Combination of a Fusogenic Glycoprotein, Prodrug Activation, and Oncolytic Herpes Simplex Virus for Enhanced Local Tumor Control

Abstract

We have previously developed an oncolytic herpes simplex virus-1 based on a clinical virus isolate, which was deleted for ICP34.5 to provide tumor selected replication and ICP47 to increase antigen presentation as well as tumor selective virus replication. A phase I/II clinical trial using a version of this virus expressing granulocyte macrophage colony-stimulating factor has shown promising results. The work reported here aimed to develop a version of this virus in which local tumor control was further increased through the combined expression of a highly potent prodrug activating gene [yeast cytosine deaminase/uracil phospho-ribosyltransferase fusion (Fcy::-Fur)] and the fusogenic glycoprotein from gibbon ape leukemia virus (GALV), which it was hoped would aid the spread of the activated prodrug through the tumor. Viruses expressing the two genes individually or in combination were constructed and tested, showing (a) GALV and/or Fcy::Fur expression did not affect virus growth; (b) GALV expression causes cell fusion and increases the tumor cell killing at least 30-fold in vitro and tumor shrinkage 5-to 10-fold in vivo; (c) additional expression of Fcy::Fur combined with 5-fluorocytosine administration improves tumor shrinkage further. These results indicate, therefore, that the combined expression of the GALV protein and Fcy::Fur provides a highly potent oncolytic virus with improved capabilities for local tumor control. It is intended to enter the GALV/Fcy::Fur expressing virus into clinical development for the treatment of tumor types, such as pancreatic or lung cancer, where local control would be anticipated to be clinically advantageous. (Cancer Res 2006; 66(9): 4835-42)

Fusogenic membrane glycoproteins induce syncytia formation and death in vitro and in vivo: a potential therapy agent for lung cancer

“…[1][2][3][4][7][8][9][10][11][12][13][14][15] In this study, we demonstrate that HERV-W FMGs' cytotoxicity resulting from the formation of gigantic cells is sufficient to induce tumor regression, with a very strong bystander effect, after non-viral, intratumoral gene delivery as previously described for GALV.…”

“…[4][5][6][7] In addition to this syncytia-mediated toxicity, FMG has also been shown to enhance the antitumor therapeutic activity of replicating adenovirus, oncolytic HSV and vesicular stomatitis virus. [8][9][10][11][12] FMG-induced cytotoxicity is not immediate. Multinucleated syncytia develop within 24 h after transfection and gradually die in 5 days.…”

Syncytia formation affects the yield and cytotoxicity of an adenovirus expressing a fusogenic glycoprotein at a late stage of replication

“…[8][9][10][11] Various FMGs have been evaluated as a means to increase the potency of oncolytic viruses. 4,6,[12][13][14][15][16] Expression of the HIV gp120 FMG by a replicative adenovirus enhanced viral release and facilitated dispersion of virus particles through a culture of tumor cells in vitro. 4 In addition, a more recent report demonstrated that coinjection of plasmid DNA encoding the hyperfusogenic form of the GALV envelope glycoprotein significantly enhanced the in vivo efficacy of the adenovirus therapy.…”

“Armed” oncolytic herpes simplex viruses for brain tumor therapy

“…3), an oncolytic HSV-1 termed OncoVEX GALV/CD double-armed with yCD/uracil phosphoribosyltransferase fusion and GALV.fus has been created. 39 In Fischer f344 rats bearing subcutaneous 9L glioma, OncoVEX GALV/ CD proved most efficacious compared with the control viruses (OncoVEX, OncoVEX GALV or OncoVEX CD ) when combined with systemic 5-FC administration. Han et al recently created an oncolytic HSV-1, with double deletions in the γ34.5 and a47 genes, armed with tumor necrosis factor alpha (TNFa).…”