Systemic vector leakage and transgene expression by intratumorally injected recombinant adenovirus vectors

Interleukin 12 is a heterodimeric cytokine that exhibits potent immunostimu latory effects. It has shown some promise in preclinical and clinical studi es but was accompanied by serious systemic toxicity such as flu-like syndro mes, a rapid transient leukopenia, elevated liver transaminases, gastrointe stinal toxicity, and/or liver dysfunction. Gene therapy with intratumorally injected recombinant adenoviral vectors offers the potential to restrict t herapeutic gene expression in the tumor. Here we show that a substantial am ount of adenoviral vectors disseminates into the systemic circulation and i nfects parenchymal organs. We further show that this results in high system ic levels of potentially toxic transgene products. To reduce potential toxi city, we tested an inducible promoter based on the heat shock proteins (hsp 70B) and present evidence that high intratumoral levels of a therapeutic tr ansgene can be obtained while systemic expression is reduced to a minimum, increasing the safety of adenovirus-based tumor gene therapy.