Oncolytic HSV armed with platelet factor 4, an antiangiogenic agent, shows enhanced efficacy.
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 G47Delta utilizing a bacterial artificial chromosome construction system. Whereas bG47Delta-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, bG47Delta-PF4 was more efficacious than its nonexpressing parent bG47Delta-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.
Liu
Ta-Chiang
TC
Molecular Neurosurgery Laboratory, Massachusetts General Hospital and Harvard Medical School, CPZN-3800 Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA.
Zhang
Tingguo
T
Fukuhara
Hiroshi
H
Kuroda
Toshihiko
T
Todo
Tomoki
T
Martuza
Robert L
RL
Rabkin
Samuel D
SD
Kurtz
Andreas
A
D020533:Angiogenesis Inhibitors / Q000235:genetics / Q000502:physiology; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D004797:Enzyme-Linked Immunosorbent Assay; D005822:Genetic Vectors / Q000235:genetics; D005910:Glioma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000628:therapy; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics; D010978:Platelet Factor 4 / Q000235:genetics* / Q000502:physiology; D018139:Simplexvirus / Q000235:genetics*; D013997:Time Factors; D014162:Transfection; D016896:Treatment Outcome; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D010978:Platelet Factor 4