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A Direct Comparison of Immunological and Clinical Effects of Interleukin 2 with and without Interferon- in Humans¹

University of Wisconsin Comprehensive Cancer Center, Madison, Wisconsin 53792

Interleukin 2 (IL-2) and interferon- (IFN-) are cytokines with synergistic antitumor effects in mouse models. The biological effects of this combination, however, have not been directly compared to each agent alone in humans. We conducted a Phase 1B trial of IL-2 plus or minus IFN- in 38 cancer patients. The objectives of this trial were to determine which doses of IFN- and IL-2 maximally enhanced biological responses, and to determine whether the combined administration of IFN- and IL-2 would result in a potentiation of biological responses over IL-2 alone. Patients received 4 days of IL-2 (1.5 x 10⁶ units/m²/day or 3.0 x 10⁶ units/m²/day) as a continuous infusion followed by a 3-day rest period, weekly for 3 weeks, with a 3-week rest period between 2 treatment courses. IFN- (0.5 x 10⁶ or 5 x 10⁶ units/m²/day) was administered S.C. on days 1–4 weekly for 3 weeks with one of the 3-week courses. Patients were randomized to receive either IL-2 alone for course 1, followed by IL-2/IFN- for course 2, or IL-2/IFN- in course 1, followed by IL-2 alone. Immunological parameters were evaluated before treatment, and 24 h after completion of the third week of IL-2.

A statistically significant increase in the percentage of circulating natural killer cells (CD56), natural killer cells bearing the Fc receptor (CD16), and activated T cells (CD25) was observed following IL-2 alone, and following IL-2 plus IFN-. Significant increases in lymphocyte-activated killer cell cytotoxicity, antibody cellular cytotoxicity, and serum IL-2 receptor were also observed following both IL-2 and IL-2 plus IFN-. However, no significant differences were observed in the magnitude of the increase in the IL-2-alone group when compared to the IL-2 plus IFN- group. The mean fluorescent intensity of monocytes positive for HLA-DR and Fc receptor expression also increased significantly in both groups, as did serum ß₂-microglobulin expression and indoleamine 2,3-dioxygenase activity. However, increases were not significantly different between patients receiving IL-2 alone and IL-2 plus IFN-. No dose response effect for IFN- was observed for any of the parameters assessed.

Toxicities consisted primarily of constitutional toxicities, including fever, rigors, malaise, headache, anorexia, and a decrease in performance status. No clinically significant differences in toxicities were observed between courses consisting of IL-2 and those consisting of IFN- and IL-2. Two patients had a partial response, and 5 patients had a minor response (partial plus minor response rate, 18%).

In conclusion, we did not observe a difference in biological activity between IL-2 and IL-2 plus IFN- in any of the immunological parameters we studied. Although this regimen was relatively well-tolerated, we cannot conclude that IFN- adds significantly to the immunological or therapeutic activity of IL-2 alone.

¹ J. H. S. is supported in part by the Veterans Administration. This work was supported in part by NIH Grants CM-87290, CA-53441, and CA-22685, and the General Clinical Research Center's Program, NIH Grant MO1 RRO3186.

² To whom requests for reprints should be addressed, at Room K4/6, CSC, University of Wisconsin Hospital and Clinics, 600 Highland Avenue, Madison, WI 53792.

Received 8/14/92. Accepted 1/ 5/93.

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