Antifibrotic Properties of Transarterial Oncolytic VSV Therapy for Hepatocellular Carcinoma in Rats With Thioacetamide-Induced Liver Fibrosis

Abstract

Recombinant vesicular stomatitis virus (VSV) shows promise for the treatment of hepatocellular carcinoma (HCC), but its safety and efficacy when administered in a setting of hepatic fibrosis, which occurs in the majority of clinical cases, is unknown. We hypothesized that VSV could provide a novel benefit to the underlying fibrosis, due to its ability to replicate and cause cell death specifically in activated hepatic stellate cells. In addition to the ability of VSV to produce a significant oncolytic response in HCC-bearing rats in the background of thioacetamide-induced hepatic fibrosis without signs of hepatotoxicity, we observed a significant downgrading of fibrosis stage, a decrease in collagen content in the liver, and modulation of gene expression in favor of fibrotic regression. Together, this work suggests that VSV is not only safe and effective for the treatment of HCC with underlying fibrosis, but it could potentially be developed for clinical application as a novel antifibrotic agent.

Recent advances in vesicular stomatitis virus-based oncolytic virotherapy: a 5-year update

“…First of all, it is not fully understood what cancers are the best targets for VSV-based OV therapy. In the last 5 years VSV has been tested in many novel cancer models, and VSV showed promising results in the following cancer models: endometrial cancer [135], metastatic colon cancer [136], neuroendocrine tumours [137], small cell ovarian carcinoma [138], metastatic Erwing sarcoma [139], malignant ascites [140], metastatic lesions associated with advanced prostate cancer and HCC with hepatic fibrosis [141], murine plasmacytoma [105]. Our laboratory tested VSV in an immunocompetent mouse model of PDAC overexpressing or not expressing human mucin 1 (MUC1), a major marker for poor PDAC (and some other cancers) prognosis in patients [142].…”

Natural killer cells mediate pathophysiology in response to reduced uterine perfusion pressure

“…It has also been suggested that IL-17may enhance cytolytic activity of human NK cells [16]. Rodent natural killer cells do not express CD56 and CD16 surface markers; however, they can be identified by surface expression of the NK cell marker named ANK61 [17–21]. Activated rat cNKs are distinguished from nonactivated NK cells by surface expression of ANK44, a protein preferentially expressed on rat cNK cells, and secretion of IFN- γ and TNF- α , similar to human cNK cells [22].…”

Preclinical safety evaluation of hepatic arterial infusion of oncolytic poxvirus

“…In addition, it should be noted that >70% HCC patients have liver cirrhosis and/or other liver disorders; in a previous study conducted by Altomonte et al, the HAI administration of VSV showed no acute (up to 3 days) toxicity in rats with liver fibrosis. 15 In this study, we aimed to investigate the acute and chronic (up to 2–6 months) toxicity of HAI administration of oncolytic poxvirus in a rabbit model with normal liver function and in a rat model with N-nitrosomorpholin (NNM)-induced precancerous liver cirrhosis.…”