Viruses as anticancer drugs

Russell, Stephen J.; Peng, Kah Whye

doi:10.1016/j.tips.2007.05.005

Cited by 175 publications

(143 citation statements)

References 87 publications

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“…However, VSV causes fatal neurotoxicity when administered intracerebrally to rodents, cattle, goats, and nonhuman primates (Clarke et al, 2006;Johnson et al, 2007). Because VSV is exquisitely sensitive to the antiviral effects of type I interferon, development of interferon-inducing or interferon-expressing VSV has been the primary engineering strategy to attenuate neurovirulence of oncolytic VSV (Russell and Peng, 2007). Investigators generated recombinant VSV that expresses the IFN-b gene (Obuchi et al, 2003) or matrix (M) protein mutants of VSV that are unable to suppress cellular innate immunity (Stojdl et al, 2003;Ahmed et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2010

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Toxicology studies were performed in rats and rhesus macaques to establish a safe starting dose for intratumoral injection of an oncolytic vesicular stomatitis virus expressing human interferon-b (VSV-hIFNb) in patients with hepatocellular carcinoma (HCC). No adverse events were observed after administration of 7.59Â10 9 TCID 50 (50% tissue culture infective dose) of VSV-hIFNb into the left lateral hepatic lobe of Harlan Sprague Dawley rats. Plasma alanine aminotransferase and alkaline phosphatase levels increased and platelet counts decreased in the virus-treated animals on days 1 and 2 but returned to pretreatment levels by day 4. VSV-hIFNb was also injected into normal livers or an intrahepatic McA-RH7777 HCC xenograft established in Buffalo rats. Buffalo rats were more sensitive to neurotoxic effects of VSV; the no observable adverse event level (NOAEL) of VSV-hIFNb in Buffalo rats was 10 7 TCID 50 . Higher doses were associated with fatal neurotoxicity and infectious virus was recovered from tumor and brain. Compared with VSV-hIFNb, toxicity of VSV-rIFNb (recombinant VSV expressing rat IFN-b) was greatly diminished in Buffalo rats (NOAEL, >10 10 TCID 50 ). Two groups of two adult male rhesus macaques received 10 9 or 10 10 TCID 50 of VSV-hIFNb injected directly into the left hepatic lobe under computed tomographic guidance. No neurological signs were observed at any time point. No abnormalities (hematology, clinical chemistry, body weights, behavior) were seen and all macaques developed neutralizing anti-VSV antibodies. Plasma interleukin-6, tumor necrosis factor-a, and hIFN-b remained below detection levels by ELISA. On the basis of these studies, we will be proposing a cautious approach to dose escalation in a phase I clinical trial among patients with HCC.

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Section: Discussionmentioning

confidence: 99%

“…Numerous viruses from diverse families are being investigated as oncolytic agents (Russell and Peng, 2007). The Indiana strain of vesicular stomatitis virus (VSV) and its recombinant derivatives have promising oncolytic activity against a variety of tumor types (Barber, 2004;Lichty et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2010

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“…O ncolytic viruses (OVs) are promising anticancer therapeutics engineered or selected to infect and multiply specifically in tumour cells while having attenuated replication capacity in normal tissues 1,2 . The attenuation of OV growth in normal tissues is often due to the inability of OVs to antagonize normal cellular, interferon (IFN)-mediated antiviral responses.…”

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confidence: 99%

Model-based rational design of an oncolytic virus with improved therapeutic potential

et al. 2013

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Oncolytic viruses are complex biological agents that interact at multiple levels with both tumour and normal tissues. Antiviral pathways induced by interferon are known to have a critical role in determining tumour cell sensitivity and normal cell resistance to infection with oncolytic viruses. Here we pursue a synthetic biology approach to identify methods that enhance antitumour activity of oncolytic viruses through suppression of interferon signalling. On the basis of the mathematical analysis of multiple strategies, we hypothesize that a positive feedback loop, established by virus-mediated expression of a soluble interferon-binding decoy receptor, increases tumour cytotoxicity without compromising normal cells. Oncolytic rhabdoviruses engineered to express a secreted interferon antagonist have improved oncolytic potential in cellular cancer models, and display improved therapeutic potential in tumour-bearing mice. Our results demonstrate the potential of this methodology in evaluating potential caveats of viral immune-evasion strategies and improving the design oncolytic viruses.

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“…Examples include dl922-947, where the E1A binding to the retinoblastoma protein is disrupted, and p53-defective adenovirus, such as dl1520 (Onyx-015). 2,3 However, our strategy is on the basis of the multifunctional protein YB-1, which is involved in transcriptional and translational regulation, mRNA splicing, drug resistance and DNA repair. 4 We could earlier show that YB-1 facilitates E1-independent adenoviral replication by targeting the adenoviral E2-late promoter.…”

Section: Introductionmentioning

confidence: 99%

Adenovirus-based virotherapy enabled by cellular YB-1 expression in vitro and in vivo

et al. 2009

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We have earlier described the oncolytic adenovirus vector dl520 that was rendered cancer-specific by deletion of the transactivation domain CR3 of the adenoviral E1A13S protein; this deletion causes antitumor activity in drug-resistant cells displaying nuclear YB-1 expression. We hypothesized that the anticancer activity of dl520 could be further improved by introducing the RGD motif in the fiber knob and by deletion of the adenoviral E1B19K protein (Ad-Delo3-RGD). In this study, the in vitro and in vivo antitumor activity of Ad-Delo3-RGD was investigated focussing on two pancreatic cancer cell lines MiaPaCa-2 and BxPC3 alone and in combination with cytotoxic drugs. Furthermore, luciferin-based bioluminescence imaging was established to study the therapeutic response in vivo. In addition, to confirm the specificity of Ad-Delo3-RGD for YB-1 a tetracycline-inducible anti-YB-1 shRNA-expressing cell variant EPG85-257RDB/tetR/YB-1 was used. This TetON regulatable expression system allows us to measure adenoviral replication by real-time PCR in the absence of YB-1 expression. The results confirmed the YB-1 dependency of Ad-Delo3-RGD and showed that Ad-Delo3-RGD has potent activity against human pancreatic cancer cells in vitro and in vivo, which was augmented by the addition of paclitaxel. However, although high replication capacity was measured in vitro and in vivo, complete tumor regression was not achieved, indicating the need for further improvements to treat pancreatic cancer effectively.

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Viruses as anticancer drugs

Cited by 175 publications

References 87 publications

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

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

Model-based rational design of an oncolytic virus with improved therapeutic potential

Adenovirus-based virotherapy enabled by cellular YB-1 expression in vitro and in vivo

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