A phase I trial of continuous infusion interleukin-4 (IL-4) alone and following interleukin-2 (IL-2) in cancer patients

Background: Interleukin-4 (IL-4) can enhance immune function within various leukocyte populations and mediate anti-tumor effects in mice. In vitro, IL-4 activation of human lymphocytes is enhanced by prior exposure to interleukin-2 (IL-2). This phase I trial of continuous intravenous infusion (CI IV) IL-4 was performed to determine its toxicity and biologic activity. IL-2 was administered prior to a second course of IL-4 in the same patients to determine whether IL-2 exposure can enhance IL-4 effects in vivo. Patients and methods: Seventeen patients with non-hema-tologic malignancies were entered on this trial. Treatment consisted of 7 days of CI IV IL-4 followed by a 2 week period off therapy, then a 4 day course of CI IV IL-2 at 11.2 MIU/m²/day followed by 3 days rest, and then a second 7 day course of CI IV IL-4. IL-4 dose escalation included 40 μg/m²/day (6 pts.), 120 μg/m²/day (3 pts.), 360 μg/m²/day (5 pts.), and 600 μg/m²/day (3 pts.). Results: Dose limiting toxicity occurred at 600 μg/m²/day of IL-4; a dose at which 2 of 3 patients exhibited a vascular leak syndrome characterized by weight gain, peripheral edema, effusions, oliguria, and diffuse rash. Pretreatment with IL-2 did not significantly enhance IL-4 toxicity in the 40-360 μg dose range. IL-4 treatment was associated with a modest, but significant increase in peripheral eosinophil counts (p = 0.004), but no consistent change in lymphocyte phenotype or function. Patients treated at the higher dose of IL-4 (360 μg) administered following IL-2, exhibited a marked increase in peripheral eosinophils after IL-4 therapy (p = 0.007). Following the second course of IL-4, we observed increases in the percent CD 56+ (NK/LAK marker) lymphocytes (mean increase = 6.8%), above levels induced by the preceding EL-2 treatment (p = 0.055). A single minor durable tumor response was seen in a patient with metastatic renal cancer. Conclusions: IL-4 administered at 360 μg/m²/day CI i.v. over seven days is the maximum tolerated dose and is tolerable following a 4 day course of IL-2. IL-4 therapy alone is associated with a modest eosinophilia. In patients receiving IL-2 prior to IL-4, both circulating eosinophils and CD 56+ cells increased above levels observed early after IL-2 treatment. Based upon these results, phase II trials of IL-4 in combination with IL-2 could be planned in 'IL-2 sensitive' malignancies.