Impact of Preimmunization on Adenoviral Vector Expression and Toxicity in a Subcutaneous Mouse Cancer Model
Authors: Maria T. Vlachaki, Andres Hernandez-Garcia, Michael Ittmann, Madhu Chhikara, Laura K. Aguilar, Xiaohong Zhu, Bin S. The, E.Brian Butler, Shiao Woo, Timothy C. Thompson, Hugo Barrera-Saldana, Estuardo Aguilar-Cordova
Journal: Molecular Therapy (2002)

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 naı¨ve 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. 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 naı¨ve 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.