IN-VIVO GENE-THERAPY OF A MURINE PANCREAS TUMOR WITH RECOMBINANT VACCINIA VIRUS ENCODING HUMAN INTERLEUKIN-1BETA

Background. Recombinant vaccinia virus (VV) encoding human interleukin -1 beta (vMJ601hIL-1 beta) given intravenously persists in tumor tissu e and expresses hIL-1 beta for at feast 9 days after treatment and is associated with significant retardation of tumor growth. To doc ument the significance of this approach and to further elucidate the mechani sm, this study compares the antitumor effect of vIMJ601hIL-1 beta admi nistered either intravenously or intratumorally and intravenous recomb inant hIL-1 beta protein. Methods, C57BL/6 mice with established subcu taneous pancreatic tumors were randomized to treatment with intravenou s or intratumoral vMJ601hIL-1 beta, wild-type W, saline solution or in travenous recombinant hIL-1 beta protein in a blinded fashion. Toxicit y and tumor size were measured. Data were analyzed with the Kruskal-Wa llis and Wilcoxon tests. Results, Treatment with intratumoral vMJ601hI L-1 beta repeatedly resulted in significant reduction in tumor size as compared with saline treated controls (p < 0.001). Tumor growth inhib ition was consistently similar after intravenous or intratumoral vMJ60 1hIL-1 beta administration (p > 0.52). Wild-type W given intratumorall y or intravenously had no antitumor effect versus saline controls (p > 0.30). No significant toxicity or deaths resulted from vMJ601hIL-1 be ta treatment. Recombinant hIL-1 beta protein administered intravenousl y caused severe toxicity (median lethal dose approximate to 100 mu g/g ), 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 W given intravenousl y or intratumorally results in significant tumor growth inhibition, wh ich appears to be a consequence of local, intratumoral vaccinia infect ion and production of hIL-1 beta.