Down-regulation of the pharmacokinetic-pharmacodynamic response to interleukin-12 during long-term administration to patients with renal cell carcinoma and evaluation of the mechanism of this "adaptive response" in mice

Background: Interleukin-12 (IL-12) is a cytokine that promotes type-1 helpe r T-cell responses and may have therapeutic utility in the treatment of can cer, asthma, and a variety of infectious diseases. Methods: In a phase I trial, recombinant human IL-12 (rHuIL-12) was adminis tered subcutaneously once a week at a fixed dose of 0.1 to 1.0 mu g/kg to 2 4 patients with renal cell carcinoma. A similar study was later performed i n mice to evaluate the mechanism of down-regulation of pharmacokinetic-phar macodynamic response observed in patients with cancer. Results: Adverse events, serum IL-12 levels, and serum levels of interferon -gamma (IFN-gamma) and interleukin-10 (IL-10) produced in response to IL-12 were all maximum in the week after the first dose of rHuIL-12 and decrease d after long-term administration. Similar to these results, repetitive subc utaneous administration of recombinant mouse IL-12 (rMoIL-12) to normal mic e led to down-regulation of serum levels of IL-12 and IFN-gamma measured 5 hours after rMoIL-12 injection. Down-regulation of IL-12 serum levels was i nversely correlated with the up-regulation of IL-12 receptor expression and may be the result of increased clearance of rMoIL-12 from serum by binding to lymphoid cells expressing increased amounts of IL-12 receptor. The down -regulation of serum IFN-gamma levels correlated with decreased IFN-gamma m essenger ribonucleic acid expression and may result from feedback inhibitio n of IL-12 signaling or from a more specific inhibition of IFN-gamma synthe sis. Conclusion: Administration of rHuIL-12 in fixed weekly doses resulted in de creased serum levels of IL-12 and of IFN-gamma, a secondary cytokine believ ed to be critical to response of IL-12. A better understanding of the compl ex regulation of the pharmacokinetic-pharmacodynamic response to IL-12 shou ld facilitate the development of more effective dosing regimens for its use in the clinic.