Resistance of pancreatic cancer cells to oncolytic vesicular stomatitis virus: Role of type I interferon signaling

Moerdyk-Schauwecker, Megan; Shah, Nirav R.; Murphy, Andrea M.; Hastie, Eric; Mukherjee, Pinku; Grdzelishvili, Valery Z.

doi:10.1016/j.virol.2012.11.014

Cited by 96 publications

(180 citation statements)

References 60 publications

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“…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).…”

Section: Discussionmentioning

confidence: 99%

“…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-␤).…”

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confidence: 99%

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Vesiculovirus Neutralization by Natural IgM and Complement

Tesfay

Ammayappan

Federspiel

et al. 2014

J Virol

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Because of its very low human seroprevalence, vesicular stomatitis virus (VSV) has promise as a systemic oncolytic agent for human cancer therapy. However, as demonstrated in this report, the VSV infectious titer drops by 4 log units during the first hour of exposure to nonimmune human serum. This neutralization occurs relatively slowly and is mediated by the concerted actions of natural IgM and complement. Maraba virus, whose G protein is about 80% homologous to that of VSV, is relatively resistant to the neutralizing activity of nonimmune human serum. We therefore constructed and rescued a recombinant VSV whose G gene was replaced by the corresponding gene from Maraba virus. Comparison of the parental VSV and VSV with Maraba G substituted revealed nearly identical host range properties and replication kinetics on a panel of tumor cell lines. Moreover, in contrast to the parental VSV, the VSV with Maraba G substituted was resistant to nonimmune human serum. Overall, our data suggest that VSV with Maraba G substituted should be further investigated as a candidate for human systemic oncolytic virotherapy applications. IMPORTANCEOncolytic virotherapy is a promising approach for the treatment of disseminated cancers, but antibody neutralization of circulating oncolytic virus particles remains a formidable barrier. In this work, we developed a pseudotyped vesicular stomatitis virus (VSV) with a glycoprotein of Maraba virus, a closely related but serologically distinct member of the family Rhabdoviridae, which demonstrated greatly diminished susceptibility to both nonimmune and VSV-immune serum neutralization. VSV with Maraba G substituted or lentiviral vectors should therefore be further investigated as candidates for human systemic oncolytic virotherapy and gene therapy applications.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Vesiculovirus Neutralization by Natural IgM and Complement

Tesfay

Ammayappan

Federspiel

et al. 2014

J Virol

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“…Our recent study analyzed several VSV recombinants in an array of human PDA cell lines in vitro (23,24) and in xenografts in athymic mice (24). These studies demonstrated excellent abilities of VSV recombinants to infect and kill a majority of tested human PDAs and revealed that intact type I IFN signaling in some PDAs was responsible for their resistance to OV therapy (23).…”

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confidence: 99%

Oncolytic Vesicular Stomatitis Virus in an Immunocompetent Model of MUC1-Positive or MUC1-Null Pancreatic Ductal Adenocarcinoma

Hastie

Besmer

Shah

et al. 2013

J Virol

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Vesicular stomatitis virus (VSV) is a promising oncolytic agent against various malignancies. Here, for the first time, we tested VSV in vitro and in vivo in a clinically relevant, immunocompetent mouse model of pancreatic ductal adenocarcinoma (PDA). Our system allows the study of virotherapy against PDA in the context of overexpression (80% of PDA patients) or no expression of human mucin 1 (MUC1), a major marker for poor prognosis in patients. In vitro, we tested three VSV recombinants, wildtype VSV, VSV-green fluorescent protein (VSV-GFP), and a safe oncolytic VSV-⌬M51-GFP, against five mouse PDA cell lines that either expressed human MUC1 or were MUC1 null. All viruses demonstrated significant oncolytic abilities independent of MUC1 expression, although VSV-⌬M51-GFP was somewhat less effective in two PDA cell lines. In vivo administration of VSV-⌬M51-GFP resulted in significant reduction of tumor growth for tested mouse PDA xenografts (؉MUC1 or MUC1 null), and antitumor efficacy was further improved when the virus was combined with the chemotherapeutic drug gemcitabine. The antitumor effect was transient in all tested groups. The developed system can be used to study therapies involving various oncolytic viruses and chemotherapeutics, with the goal of inducing tumor-specific immunity while preventing premature virus clearance.

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“…PCR was carried with the following conditions: reverse transcription at 50 C for 30 min, denaturation at 94 C for 15 min followed by 35 cycles of denaturation at 94 C for 45 s, annealing at 57 C for 45 s, extension at 72 C for 45 s before a final elongation step at 72 C for 8 min. All the primers used for the PCR were previously published and designed to amplify cellular mRNAs by Moerdyk-Schauwecker et al (2012). PCR products were electrophoresed on a 1 % agarose gel with GelRed nucleic acid stain (Biotium) and pictures acquired using Gel Doc EZ Imager (Bio-Rad).…”

Section: Methodsmentioning

confidence: 99%

“…However, so far PDA cells have displayed mixed susceptibility to OVs (Lee et al, 2014;Moerdyk-Schauwecker et al, 2012;Murphy et al, 2012;Wennier et al, 2011), underscoring that virotherapy for tumours which tend to be heterogeneous in nature should not rely on a short list of possible candidates.…”

Section: Introductionmentioning

confidence: 99%

An engineered avian-origin influenza A virus for pancreatic ductal adenocarcinoma virotherapy

Pizzuto

Silic-Benussi

Ciminale

et al. 2016

Journal of General Virology

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Pancreatic ductal adenocarcinoma (PDA) is one of the leading causes of cancer-related deaths worldwide and the development of new treatment strategies for PDA patients is of crucial importance. Virotherapy uses natural or engineered oncolytic viruses (OVs) to selectively kill tumour cells. Due to their genetic heterogeneity, PDA cells are highly variable in their permissiveness to various OVs. The avian influenza A virus (IAV) H7N3 A/turkey/Italy/2962/03 is a potent inducer of apoptosis in PDA cells previously shown to be resistant to other OVs (Kasloff et al., 2014), suggesting that it might be effective against specific subclasses of pancreatic cancer. To improve the selectivity of the avian influenza isolate for PDA cells, here confirmed deficient for IFN response, we engineered a truncation in the NS1 gene that is the major virusencoded IFN antagonist. The recombinant virus (NS1-77) replicated efficiently in PDA cells, but was attenuated in non-malignant pancreatic ductal cells, in which it induced a potent IFN response that acted upon bystander uninfected cancer cells, triggering their death. The engineered virus displayed an enhanced ability to debulk a PDA-derived tumour in xenograft mouse model. Our results highlight the possibility of selecting an IAV strain from the diverse natural avian reservoir on the basis of its inherent oncolytic potency in specific PDA subclasses and, through engineering, improve its safety, selectivity and debulking activity for cancer treatment.

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Resistance of pancreatic cancer cells to oncolytic vesicular stomatitis virus: Role of type I interferon signaling

Cited by 96 publications

References 60 publications

Vesiculovirus Neutralization by Natural IgM and Complement

Vesiculovirus Neutralization by Natural IgM and Complement

Oncolytic Vesicular Stomatitis Virus in an Immunocompetent Model of MUC1-Positive or MUC1-Null Pancreatic Ductal Adenocarcinoma

An engineered avian-origin influenza A virus for pancreatic ductal adenocarcinoma virotherapy

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