Phase I trial of twice-weekly intravenous interleukin 12 in patients with metastatic renal cell cancer or malignant melanoma: Ability to maintain IFN-gamma induction is associated with clinical response

The aim of this study was to examine the tolerability, antitumor activity, and biological effects of a new schedule of i.v. recombinant human interleu kin 12 (rhIL-12). Twenty-eight patients were enrolled in a Phase I trial in which rhIL-12 was administered twice weekly as an i.v. bolus for 6 weeks, Stable or responding patients were eligible to receive additional 6-week cy cles until there was no evidence of disease or until tumor progression. Pat ient cohorts were treated with escalating doses of rhIL-12 (30-700 ng/kg). The maximum tolerated dose (MTD) was 500 ng/kg, with dose-limiting toxiciti es consisting of elevated hepatic transaminases and cytopenias. At the MTD (n = 14), there was one partial response occurring after 6 cycles of rhIL-1 2 in a patient with renal cell cancer. Two additional renal cell cancer pat ients treated at the MTD had prolonged disease stabilization, with one of t hese exhibiting tumor regression after 8 cycles of rhIL-12. IFN-gamma, IL-1 5, and IL-18 were induced in patients treated with rhIL-12. Whereas IFN-gam ma and IL-15 induction were attenuated midway through the first cycle in pa tients with disease progression, those patients with tumor regression or pr olonged disease stabilization were able to maintain IFN-gamma, IL-15, and I L-18 induction, The down-modulation of IFN-gamma induction during rhIL-12 t reatment did not relate to IL-10 production or alterations in rhIL-12 bioav ailability but was associated with an acquired defect in lymphocyte IFN-gam ma production in response to IL-12, IL-2, or IL-15, This defect could be pa rtially overcome in vitro through combined stimulation with IL-12 plus IL-2 , These findings shaw that the chronic administration of twice-weekly i.v. rhIL-12 is well-tolerated, stimulates the production of IL-12 costimulatory cytokines and IFN-gamma, and can induce delayed tumor regression. Strategi es aimed at maintaining IFN-gamma induction, such as the addition of IL-2, may further augment the response rate to this schedule of rhIL-12.