ADMINISTRATION OF INTERLEUKIN-12 WITH PULSE INTERLEUKIN-2 AND THE RAPID AND COMPLETE ERADICATION OF MURINE RENAL-CARCINOMA

Background: Interleukin 2 (IL-2) and interleukin 12 (IL-12) are potent immunoregulatory cytokines that exhibit antitumor activity. Prelimina ry evidence suggests that combined administration of IL-2 and IL-12 ma y yield greater antitumor activity than that observed with either agen t alone. Purpose: We evaluated the ability of combination regimens of IL-2 and IL-12 to induce regression of established primary and metasta tic murine renal carcinoma (Renca) tumors. Methods: BALB/c mice were g iven either subcutaneous or intrarenal injections of 10(5) Renca cells ; tumor cell injections were given to 10-12 mice for each treatment gr oup. Mice bearing subcutaneous primary tumors were treated with chroni c IL-2 (300 000 IU given on a daily basis) or pulse 1L-2 (300 000 IU g iven twice daily one day per week) alone, IL-12 alone (0.5 mu g given on a daily basis), or IL-12 in combination with either chronic or puls e IL-2. Mice with metastatic tumors (arising from intrarenal implants; animals were nephrectomized to remove the primary tumors) were treate d 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 mu g. In most experiments, treatm ent was continued for at least 3 weeks. Two-sided statistical tests we re used to evaluate the data. Results: Most mice with subcutaneous Ren ca tumors treated with the combination of IL-12 and chronic IL-2 died of treatment-related toxic effects within 7-14 days. In contrast, trea tment with IL-12 plus pulse IL-2 was well tolerated, and six of 10 mic e experienced complete tumor regression; none of the mice treated with either IL-12 alone or pulse IL-2 alone experienced a curative respons e. Seven of eight and nine of nine mice with metastatic tumors experie nced complete tumor regression after treatment with 0.5 mu g IL-12 plu s pulse IL-2 or 1.0 mu g IL-12 plus pulse IL-2, respectively; two of 1 2 mice treated with pulse IL-2 alone and 10% or less of mice treated w ith IL-12 alone were cured of metastatic tumors (with 0.5 mu g IL-12, none of 10 mice; with 1.0 mu g IL-12, one of 10 mice). Five of 10 mice with metastatic tumors treated with a short-course regimen of IL-12 a nd pulse IL-2 (two pulses of IL-2 flanking 5 days of 0.5 mu g IL-12) e xperienced complete tumor regression, while only one of the 12 mice tr eated with IL-2 alone and none of the mice treated with IL-12 alone ex perienced complete tumor regression. Virtually ail curative response f requencies obtained with IL-12 and pulse IL-2 combination regimens dif fered significantly (P<.05) from those obtained with corresponding sin gle-agent treatments. Conclusions: IL-12 administered in combination w ith pulse IL-2 induced rapid and complete regression of primary and me tastatic Renca tumors and displayed greater antitumor activity than th at observed with either IL-12 or IL-2 alone.