Evaluation of Long-Term Toxicity of Ad/hIFN-γ, an Adenoviral Vector Encoding the Human Interferon-γGene, in Nonhuman Primates

Abstract

Interferon-gamma(IFN-gamma) plays an important role in the immunomodulation and growth inhibition of many tumor cells, but its clinical application is limited by its systemic toxicity. Ad/hIFN-gamma, a nonreplicating adenoviral vector encoding human IFN-gamma, has been reported to inhibit tumor growth in vitro and in a xenograft model. In this study, the long-term toxicity of Ad/hIFN-gamma was assessed in cynomolgus macaques (Macaca fascicularis). Thirty animals were enrolled into 5 groups, and administered intramuscularly, respectively, Ad/hIFN-gamma (3.3 x 10(10), 3.3 x 10(11), or 3.3 x 10(12) VP/kg), Ad/LacZ (vector control, 3.3 x 10(11) VP/kg), or excipient 3 times per week for 8 weeks, followed by a 4-week recovery period. At 12 weeks all experimental animals appeared generally healthy, and there were no statistically significant differences in body weight, urinalysis, hemogram, blood biochemistry, and electrocardiogram results between the treatment and control groups. No significant toxic effects were noted on macroscopic and microscopic examinations of organs and tissues. Preliminary investigation of the immunotoxicity of Ad/IFN-gamma indicated that anti-adenoviral and anti-hIFN-gamma antibodies were generated. These data demonstrate that long-term, high-dose intramuscular administration of Ad/IFN-gamma was not notably toxic and might be safe for clinical therapeutic use.

Co-expression of ING4 and P53 enhances hypopharyngeal cancer chemosensitivity to cisplatin in vivo

“…The present study demonstrated that the Ad, Ad-ING4-P53, and Ad-ING4-P53 + cisplatin groups exhibited liver toxicity, however they exerted no effect on kidney cells, consistent with previous demonstrations that adenoviral vectors damage liver function ( 36 , 37 ). Haisma et al ( 38 ) demonstrated that liver toxicity arises from removal of Kupffer cells by adenoviral vectors, potentially as an immune response to the virus and its transduction gene products ( 39 ).…”

Biosafety studies of carrier cells infected with a replication-competent adenovirus introduced by IAI.3B promoter

“…To enable clinical trials of type 5 adenovirus vectors to be undertaken, toxicity tests were reported in mice, 14 dogs, 15 and monkeys 16 for nonreplicative vectors, and in mice 17 and cats 18 for replicative vectors to establish the safety of these vectors. The safety and efficacy of autologous and allogeneic cell-based adenoviral vector GVAX vaccines have been reported in non–small-cell lung cancer, 19 but toxicity studies in experimental animals have not yet been reported.…”

Gene doping detection: evaluation of approach for direct detection of gene transfer using erythropoietin as a model system

“…As summarized in Table 5, following intramuscular or intravenous delivery, rAAV or recombinant adenoviral vector was detected in serum or blood within several days and in peripheral blood mononuclear cells up to 10 months at levels significantly exceeding the minimal amounts detectable by the assays developed in our study. [15][16][17][18][19] Comparing performance parameters of assays 1, 2 and 3 with data from gene therapy clinical trials and animal studies for which details of a method for vectors detection and results on vector persistence are available ( Table 5), we concluded that direct detection of gene doping through gene transfer using the approach developed and tested in this project is feasible. As evidenced from the referenced papers, viral and nonviral vectors could be detected in blood components days, weeks and sometimes even months after vector transfer using PCR methods whose sensitivity was similar or lower (between several or hundred(s) times) than that of assays 1, 2 and 3.…”