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Development of an Adenovirus Vector with Tetracycline-regulatable Human Tumor Necrosis Factor Gene Expression¹

Departments of Molecular Oncology [W. J., Y. Z. H-J. X.] and Hematology [S-X. H.], University of Texas M. D. Anderson Cancer Center, The Woodlands, Texas 77381, and Department of Genitourinary Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 [C. L.]

Tumor necrosis factor (TNF-) is a multifunctional cytokine with direct antitumor activity. However, clinical trials using TNF- for cancer treatment have been disappointing due in part to its severe side effects, and it has been estimated that TNF- 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-. A variety of human tumor cells and T lymphocytes transduced by AdVtTA.TNF- secreted high-titer (5,000–100,000 pg/10⁶ cells/24 h) and biologically active TNF- in the absence of Tc. Expression of TNF- in the transduced cells was nondetectable when the culture medium contained as little as 0.1 µg/ml of Tc. At least a fraction of the clonogenic cells from human peripheral blood stem cell concentrates were also transducible by AdVtTA.TNF-. The availability of this type of adenovirus vector opens a door to tumor- or organ-specific delivery of high-dose TNF- and other therapeutic gene products for systemic cancer gene therapy.

¹ Supported in part by NIH Grant CA67274, the Texas Higher Education Coordinating Board Grant ATP 4949018, and the CaPCure Research Foundation. S-X. H. and W. J. contributed equally to this work.

² To whom request for reprints should be addressed, at Department of Molecular Oncology, University of Texas M. D. Anderson Cancer Center, 4000 Research Forest Drive, The Woodlands, TX 77381.

Received 5/28/97. Accepted 6/30/97.

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