rVSV(MΔ51)-M3 Is an Effective and Safe Oncolytic Virus for Cancer Therapy

Abstract

Oncolytic vesicular stomatitis virus (VSV) is being developed as a novel therapeutic agent for cancer treatment, although it is toxic in animals when administered systemically at high doses. Its safety can be substantively improved by an M Delta 51 deletion in the viral genome, and yet VSV(M Delta 51) induces a much greater, robust cellular inflammatory response in the host than wild-type VSV, which severely attenuates its oncolytic potency. We have reported that the oncolytic potency of wild-type VSV can be enhanced by vector-mediated expression of a heterologous viral gene that suppresses cellular inflammatory responses in the lesions. To develop an effective and safe VSV vector for cancer treatment, we tested the hypothesis that the oncolytic potency of VSV(M Delta 51) can be substantively elevated by vector-mediated expression of M3, a broad-spectrum and high-affinity chemokine-binding protein from murine gammaherpesvirus-68. The recombinant vector rVSV(M Delta 51)-M3 was used to treat rats bearing multifocal lesions (1-10 mm in diameter) of hepatocellular carcinoma (HCC) in their liver by hepatic artery infusion. Treatment led to a significant reduction of neutrophil and natural killer cell accumulation in the lesions, a 2-log elevation of intratumoral viral titer, substantively enhanced tumor necrosis, and prolonged animal survival with a 50% cure rate. Importantly, there were no apparent systemic and organ toxicities in the treated animals. These results indicate that the robust cellular inflammatory responses induced by VSV(M Delta 51) in HCC lesions can be overcome by vector-mediated intratumoral M3 expression, and that rVSV(M Delta 51)-M3 can be developed as an effective and safe oncolytic agent to treat advanced HCC patients in the future.

Soluble M3 proteins of murine gammaherpesviruses 68 and 72 expressed in Escherichia coli: analysis of chemokine-binding properties

“…Because of its strong and specifi c binding of chemokines of all four subfamilies (Parry et al, 2000;Belvončíková et al, 2008), it can serve as a potential therapeutic tool for treating diseases linked to the deregulation of chemokine network, such as diabetes mellitus type I (Martin et al, 2007(Martin et al, , 2008Lira et al, 2009). A number of other autoimmune diseases leading to chronic infl ammation could be treated with chemokine antagonists (Proudfoot et al, 2003;Pyo et al, 2004;Wu et al, 2008).…”

Safety Studies on Intrahepatic or Intratumoral Injection of Oncolytic Vesicular Stomatitis Virus Expressing Interferon-β in Rodents and Nonhuman Primates

“…To enhance the oncolytic potency of VSV, investigators have genetically modified the virus to express a variety of transgenes such as chemokine-binding protein, IL-12, and fusogenic glycoproteins (Ebert et al, 2004;Shin et al, 2007;Wu et al, 2008). In addition, Goel and colleagues have demonstrated that addition of the human thyroidal sodium iodide symporter gene to the VSV genome permits radioiodine imaging of the sites of viral infection as well as enhancement of the antitumor activity of VSV by using 131 I, a b particle-emitting radionuclide (Goel et al, 2007).…”

Vesicular Stomatitis Virus Expressing Tumor Suppressor p53 Is a Highly Attenuated, Potent Oncolytic Agent

“…Genetically modifying the VSV genome itself is also possible and has proved useful in anticancer strategies. For example, VSVs harboring a mutation of the matrix (M) gene that renders the protein incapable of blocking mRNA export from the nucleus enabled the stimulation of robust innate immune responses following the infection of cancer cells that were characterized by an increase in IFN-␤ and interferon-stimulated gene (ISG) production (59,61). The triggering of innate immune responses is essential to facilitate upregulation of antigen-presenting machinery, stimulate NK cell activity, and induce anticancer cytokines.…”

“…This mutation prevents the M protein from binding to the Rae1-Nup98 mRNA export complex and allows cells infected with VSV-M(mut) to efficiently export mRNA from the nucleus, such as type I IFN and other virus-or p53-activated host genes (16,59,61). This facilitates the initiation of stronger innate immune responses, which can facilitate antitumor immunity in tumor cells, as well as prevent viral infection of cells with intact innate immune signaling pathways.…”