VSV strains with defects in their ability to shutdown innate immunity are potent systemic anti-cancer agents

Stojdl, David F.; Lichty, Brian D.; tenOever, Benjamin R.; Paterson, Jennifer M; Power, Anthony; Knowles, Shane; Marius, Ricardo; Reynard, Jennifer; Poliquin, Laurent; Atkins, Harold L.; Brown, Earl G.; Durbin, Russell K.; Durbin, Joan E.; Hiscott, John; Bell, John C.

doi:10.1016/s1535-6108(03)00241-1

Cited by 744 publications

(899 citation statements)

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“…Amplified product was digested with Xho1/Xba1 and ligated into the Xho1/Nhe1 unique site between the G and L viral genes of the VSV genome-expressing vector harboring the methionine 51 deletion in the M-coding sequence. 6 Infectious recombinant VSV was recovered as described previously. 14 VSV-GFP and VSV-Luc are recombinant VSV-MD51 containing green fluorescent protein (GFP) or GFP::Firefly Luciferase gene insertion between the G and L viral genes and were kindly provided by Dr John Bell (Ottawa Cancer Centre, Ottawa, ON).…”

Section: Methodsmentioning

confidence: 99%

“…VSV is exquisitely sensitive to type 1 interferon-mediated antiviral responses in untransformed cells, and consequently its selective oncotropism is attributed to the innate antiviral response suppression in tumor cells. [4][5][6][7] Although successful tumor eradication and tumor growth delay have been reported in animal models following treatment with OVs, several cancer models remain partially or completely resistant to viral oncolysis. Barriers to effective tumor oncolysis include intrinsic resistance of tumor cells to infection, limited tumor cell death induced by direct viral replication and inefficient viral spreading within the tumor mass.…”

Section: Introductionmentioning

confidence: 99%

“…6 Because of the altered M protein, VSV-MD51 no longer blocks the nuclear export of host RNA encoding antiviral proteins, including multiple species of interferons, and thus triggers a stronger interferon response in normal tissues that inhibits VSV infection, whereas VSV replication in interferon-defective tumor cells is not altered. 4,6,23,24 In the present study we merged the attributes of VSV-MD51 with the CD::UPRT/5FC suicide gene system and further improved the previously reported VSV-CD::UPRT strategy. 22 Recombinant VSV-MD51 engineered to express CD::UPRT in combination with 5FC increased cancer cell killing in vitro in VSV-resistant cell lines and in a viral dissemination blocking model.…”

Section: Introductionmentioning

confidence: 99%

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Enhancing VSV oncolytic activity with an improved cytosine deaminase suicide gene strategy

Léveillé

Samuel

et al. 2011

Cancer Gene Ther

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Oncolytic viruses (OVs) are promising therapeutic agents for cancer treatment, with recent studies emphasizing the combined use of chemotherapeutic compounds and prodrug suicide gene strategies to improve OV efficacy. In the present study, the synergistic activity of recombinant vesicular stomatitis virus (VSV)-MD51 virus expressing the cytosine deaminase/uracil phosphoribosyltransferase (CD::UPRT) suicide gene and 5-fluorocytosine (5FC) prodrug was investigated in triggering tumor cell oncolysis. In a panel of VSV-sensitive and -resistant cells-prostate PC3, breast MCF7 and TSA, B-lymphoma Karpas and melanoma B16-F10-the combination treatment increased killing of non-infected bystander cells in vitro via the release of 5FC toxic derivatives. In addition, we showed a synergistic effect on cancer cell killing with VSV-MD51 and the active form of the drug 5-fluorouracil. Furthermore, by monitoring VSV replication at the tumor site and maximizing 5FC bioavailability, we optimized the treatment regimen and improved survival of animals bearing TSA mammary adenocarcinoma. Altogether, this study emphasizes the potency of the VSV-CD::UPRT and 5FC combination, and demonstrates the necessity of optimizing each step of a multicomponent therapy to design efficient treatment.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Enhancing VSV oncolytic activity with an improved cytosine deaminase suicide gene strategy

