Oncolytic virotherapy for ovarian carcinomatosis using a replication-selective vaccinia virus armed with a yeast cytosine deaminase gene

Abstract

In this study, we assessed the ability of a highly tumor-selective oncolytic vaccinia virus armed with a yeast cytosine deaminase gene to infect and lyse human and murine ovarian tumors both in vitro and in vivo. The virus vvDD-CD could infect, replicate in and effectively lyse both human and mouse ovarian cancer cells in vitro. In two different treatment schedules involving either murine MOSEC or human A2780 ovarian carcinomatosis models, regional delivery of vvDD-CD selectively targeted tumor cells and ovarian tissue, effectively delaying the development of either tumor or ascites and leading to significant survival advantages. Oncolytic virotherapy using vvDD-CD in combination with the prodrug 5-fluorocytosine conferred an additional long-term survival advantage upon tumor-bearing immunocompetent mice. These findings demonstrate that a tumor-selective oncolytic vaccinia combined with gene-directed enzyme prodrug therapy is a highly effective strategy for treating advanced ovarian cancers in both syngeneic mouse and human xenograft models. Given the biological safety, tumor selectivity and oncolytic potency of this armed oncolytic virus, this dual therapy merits further investigation as a promising new treatment for metastatic ovarian cancer.

A Novel Recombinant Vaccinia Virus Expressing the Human Norepinephrine Transporter Retains Oncolytic Potential and Facilitates Deep-Tissue Imaging

“…Various recombinant versions of this virus have been used to lyse tumor cells ex vivo and in vivo to stimulate the native immune response to cancer (21,22). More recently, engineered VACVs have also been successfully used as direct oncolytic agents, capable of preferentially infecting, replicating within, and killing a wide variety of cancer cell types (23)(24)(25). One such promising virus is GLV-1h68.…”

Use of an oncolytic vaccinia virus for the treatment of canine breast cancer in nude mice: preclinical development of a therapeutic agent

“…7,8 The concept that viruses may be useful in the eradication of cancer has existed since the early twentieth century. 9,10 However, during the last 10 years numerous reports have confirmed that intratumorally or systemically delivered viruses such as Newcastle disease virus, 11,12 reovirus, 13,14 lentivirus, 15 herpes simplex virus, 16,17 enterovirus, 18 Sindbis virus, 19 Semliki Forest virus, 20 Seneca Valley virus 21 and vaccinia virus 22,23 can display an antitumor activity in vivo. In comparison, vaccinia virus has significant advantages as a live viral vector: (1) large foreign gene-carrying capacity; (2) broad host cell range; (3) replication exclusively in the cytoplasm, with no risk of chromosomal DNA integration and (4) natural tropism for targeting tumors on systemic administration.…”

Efficacy of Systemically Administered Oncolytic Vaccinia Virotherapy for Malignant Gliomas Is Enhanced by Combination Therapy with Rapamycin or Cyclophosphamide

“…Many strains of attenuated replicating vaccinia viruses have shown promising efficacy in the treatment of murine models of human gliomas (17) and other cancers (14,18,19), as well as primary cultures of human tumors (20). Because there may be a potential concern about the safety of a replicating vaccinia virus, a mutant ''double-deleted'' version of the Western Reserve (WR) strain [double-deleted vaccinia virus (vvDD)] with deletions of the thymidine kinase and vaccinia growth factor genes was created to enhance its safety (14).…”