| Title | Safety Studies on Intrahepatic or Intratumoral Injection of Oncolytic Vesicular Stomatitis Virus Expressing Interferon-Beta in Rodents and Nonhuman Primates. | | Author(s) | Jenks N, Myers R, Greiner SM, Thompson J, Mader EK, Greenslade A, Griesmann GE, Federspiel MJ, Rakela J, Borad M, Vile RG, Barber GN, Meier TR, Blanco MC, Carlson SK, Russell SJ, Peng KW | | Institution | Mayo Clinic, Toxicology and Pharmacology Laboratory, Rochester, Minnesota, United States; jenks.nathan@mayo.edu. | | Source | Hum Gene Ther 2009 Nov 13. | | 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-beta (VSV-hIFNbeta) in patients with hepatocellular carcinoma (HCC). No adverse events were observed after administration of 7.59x109 TCID50 VSV-hIFNbeta 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 pre-treatment levels by day 4. VSV-hIFNbeta 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-hIFNbeta in Buffalo rats was 10e7 TCID50. Higher doses were associated with fatal neurotoxicity and infectious virus was recovered from tumor and brain. Compared to VSV-hIFNbeta, toxicity of VSV-rIFNbeta (recombinant VSV expressing rat IFNbeta) was greatly diminished in Buffalo rats (NOAEL >10e10 TCID50). Two groups of two adult male Rhesus macaques received 10e9 or 10e10 TCID50 VSV-hIFNbeta injected directly into the left hepatic lobe under CT 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 IL-6, TNF-alpha and hIFNbbeta remained below detection levels by ELISA. Based on these studies, we will be proposing a cautious approach to dose escalation in a phase I clinical trial among patients with HCC. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19911974 |
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