Administration of Interleukin 12 with pulse Interleukin 2 and the rapid and complete eradication of murine renal carcinoma

Abstract

Background: Interleukin 2 (IL-2) and interleukin 12 (IL-12) are potent immunoregulatory cytokines that exhibit antitumor activity. Preliminary evidence suggests that combined administration of IL-2 and IL-12 may yield greater antitumor activity than that observed with either agent alone. Purpose: We evaluated the ability of combination regimens of IL-2 and IL-12 to induce regression of established primary and metastatic murine renal carcinoma (Renca) tumors. Methods: BALB/c mice were given either subcutaneous or intrarenal injections of 105 Renca cells; tumor cell injections were given to 10-12 mice for each treatment group. Mice bearing subcutaneous primary tumors were treated with chronic IL-2 (300 000 IU given on a daily basis) or pulse IL-2 (300 000 IU given twice daily one day per week) alone, IL-12 alone (0.5 μg given on a daily basis), or IL-12 in combination with either chronic or pulse IL-2. Mice with metastatic tumors (arising from intrarenal implants; animals were nephrectomized to remove the primary tumors) were treated with IL-12 plus or minus pulse IL-2; in these experiments, IL-12 was given at doses of either 0.5 or 1.0 μg. In most experiments, treatment was continued for at least 3 weeks. Two-sided statistical tests were used to evaluate the data. Results: Most mice with subcutaneous Renca tumors treated with the combination of IL-12 and chronic IL-2 died of treatment-related toxic effects within 7-14 days. In contrast, treatment with IL-12 plus pulse IL-2 was well tolerated, and six of 10 mice experienced complete tumor regression; none of the mice treated with either IL-12 alone or pulse IL-2 alone experienced a curative response. Seven of eight and nine of nine mice with metastatic tumors experienced complete tumor regression after treatment with 0.5 μg IL-12 plus pulse IL-2 or 1.0 μg IL- 12 plus pulse IL-2, respectively; two of 12 mice treated with pulse IL-2 alone and 10% or less of mice treated with IL-12 alone were cured of metastatic tumors (with 0.5 μg IL-12, none of 10 mice; with 1.0 μg IL-12, one of 10 mice). Five of 10 mice with metastatic tumors treated with a short- course regimen of IL-12 and pulse IL-2 (two pulses of IL-2 flanking 5 days of 0.5 μg IL-12) experienced complete tumor regression, while only one of the 12 mice treated with IL-2 alone and none of the mice treated with IL-12 alone experienced complete tumor regression. Virtually all curative response frequencies obtained with IL-12 and pulse IL-2 combination regimens differed significantly (P