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Interleukin 2 Gene Transfer Prevents NKG2D Suppression and Enhances Antitumor Efficacy in Combination with Cisplatin for Head and Neck Squamous Cell Cancer¹

Department of Otolaryngology-Head and Neck Surgery [D. L., B. R., M. G., S. L., B. W. O.], Greenebaum Cancer Center [D. L., D. A. V. E., B. W. O.], and Department of Medicine [D. A. V. E.], University of Maryland School of Medicine, Baltimore, Maryland 21201, and Valentis, Inc., The Woodlands, Texas 77381 [J. S. B.]

Cisplatin has been the most promising single chemotherapeutic agent usedagainst head and neck squamous cell cancer to date. However, dose-related toxicity has been one of the major limiting factors in cisplatin-based therapies, because high doses are required for obtaining a significant antitumor effect. To face the challenge of this limiting factor, a novel interleukin 2 (IL-2)-based combination strategy has been developed. Here we show that the strategy of combination of cisplatin with nonviral IL-2 gene therapy resulted in significant antitumor effects while avoiding dose-limiting toxicity in a head and neck squamous cell cancer murine model. Cisplatin systemic therapy alone suppressed NKG2D expression in lymphocytes. The use of local regional IL-2 gene transfer prevented NKG2D suppression. The combination strategy demonstrated a clear synergistic interaction between cisplatin and IL-2, and NKG2D-based cytotoxicity manifested by increased tumor specific lysis from CTLs and natural killer cells. Moreover, the combination of cisplatin and IL-2 gene therapy greatly enhanced apoptosis and growth inhibition in the treated tumors. This novel combination strategy holds promise for the treatment of head and neck cancer, and the mechanism of NKG2D in activating natural killer and CTL receptors provides a foundation for additional investigation, and development of immune modulation and chemotherapy regimens.

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