Safety studies on intrahepatic or intratumoral injection of oncolytic vesicular stomatitis virus expressing interferon-beta in rodents and nonhuman primates.
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 7.59 x 10(9) TCID(50) (50% tissue culture infective dose) of 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 pretreatment 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 10(7) TCID(50). Higher doses were associated with fatal neurotoxicity and infectious virus was recovered from tumor and brain. Compared with VSV-hIFNbeta, toxicity of VSV-rIFNbeta (recombinant VSV expressing rat IFN-beta) 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-hIFNbeta 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-alpha, and hIFN-beta 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.
Jenks
Nathan
N
Toxicology and Pharmacology Laboratory, Mayo Clinic, Rochester, MN 55905, USA.
Myers
Rae
R
Greiner
Suzanne M
SM
Thompson
Jill
J
Mader
Emily K
EK
Greenslade
Andrew
A
Griesmann
Guy E
GE
Federspiel
Mark J
MJ
Rakela
Jorge
J
Borad
Mitesh J
MJ
Vile
Richard G
RG
Barber
Glen N
GN
Meier
Thomas R
TR
Blanco
Michael C
MC
Carlson
Stephanie K
SK
Russell
Stephen J
SJ
Peng
Kah-Whye
KW
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000628:therapy / Q000821:virology*; D002522:Chlorocebus aethiops; D004333:Drug Administration Routes; D005260:Female; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000009:adverse effects*; D006801:Humans; D016899:Interferon-beta / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000473:pathology / Q000821:virology*; D008114:Liver Neoplasms, Experimental / Q000628:therapy / Q000821:virology*; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome; D014709:Vero Cells; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D016899:Interferon-beta