Selective intratumoral amplification of an antiangiogenic vector by an oncolytic virus produces enhanced antivascular and anti-tumor efficacy.
The development of effective cancer therapy will require the simultaneous targeting of multiple steps in tumor development. We have previously described an antiangiogenic gene therapy vector, Ad Flk1-Fc, which expresses a soluble VEGF receptor capable of inhibiting tumor angiogenesis and growth. We have also described an oncolytic virus, dl922/947, whose replication and subsequent cytotoxicity are restricted to cancer cells with a loss of the G1-S cell cycle checkpoint. Here we have optimized methods for combining these therapies, yielding significantly greater anti-tumor effects than the respective monotherapies. In cultured tumor lines, co-infection with both Ad Flk1-Fc and dl922/947 allowed replication and repackaging of the replication-deficient Ad Flk1-Fc and enhanced soluble VEGF receptor expression. Similar repackaging and increased gene expression were demonstrated in vivo using bioluminescence imaging studies. Finally, coadministration of these therapeutic viral therapies in vivo produced significantly enhanced anti-tumor effects in colon HCT 116 and prostate PC-3 xenografts in mice. This increased therapeutic benefit correlated with replication of Ad Flk1-Fc viral genomes, increased intratumoral levels of Flk1-Fc protein, and decreased microvessel density, consistent with enhanced antiangiogenic activity.
Thorne
Stephen H
SH
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
Tam
Betty Y Y
BY
Kirn
David H
DH
Contag
Christopher H
CH
Kuo
Calvin J
CJ
D000230:Adenocarcinoma / Q000098:blood supply / Q000235:genetics / Q000473:pathology / Q000628:therapy; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D045744:Cell Line, Tumor; D003588:Cytopathogenic Effect, Viral / Q000502:physiology; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000627:therapeutic use; D045325:HCT116 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D050504:Oncolytic Viruses / Q000235:genetics* / Q000502:physiology; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000235:genetics / Q000473:pathology / Q000628:therapy; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
D040262:Receptors, Vascular Endothelial Growth Factor