Gene gun-mediated IL-12 gene therapy induces antitumor effects in the absence of toxicity: A direct comparison with systemic IL-12 protein therapy

Using three murine tumor models, we compared the antitumor efficacy and cer tain physiological effects of an in vivo interleukin-12 (IL-12) gene therap y protocol and a systemic IL-12 protein therapy protocol. An IL-12 cDNA gen e construct was administered in situ into skin tissue via gene gun delivery , and recombinant IL-12 protein was administered subcutaneously at a dose o f 1 mu g/mouse/treatment. Both treatment regimes induced a comparable level of regression of established intradermal MethA sarcomas. In B16 melanoma a nd P815 mastocytoma models, antitumor efficacy of IL-12 protein therapy app eared to be slightly higher than that of IL-12 gene therapy; however, the p rotein therapy protocol in this comparative study resulted in a high level of mortality of mice. It was also demonstrated that IL-12 gene therapy, in contrast to the IL-12 protein therapy, was not associated with weight loss, splenomegaly, increased Ly6 antigen expression in the spleen, or visible s igns of toxicity, such as fur ruffling and lethargy. Moreover, serum levels of interferon-gamma (IFN-gamma) induced in response to IL-12 gene therapy were 300-1000 times lower than those induced by the systemic IL-12 protein administration. Together, these results suggest that gene gun-mediated in v ivo delivery of IL-12 cDNA may be considered as a safer alternative to IL-1 2 protein therapy for certain human cancers.