Tumor-specific gene delivery using recombinant vaccinia virus in a rabbit model of liver metastases

Background: Several approaches to gene therapy for cancer have yielded prom ising results in rodent models. The translation of these results to the cli nical realm has been delayed by the lack of tumor models in large animals W e investigated the pattern of transgene (i.e., foreign or introduced gene) expression and virus vector elimination after systemic gene delivery using a thymidine kinase-negative vaccinia virus in a rabbit model of disseminate d liver metastases. Methods: VX-2 rabbit carcinoma cells were maintained by serial transplantation in the thigh muscles of New Zealand White rabbits, and disseminated liver metastases were established by direct injection of t umor cells into the portal vein of the animals. Different doses of a recomb inant thymidine kinase-negative vaccinia virus vector encoding the firefly luciferase reporter gene (i.e., transgene) were injected into tumor-bearing rabbits, Transgene activity in tumors and other organs was measured at mul tiple time points thereafter, The pattern of development of antibodies agai nst the vaccinia virus vector was also examined. Two-tailed Student's paire d t test was used for comparisons of transgene activity, Results: Transgene expression was increased in tumors by at least 16-fold in comparison with expression in other tissues by day 4 after vector injection (all P<.001) an d was maintained for approximately 1 meek, providing evidence of tumor-spec ific gene delivery in this model. Rapid elimination of the circulating vect or by the host immune system was observed. Anti-vector antibodies were dete ctable in serum as early as day 6 and were maintained for more than 3 month s. Conclusions: Tumor-specific gene delivery is possible after systemic inj ection of a thymidine kinase-negative vaccinia virus vector in a model of r abbit liver metastases, Al-though the period of transgene expression appear s limited because of a rapid immune response, the therapeutic window might be sufficient for an enzyme/prodrug gene therapy approach in clinical appli cation.