Virotherapy of canine tumors with oncolytic vaccinia virus GLV-1h109 expressing an anti-VEGF single-chain antibody

PLoS One. 2012;7(10):e47472. doi: 10.1371/journal.pone.0047472. Epub 2012 Oct 16.

Abstract

Virotherapy using oncolytic vaccinia virus (VACV) strains is one promising new strategy for cancer therapy. We have previously reported that oncolytic vaccinia virus strains expressing an anti-VEGF (Vascular Endothelial Growth Factor) single-chain antibody (scAb) GLAF-1 exhibited significant therapeutic efficacy for treatment of human tumor xenografts. Here, we describe the use of oncolytic vaccinia virus GLV-1h109 encoding GLAF-1 for canine cancer therapy. In this study we analyzed the virus-mediated delivery and production of scAb GLAF-1 and the oncolytic and immunological effects of the GLV-1h109 vaccinia virus strain against canine soft tissue sarcoma and canine prostate carcinoma in xenograft models. Cell culture data demonstrated that the GLV-1h109 virus efficiently infect, replicate in and destroy both tested canine cancer cell lines. In addition, successful expression of GLAF-1 was demonstrated in virus-infected canine cancer cells and the antibody specifically recognized canine VEGF. In two different xenograft models, the systemic administration of the GLV-1h109 virus was found to be safe and led to anti-tumor and immunological effects resulting in the significant reduction of tumor growth in comparison to untreated control mice. Furthermore, tumor-specific virus infection led to a continued production of functional scAb GLAF-1, resulting in inhibition of angiogenesis. Overall, the GLV-1h109-mediated cancer therapy and production of immunotherapeutic anti-VEGF scAb may open the way for combination therapy concept i.e. vaccinia virus mediated oncolysis and intratumoral production of therapeutic drugs in canine cancer patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Survival
  • Dog Diseases / immunology
  • Dog Diseases / pathology
  • Dog Diseases / therapy*
  • Dogs
  • Female
  • Gene Expression
  • Gene Order
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / genetics*
  • Genetic Vectors / pharmacokinetics
  • Glucuronidase / genetics
  • Glucuronidase / metabolism
  • Humans
  • Mice
  • Mice, Nude
  • Neoplasms / immunology
  • Neoplasms / therapy
  • Neoplasms / veterinary*
  • Oncolytic Virotherapy*
  • Single-Chain Antibodies / genetics*
  • Single-Chain Antibodies / metabolism
  • Tumor Burden
  • Vaccinia virus / genetics*
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor A / immunology
  • Virus Replication
  • Xenograft Model Antitumor Assays

Substances

  • Single-Chain Antibodies
  • Vascular Endothelial Growth Factor A
  • Glucuronidase

Grant support

The research was supported by the Research and Development Division of Genelux Corporation, San Diego, USA, and a Service Grant to the University of Würzburg, Germany also funded by Genelux Corp., San Diego, USA. IG AF and AAS are employees and shareholders of Genelux. MA, UD, MH and SW were supported by grants of Genelux Corporation. SSP is a graduate fellow and supported by a grant of the German Excellence Initiative to the Graduate School of Life Sciences, University of Wuerzburg. This publication was funded by the German Research Foundation (DFG) and the University of Wuerzburg in the funding programme Open Access Publishing. No additional external funding was received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.