Interferon Beta and Interferon Alpha 2a Differentially Protect Head and Neck Cancer Cells from Vesicular Stomatitis Virus-Induced Oncolysis

Abstract

Oncolytic viruses (OV IMPORTANCEThere has been a great deal of progress in the development of oncolytic viruses. However, a major problem is that individual cancers vary in their sensitivity to oncolytic viruses. In many cases this is due to differences in their production and response to interferons (IFNs). The experiments described here compared the responses of head and neck squamous cell carcinoma cell lines to two IFN subtypes, IFN-␣2a and IFN-␤, in protection from oncolytic vesicular stomatitis virus. We found that IFN-␣2a was significantly less protective for cancer cells than was IFN-␤, whereas normal cells were equivalently protected by both IFNs. These results suggest that from a therapeutic standpoint, selectivity for cancer versus normal cells may be enhanced by pairing VSV with IFN-␣2a. T he use of viruses to selectively kill cancer cells (oncolytic virotherapy) is a promising alternative therapy for cancer (1). The basis for this treatment approach is that cancer cells frequently have defective antiviral responses that develop as a consequence of cellular transformation (2-5). As a result, they are more susceptible than their normal cellular counterparts to infection and apoptotic death induced by cytopathic viruses (6, 7). Vesicular stomatitis virus (VSV), a negative-strand RNA virus of the family Rhabdoviridae, is being investigated as an oncolytic agent for the treatment of prostate (6, 8), skin (9, 10), colorectal (2, 11, 12), pancreatic (13), brain (14, 15), and other cancers. A variety of attenuated VSV strains have been engineered to express heterologous genes to increase selectivity for tumor cells, to augment tumor cell killing, or to enhance antitumor immunity (reviewed in reference 16). Recombinant VSV strains have produced encouraging preclinical results for a broad range of tumor types (17-22), and VSV expressing the human beta interferon (IFN-␤) gene currently is undergoing a phase I clinical trial for the treatment of hepatocellular carcinoma (http://www.clinicaltrials.gov/ct2/show /study/NCT01628640).Because normal cells respond to viral infection by mounting a protective type I IFN response while many cancer cells do not share this capability (7), the selectivity of VSV for cancer cells has been improved by combination treatment with type I IFN, for example, by incorporating the gene for IFN-␤ into the VSV genome or by the use of mutant or engineered VSV strains that induce robust IFN production (2, 6, 18). Wild-type VSV inhibits host antiviral responses by globally suppressing host-directed gene expression due to the activity of the viral matrix (M) protein (2,(23)(24)(25). M protein mutant strains of VSV, such as M51R VSV, are severely defective for inhibition of the host antiviral response

Newcastle Disease Virus Establishes Persistent Infection in Tumor Cells In Vitro : Contribution of the Cleavage Site of Fusion Protein and Second Sialic Acid Binding Site of Hemagglutinin-Neuraminidase

“…Similar to other RNA viruses such as measles virus (14), Sendai virus (SeV) (15), mumps virus (16), vesicular stomatitis virus (17,18), parainfluenza virus type 3 (PIV3) (19), and respiratory syncytial virus (RSV) (20), NDV can establish persistent infection under some circumstances, as reported previously (15,21,22). For establishment of persistent infection in vitro, there is normally a fine dynamic equilibrium between virus infection and viral clearance by host innate immune responses.…”

Oncolytic activity of the rhabdovirus VSV‐GP against prostate cancer

“…Although Stojdl et al . showed that around 80% of the tested tumor cell lines had lost the capacity to mount an antiviral response upon IFN‐I exposure, several tumor cell lines are still responsive to IFN‐I . Also in PCa, Dunn et al .…”

“…Although Stojdl et al showed that around 80% of the tested tumor cell lines had lost the capacity to mount an antiviral response upon IFN-I exposure, 12,14 several tumor cell lines are still responsive to IFN-I. 17,29,30 Also in PCa, Dunn et al showed loss of IFN-I response in some cell lines, 31 while other studies have shown that IFN-I induced genes are active and play an important role in protecting cells from VSV infection. 32 Using a larger panel of PCa cell lines, we have now observed considerable heterogeneity in the IFN-I induced antiviral response.…”

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

“…This difference could be due to the threshold for induction of type I IFN signalling being raised in some cancer cells compared to normal cells (e.g. receptor levels, negative regulatory factors) and to IFNb binding with 1000-fold higher affinity to IFNAR than IFN-a2a [32]. Previously, cellular IFN-l (type III IFN) produced during VSV infection was shown to enhance VSV therapy in the B16ova/C57Bl/6 mouse model by activating NK cells against B16ova cells [33].…”