nuclei and high expression of pERK1/2 and Ki-67, and not in stromal cells. Our findings suggest that systemic injections of CD/UPRT-armed MDRVV alone or in combination with 5-FC are promising therapeutic strategies for pancreatic ductal adenocarcinoma.

Highlights

Vaccinia virus (VV), a double-stranded DNA virus of the family Poxviridae, is best known for its use as a smallpox vaccine until the 1970s
Tumor Specificity of vaccinia growth factor (VGF)−/O1−VV Is Dependent on Cellular mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase 1/2 (ERK1/2) Activity
The expression cassette encoding Discosoma sp. red fluorescent protein (DsRed) was inserted into the O1 locus of the VGF−/O1+VV, resulting in

Summary

Introduction

Vaccinia virus (VV), a double-stranded DNA virus of the family Poxviridae, is best known for its use as a smallpox vaccine until the 1970s. VV has been shown to kill cancer cells in a variety of ways, including through lysis following viral infection and subsequent replication, triggering antitumor immune responses, and disrupting the tumorassociated vasculature [1,2]. The most advanced VV immunotherapeutic agent, Pexa-Vec (JX-594), has been engineered by deleting the viral gene that encodes thymidine kinase (TK) for tumor selectivity through insertion and expression of the immuno-stimulating gene that encodes granulocyte/macrophage-colony-stimulating factor (GM-CSF), to enhance antitumor immune responses via dendritic cell activation and the subsequent stimulation of T-lymphocyte activity [3]. As tumor and not normal cells express abundant TK, deleting the viral TK gene is compensated by cellular TK and does not impair therapeutic replication in cancer cells. Viral TK deletion inhibits pathogenic viral replication in normal cells [1,2,3]

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