TY - JOUR
T1 - Impact of preimmunization on adenoviral vector expression and toxicity in a subcutaneous mouse cancer model
AU - Vlachaki, Maria T.
AU - Hernandez-Garcia, Andres
AU - Ittmann, Michael
AU - Chhikara, Madhu
AU - Aguilar, Laura K.
AU - Zhu, Xiaohong
AU - The, Bin S.
AU - Butler, Edward Brian
AU - Woo, Shiao
AU - Thompson, Timothy C.
AU - Barrera-Saldana, Hugo
AU - Aguilar-Cordova, Estuardo
N1 - Funding Information:
This work was supported by a Specialized Program of Research Excellence (SPORE) Grant (CA58204) from the National Cancer Institute, by a Merit Review Award, by the Department of Veterans Affairs, and by Advantagene, Inc. (San Diego, CA).
PY - 2002/9/1
Y1 - 2002/9/1
N2 - Immune responses against adenoviral vectors may influence the toxicity and therapeutic effectiveness of adenovirus-mediated gene transfer and may be a limiting factor in adenovirus-mediated gene therapy. The purpose of this study was to determine the effects of preimmunization on intratumoral adenoviral transduction and systemic spread. The hypothesis was that increased doses of adenoviral vectors could overcome local neutralization without added systemic toxicity. The level and duration of gene expression were assessed as a function of time and dose after intratumoral delivery of adenoviral vector (AdV) encoding the luciferase reporter gene (AdV-luc) in a subcutaneous mouse mammary tumor model. Preimmunization resulted in significantly decreased gene expression in tumor and normal tissues (P < 0.01). The decrease was significantly greater in liver than in tumor. Increased AdV doses could be used to overcome the intratumoral inhibition without a concomitant increase in liver transduction. However, preimmunized animals showed greater toxicity than naïve animals (P < 0.001). The preimmunized group developed histologic evidence of grade 2-3 hepatic toxicity and increases in the average values of hepatic enzymes. In addition, there was a significant increase in mortality (P < 0.01) in the preimmunized group (12 of 20 animals) compared with the naive group (3 of 20 animals). These findings suggest that although preimmunity can inhibit systemic expression from adenoviral vectors, at high vector doses it may potentiate hepatotoxicity.
AB - Immune responses against adenoviral vectors may influence the toxicity and therapeutic effectiveness of adenovirus-mediated gene transfer and may be a limiting factor in adenovirus-mediated gene therapy. The purpose of this study was to determine the effects of preimmunization on intratumoral adenoviral transduction and systemic spread. The hypothesis was that increased doses of adenoviral vectors could overcome local neutralization without added systemic toxicity. The level and duration of gene expression were assessed as a function of time and dose after intratumoral delivery of adenoviral vector (AdV) encoding the luciferase reporter gene (AdV-luc) in a subcutaneous mouse mammary tumor model. Preimmunization resulted in significantly decreased gene expression in tumor and normal tissues (P < 0.01). The decrease was significantly greater in liver than in tumor. Increased AdV doses could be used to overcome the intratumoral inhibition without a concomitant increase in liver transduction. However, preimmunized animals showed greater toxicity than naïve animals (P < 0.001). The preimmunized group developed histologic evidence of grade 2-3 hepatic toxicity and increases in the average values of hepatic enzymes. In addition, there was a significant increase in mortality (P < 0.01) in the preimmunized group (12 of 20 animals) compared with the naive group (3 of 20 animals). These findings suggest that although preimmunity can inhibit systemic expression from adenoviral vectors, at high vector doses it may potentiate hepatotoxicity.
KW - Adenovirus
KW - Gene therapy
KW - Preimmunization
KW - Toxicity
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U2 - 10.1006/mthe.2002.0669
DO - 10.1006/mthe.2002.0669
M3 - Article
C2 - 12231170
AN - SCOPUS:0036765084
VL - 6
SP - 342
EP - 348
JO - Molecular therapy : the journal of the American Society of Gene Therapy
JF - Molecular therapy : the journal of the American Society of Gene Therapy
SN - 1525-0016
IS - 3
ER -