Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus

Abstract

Interferons are circulating factors that bind to cell surface receptors, activating a signaling cascade, ultimately leading to both an antiviral response and an induction of growth inhibitory and/or apoptotic signals in normal and tumor cells. Attempts to exploit the ability of interferons to limit the growth of tumors in patients has met with limited results because of cancer-specific mutations of gene products in the interferon pathway. Although interferon-non-responsive cancer cells may have acquired a growth/survival advantage over their normal counterparts, they may have simultaneously compromised their antiviral response. To test this, we used vesicular stomatitis virus (VSV), an enveloped, negative-sense RNA virus exquisitely sensitive to treatment with interferon. VSV rapidly replicated in and selectively killed a variety of human tumor cell lines even in the presence of doses of interferon that completely protected normal human primary cell cultures. A single intratumoral injection of VSV was effective in reducing the tumor burden of nude mice bearing subcutaneous human melanoma xenografts. Our results support the use of VSV as a replication-competent oncolytic virus and demonstrate a new strategy for the treatment of interferon non-responsive tumors.

Vesiculovirus Neutralization by Natural IgM and Complement

“…VSV is a negative-sense RNA virus that can infect a wide variety of animals and cells and possesses a rapid lytic replication cycle but demonstrates dramatic sensitivity to the host interferon response (16,30,32,33). The high sensitivity of VSV to innate interferon responses and its lack of pathogenicity to humans have made it an attractive oncolytic platform that has been extensively investigated and has been shown to kill cancer cells selectively, particularly when they have a disrupted interferon response (28)(29)(30)(31)(32)(33)(34). Preclinical studies show that VSV is promising for the treatment of a variety of human cancers (10,(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26).…”

“…VSV is a Vesiculovirus of the family Rhabdoviridae with a negative-sense RNA genome (16,17). VSV is a preferred candidate as a platform for oncolytic virus development against a variety of cancers (10,(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27), primarily due to its very broad tropism infecting a wide variety of animals and different cells, its short replication cycle, and high sensitivity to host interferon-mediated antiviral activity (28)(29)(30)(31)(32)(33)(34)(35). Tumor-selective tropism can be further enhanced by mutating the M protein or engineering the virus to encode beta interferon (IFN-␤).…”

Vesicular Stomatitis Virus Has Extensive Oncolytic Activity against Human Sarcomas: Rare Resistance Is Overcome by Blocking Interferon Pathways

“…The oncoselectivity of VSV derives at least in part from its sensitivity to the effects of interferon (IFN), combined with the fact that various features of the IFN response are disrupted in many cancers (39,46). VSV-G/green fluorescent protein (GFP) is a recombinant VSV featuring the addition, between the G and L genes, of a gene encoding a VSV-G/GFP fusion protein.…”

Autonomous Parvoviruses neither Stimulate nor Are Inhibited by the Type I Interferon Response in Human Normal or Cancer Cells

“…The oncoselectivity of VSV is largely a function of the impaired IFN signaling of many oncogenically transformed cells (25,40). However, the antiviral response machinery retains various degrees of functionality among different tumor cells, resulting in different degrees of VSV susceptibility.…”

“…In transformed human cells, VSV often fails to trigger this response or produces a response that is ineffective against infection (24). This results in the selective growth of VSV in most transformed human tumors compared to in their untransformed normal cell counterparts of the same tissue type (25)(26)(27)(28). Other oncolytic viruses whose oncoselectivity depends, at least in part, on disruption of innate immunity in transformed cells include Newcastle disease virus (NDV) and myxoma virus (29).…”