In vivo gene therapy of a murine pancreas tumor with recombinant vaccinia virus encoding human interleukin-1 beta.

摘要

BACKGROUND. Recombinant vaccinia virus (VV) encoding human interleukin-1 beta (vMJ601hIL-1 beta) given intravenously persists in tumor tissue and expresses hIL-1 beta for at least 9 days after treatment and is associated with significant retardation of tumor growth. To document the significance of this approach and to further elucidate the mechanism, this study compares the antitumor effect of vMJ601hIL-1 beta administered either intravenously or intratumorally and intravenous recombinant hIL-1 beta protein. METHODS. C57BL/6 mice with established subcutaneous pancreatic tumors were randomized to treatment with intravenous or intratumoral vMJ601hIL-1 beta, wild-type VV, saline solution, or intravenous recombinant hIL-1 beta protein in a blinded fashion. Toxicity and tumor size were measured. Data were analyzed with the Kruskal-Wallis and Wilcoxon tests. RESULTS. Treatment with intratumoral vMJ601hIL-1 beta repeatedly resulted in significant reduction in tumor size as compared with saline treated controls (p < 0.001). Tumor growth inhibition was consistently similar after intravenous or intratumoral vMJ601hIL-1 beta administration (p > 0.52). Wild-type VV given intratumorally or intravenously had no antitumor effect versus saline controls (p > 0.30). No significant toxicity or deaths resulted from vMJ601hIL-1 beta treatment. Recombinant hIL-1 beta protein administered intravenously caused severe toxicity (median lethal dose approximately 100 micrograms/kg), and no significant antitumor effect was observed at sublethal doses versus saline controls (p = 0.19). CONCLUSIONS. Direct, in vivo hIL-1 beta gene delivery and expression by recombinant VV given intravenously or intratumorally results in significant tumor growth inhibition, which appears to be a consequence of local, intratumoral vaccinia infection and production of hIL-1 beta.