Léveillé

Samuel

et al. 2011

Cancer Gene Ther

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“…17,18 Earlier studies have demonstrated the feasibility of isolating VSV mutants with strong IFN-inducing phenotypes, 19 with many of these mutants containing point mutations in their M proteins, including the M51R mutation originally found in the ts082 and T1026R1 mutant viruses. 20 Recently, Stojdl et al 21 demonstrated that VSV M mutants with a single amino-acid (M51R) or two amino-acid (V221F and S226R) substitutions are attenuated in mice because of their potent induction of IFN but retain antitumor activity in vitro and in several animal tumor models, even when applied systemically. 21 In an alternative approach, Obuchi et al 22 have created a recombinant VSV (rVSV) expressing the IFN-b gene with enhanced selectivity for tumor cells in tissue culture and in vivo.…”

mentioning

confidence: 99%

“…20 Recently, Stojdl et al 21 demonstrated that VSV M mutants with a single amino-acid (M51R) or two amino-acid (V221F and S226R) substitutions are attenuated in mice because of their potent induction of IFN but retain antitumor activity in vitro and in several animal tumor models, even when applied systemically. 21 In an alternative approach, Obuchi et al 22 have created a recombinant VSV (rVSV) expressing the IFN-b gene with enhanced selectivity for tumor cells in tissue culture and in vivo.…”

mentioning

confidence: 99%

Systemic therapy of experimental breast cancer metastases by mutant vesicular stomatitis virus in immune-competent mice

et al. 2004

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In view of the limited success of available treatment modalities for metastatic breast cancer, alternative and complementary strategies need to be developed. Oncolytic vesicular stomatitis virus (VSV) is a promising novel therapeutic agent for the treatment of cancer. The aim of this study was to evaluate the potential of recombinant VSV containing the M51R mutation in the matrix (M) protein gene administered intravenously as an effective and safe therapeutic agent for treating mice with experimental breast cancer metastases. Recombinant VSV(M51R)-LacZ was generated and characterized in vitro on human and murine breast cancer cells. Breast cancer metastases were established in immune-competent Balb/c mice by intravenous injection of syngeneic 4T1 cells. The vector was infused into the tumor-bearing animals via the tail vein, and productive infection of pulmonary breast cancer lesions was assessed by X-gal stainings of frozen lung sections. To evaluate potential systemic toxicity, histology of major organs and serum chemistries were analyzed. To assess effectiveness, buffer-or vector-treated tumor-bearing mice were followed for survival and the results were analyzed by the Kaplan-Meier method and the log-rank test. We found that VSV(M51R)-LacZ efficiently replicated and lysed human breast cancer cells but was partially attenuated in 4T1 cells in vitro. We also demonstrated that its maximum tolerated dose after intravenous infusion in normal Balb/c mice was elevated by at least 100-fold over that of the parental VSV vector containing the wild-type M gene. When VSV(M51R)-LacZ was repeatedly injected intravenously into mice bearing syngeneic 4T1 tumors, the virus was able to infect multiple breast cancer lesions in the lungs without apparent toxicities, which led to significant prolongation of animal survival (P ¼ .003). In conclusion, systemic administration of M mutant VSV is both effective and safe in the treatment of experimental breast cancer metastases in immune-competent mice, suggesting that further development of this approach may have potential for clinical application in patients.

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Gene and Viral Therapy

Spurrell¹

2007

The Cancer Handbook

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The aim of gene therapy is to treat cancer by the introduction of genes that will sensitize tumour cells to other therapies, replace a mutated gene with a wild‐type copy, or activate an antitumour host immune response. Viruses can be used as vectors for carrying therapeutic transgenes, as well as being oncolytic in their own right. Using viruses to treat tumours derives from the inherent ability of a replicating virus to eventually destroy its host cell. Oncolytic viruses are tumour specific, causing lysis of tumour cells and not normal cells. There are viruses that are naturally tumour specific and viruses that have been engineered to become tumour specific. More recently, there has been increasing interest in the development of non‐viral vectors as gene therapy carriers. The benefits of using non‐viral vectors is that they are less likely to elicit an unwanted immune response, there is no risk of recombination, and they are easier to produce on a large scale. There are two main types of non‐viral gene delivery method—physical and via a chemical carrier. Both viral and non‐viral vectors have entered human phase I and II clinical trials in patients with a variety of solid tumour malignancies.

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VSV strains with defects in their ability to shutdown innate immunity are potent systemic anti-cancer agents

Cited by 744 publications

References 49 publications

Enhancing VSV oncolytic activity with an improved cytosine deaminase suicide gene strategy

Enhancing VSV oncolytic activity with an improved cytosine deaminase suicide gene strategy

Systemic therapy of experimental breast cancer metastases by mutant vesicular stomatitis virus in immune-competent mice

Gene and Viral Therapy

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