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We previously demonstrated that the growth of Her-2/neu-overexpressing tumors could be effectively suppressed by the administration of plasmid DNA encoding a part of Her-2/neu (HM) and GM-CSF (pCK-HM-GMCSF) (Int. J. Cancer (2004) 111:86-95). The follow-up studies showed that the anti-Her-2/neu immune responses could be enhanced by combining adenovirus
expressing HM (Ad-HM) with pCK-HM-GMCSF. To investigate the feasibility of this combined treatment in humans, its potency and safety were evaluated in large animals such as beagle dogs and cynomolgus monkeys. Beagle dogs were intramuscularly sequentially administered with pCK-HM-GMCSF and Ad-HM. The anti-Her-2/neu antibody titer was rapidly increased just after the last injection and reached the peak value 2 or 3 weeks post-injection. Repeated plasmid DNA injection could successfully boost humoral immune responses and maintain the high titer for more than one year. Furthermore, Her-2/neu-specific IFN-gamma production was detected in both peripheral blood mononuclear cells and splenocytes of immunized beagle dogs. In order to
investigate which the combined treatment could break the immune tolerance, cynomolgus monkeys were administered as described above. The production of anti-Her2/neu antibodies, Herceptin-inhibition ability of the antibodies, and ADCC activities were demonstrated. In addition to humoral immune responses, the cellular immune responses were also analyzed using T cell proliferation assay, cytotoxic T lymphocyte assay, and IFN-gamma ELISA. All assays revealed that this gene-based cancer vaccine induced Her-2/neu-specific potent cellular immune activities (Gene Ther (2008) 15:1351-1360). In order to determine the safety of the combined
treatment, we did a range of studies such as single-administration toxicity, repeated-administration toxicity, genotoxicity, and immunotoxicity. These studies did not show any material-related toxicity including autoimmune responses against host DNA, changes of lymphocytes population, hepatotoxicities, and cardiac toxicities. These results demonstrated both the efficacy and the safety of this combined treatment against Her-2/neu and strongly supported the feasibility of its use in humans.