Combination of a fusogenic glycoprotein, pro-drug activation and oncolytic HSV as an intravesical therapy for superficial bladder cancer

Abstract

Background:There are still no effective treatments for superficial bladder cancer (SBC)/non-muscle invasive bladder cancer. Following treatment, 20% of patients still develop metastatic disease. Superficial bladder cancer is often multifocal, has high recurrences after surgical resection and recurs after intravesical live Bacillus Calmette–Guérin. OncovexGALV/CD, an oncolytic herpes simplex virus-1, has shown enhanced local tumour control by combining oncolysis with the expression of a highly potent pro-drug activating gene and the fusogenic glycoprotein.Methods:In vitro fusion/prodrug/apoptotic cell-based assays. In vivo orthotopic bladder tumour model, visualised by computed microtomography.Results:Treatment of seven human bladder carcinoma cell lines with the virus resulted in tumour cell killing through oncolysis, pro-drug activation and glycoprotein fusion. OncovexGALV/CD and mitomycin C showed a synergistic effect, whereas the co-administration with cisplatin or gemcitabine showed an antagonistic effect in vitro. Transitional cell cancer (TCC) cells follow an apoptotic cell death pathway after infection with OncovexGALV/CD with or without 5-FC. In vivo results showed that intravesical treatment with OncovexGALV/CD + prodrug (5-FC) reduced the average tumour volume by over 95% compared with controls.Discussion:Our in vitro and in vivo results indicate that OncovexGALV/CD can improve local tumour control within the bladder, and potentially alter its natural history.

Intravesical therapy for bladder cancer

“…Of note, most common side effects were dysuria and hematuria, but generally the treatments were well tolerated [107]. Other formulations such as AxdAdB3-F/RGD and OncoVEXGALV/ CD have inhibited bladder cancer growth in a mice and rat model, respectively [108,109]. Further work is needed before oncolytic viruses can become part of the armamentarium against bladder cancer.…”

Cancer immunotherapy via combining oncolytic virotherapy with chemotherapy: recent advances

“…Intracellular adhesion molecule-1 and decay accelerating factor, the viral entry receptors for Coxsackie virus A21, have been shown to be upregulated in the presence of MMC, leading to synergy between virus and drug 120. HSV-1,121–123 vaccinia,124 and adenovirus177 have all shown synergy with MMC, but these studies have not identified any immune-function mechanism.…”

Expression of the fusogenic p14 FAST protein from a replication-defective adenovirus vector does not provide a therapeutic benefit in an immunocompetent mouse model of cancer

“…Various viruses have been modified to express membrane fusion proteins from Gibbon ape leukemia virus (GALV), respiratory syncytial virus (RSV), measles virus (MV), Newcastle disease virus and human immunodeficiency virus type 1 (HIV-1), and in many studies these vectors were shown to be effective in tumor regression. 6, 7, 8, 9, 10, 11, 12, 13, 14 Ad vectors expressing GALV, RSV, MV or vesicular stomatitis virus (VSV) membrane fusion proteins as a sole anti-cancer agent were able to reduce tumor burden in xenograft and immunocompetent mouse models in the absence of other complementing anti-cancer therapeutic transgenes. 8, 9, 12, 13 Thus, in many studies, the process of cancer cell fusion, and associated disruption in cellular processes, can lead to tumor regression.…”