Oncolytic HSV Armed with Platelet Factor 4, an Antiangiogenic Agent, Shows Enhanced Efficacy

Ta Chiang Liu, Tingguo Zhang, Hiroshi Fukuhara, Toshihiko Kuroda, Tomoki Todo, Robert L. Martuza, Samuel D. Rabkin, Andreas Kurtz

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

Abstract

Oncolytic herpes simplex viruses (HSV) have emerged as a promising platform for cancer therapy. However, efficacy as single agents has thus far been unsatisfactory. Tumor vasculature is critical in supporting tumor growth, but successful antiangiogenic approaches often require maintaining constant levels of antiangiogenic products. We hypothesized that oncolytic HSV has the potential to destroy tumor vasculature and that this effect can be enhanced by combination with antiangiogenic gene transfer. We examined the strategy of arming oncolytic HSV with an antiangiogenic transgene, platelet factor 4 (PF4). The PF4 transgene was inserted into oncolytic HSV G47Δ utilizing a bacterial artificial chromosome construction system. Whereas bG47Δ-empty showed robust cell killing and migration inhibition of proliferating endothelial cells (HUVEC and Py-4-1), the effect was further enhanced by PF4 expression. Importantly, enhanced potency did not impede viral replication. In vivo, bG47Δ-PF4 was more efficacious than its nonexpressing parent bG47Δ-empty at inhibiting tumor growth and angiogenesis in both human U87 glioma and mouse 37-3-18-4 malignant peripheral nerve sheath tumor models. Enhancing the antiangiogenic properties of oncolytic HSV through the expression of antiangiogenic factors such as PF4 is a powerful new strategy that targets both the tumor cells and tumor vasculature.

Original languageEnglish
Pages (from-to)789-797
Number of pages9
JournalMolecular Therapy
Volume14
Issue number6
DOIs
StatePublished - Dec 2006

Keywords

  • antiangiogenesis
  • cancer gene therapy
  • herpes simplex virus
  • oncolytic virus
  • platelet factor 4

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