Ad5/3-9HIF-Delta24-VEGFR-1-Ig, an infectivity enhanced, dual-targeted and antiangiogenic oncolytic adenovirus for kidney cancer treatment.
Despite good safety data in clinical trials, oncolytic adenoviruses have not been efficient enough to make them a viable treatment alternative for cancers. As more potent viruses are being made, transcriptional and transductional targeting to tumor tissues becomes increasingly appealing. To improve antitumor efficacy, oncolytic adenoviruses can be armed with therapeutic transgenes, such as the antiangiogenic soluble vascular endothelial growth factor receptor 1-Ig fusion protein. We hypothesized that an infectivity enhanced, targeted, vascular endothelial growth factor receptor 1-Ig armed oncolytic adenovirus would exhibit improved specificity and antitumor effect in murine kidney cancer models. Two hypoxia inducible factor-sensitive promoters were evaluated for renal cancer specificity using a novel in vivo dual luciferase-imaging system. Earlier data had shown usefulness of the 5/3-serotype chimera capsid modification for kidney cancer. Therefore, we constructed Ad5/3-9HIF-Delta24-VEGFR-1-Ig, which showed good specificity and oncolytic effect on renal cancer cells in vitro and resulted in antitumor efficacy in a subcutaneous in vivo model, in which vascular endothelial growth factor receptor 1-Ig expression and a concurrent antiangiogenic effect were confirmed. In an intraperitoneally disseminated kidney cancer model, significantly enhanced survival was observed when compared with control viruses. These results suggest that a targeted, antiangiogenic, oncolytic adenovirus might be a valuable agent for testing in kidney cancer patients.
Guse
K
K
Cancer Gene Therapy Group, Molecular Cancer Biology Program and Transplantation Laboratory and Haartman Institute and Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland.
Diaconu
I
I
Rajecki
M
M
Sloniecka
M
M
Hakkarainen
T
T
Ristimäki
A
A
Kanerva
A
A
Pesonen
S
S
Hemminki
A
A
D000256:Adenoviridae / Q000235:genetics*; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000818:Animals; D045744:Cell Line, Tumor; D018390:Gene Targeting; D006801:Humans; D007680:Kidney Neoplasms / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D040281:Vascular Endothelial Growth Factor Receptor-1