Intratumor murine interleukin-12 gene therapy suppressed the growth of local and distant Ewing's sarcoma

We evaluated the effect of interleukin-12 (IL-12) gene therapy using an Ewing's sarcoma animal model in T-cell-deficient nude mice. Subcutaneous injection of TC71 cells resulted in tumor development by day 5. Mice were treated with a single intratumor injection of adenovirus b-galactosidase (Ad. beta-gal) or adenovirus murine IL-12 (Ad.mIL-12) (2 x 10(9) PFU) and killed 1-7 days later. Reverse transcriptase-polymerase chain reaction analysis of tumor tissue demonstrated peak expression of IL-12 p35 and p40 at 48 h, which persisted up to 7 days. For in vivo therapy, mice received intratumor Ad.beta-gal or Ad. mIL-12 twice weekly for 2.5 weeks starting on day 6. Ad. mIL-12-treated tumors were significantly smaller (median volume, 19.7mm(3); range, 3.41 - 159.5mm(3)) than Ad.beta-gal-treated tumors (median volume, 3214.9mm(3); range 1679.9 - 5909.8mm(3), P < 0.003) on day 31. The weight of Ad. mIL-12-treated tumors was also lighter than the Ad.beta-gal-treated tumors (median, 2 mg; range, 1 - 5mg versus median, 1960 mg; range 1640 - 5230 mg, P < 0.01). Ad. mIL-12 therapy significantly prolonged the survival time and also inhibited the growth of an untreated tumor on the contralateral side. Immunohistochemistry analysis of the IL-12-treated tumors demonstrated IL-12 expression with increased Fas, Fas ligand and tumor cell apoptosis. CD31 and vascular endothelial growth factor expression were decreased. These data suggest that IL-12 gene therapy may be useful in the treatment of Ewing's sarcoma.