¹Molecular Neurosurgery Laboratory, Massachusetts General Hospital and Harvard Medical School, CPZN-3800 Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA

Correspondence: Samuel D. Rabkin, ^¶E-mail: rabkin@helix.mgh.harvard.edu; Andreas Kurtz, E-mail: kurtza@rki.de

^*T.-C.L., and T.Z. contributed equally; S.D.R., and A.K. contributed equally to this work.

^†Current address: Department of Pathology, Shandong University Hospital, Jinan, China.

^‡Current address: Department of Urology, University of Tokyo, Tokyo, Japan.

^§Current address: Department of Neurosurgery, University of Tokyo, Tokyo, Japan.

Current address: Robert Koch Institute, Seestrasse 10, 13353 Berlin, Germany.

Received 12 February 2006; Revised 19 July 2006; Accepted 31 July 2006.

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 G47 utilizing a bacterial artificial chromosome construction system. Whereas bG47-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, bG47-PF4 was more efficacious than its nonexpressing parent bG47-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.