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Development of an adenovirus vector with tetracycline-regulatable human tumor necrosis factor alpha gene expression.

Tumor necrosis factor alpha (TNF-alpha) is a multifunctional cytokine with direct antitumor activity. However, clinical trials using TNF-alpha for cancer treatment have been disappointing due in part to its severe side effects, and it has been estimated that TNF-alpha therapy would be effective only at 5-25 times the maximum tolerated dose. We have recently modified a tetracycline (Tc) repressor/operator-based mammalian gene expression system and have generated a Tc-responsive recombinant adenovirus vector, AdVtTA.TNF-alpha. A variety of human tumor cells and T lymphocytes transduced by AdVtTA.TNF-alpha secreted high-titer (5,000-100,000 pg/10(6) cells/24 h) and biologically active TNF-alpha in the absence of Tc. Expression of TNF-alpha in the transduced cells was nondetectable when the culture medium contained as little as 0.1 microg/ml of Tc. At least a fraction of the clonogenic cells from human peripheral blood stem cell concentrates were also transducible by AdVtTA.TNF-alpha. The availability of this type of adenovirus vector opens a door to tumor- or organ-specific delivery of high-dose TNF-alpha and other therapeutic gene products for systemic cancer gene therapy.