Safety studies on intrahepatic or intratumoral injection of oncolytic vesicular stomatitis virus expressing interferon-β in rodents and nonhuman primates

Nathan Jenks, Rae Myers, Suzanne M. Greiner, Jill Thompson, Emily K. Mader, Andrew Greenslade, Guy E. Griesmann, Mark J. Federspiel, Jorge Rakela, Mitesh J. Borad, Richard G. Vile, Glen N. Barber, Thomas R. Meier, Michael C. Blanco, Stephanie K. Carlson, Stephen J. Russell, Kah Whye Peng

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

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-β (VSV-hIFNβ) in patients with hepatocellular carcinoma (HCC). No adverse events were observed after administration of 7.59×109 TCID50 (50% tissue culture infective dose) of VSV-hIFNβ 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-hIFNβ 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-hIFNβ in Buffalo rats was 107 TCID50. Higher doses were associated with fatal neurotoxicity and infectious virus was recovered from tumor and brain. Compared with VSV-hIFNβ, toxicity of VSV-rIFNβ (recombinant VSV expressing rat IFN-β) was greatly diminished in Buffalo rats (NOAEL, >1010 TCID50). Two groups of two adult male rhesus macaques received 109 or 10 10 TCID50 of VSV-hIFNβ 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-α, and hIFN-β 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.

Original languageEnglish (US)
Pages (from-to)451-462
Number of pages12
JournalHuman gene therapy
Volume21
Issue number4
DOIs
StatePublished - Apr 1 2010

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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    Jenks, N., Myers, R., Greiner, S. M., Thompson, J., Mader, E. K., Greenslade, A., Griesmann, G. E., Federspiel, M. J., Rakela, J., Borad, M. J., Vile, R. G., Barber, G. N., Meier, T. R., Blanco, M. C., Carlson, S. K., Russell, S. J., & Peng, K. W. (2010). Safety studies on intrahepatic or intratumoral injection of oncolytic vesicular stomatitis virus expressing interferon-β in rodents and nonhuman primates. Human gene therapy, 21(4), 451-462. https://doi.org/10.1089/hum.2009.111