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

Ann Oncol. 1994 May;5(5):447-52. doi: 10.1093/oxfordjournals.annonc.a058878.


Background: Interleukin-4 (IL-4) can enhance immune function within various leukocyte populations and mediate antitumor 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 i.v.) 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-hematologic malignancies were entered on this trial. Treatment consisted of 7 days of CI i.v. IL-4 followed by a 2 week period off therapy, then a 4 day course of CI i.v. IL-2 at 11.2 MIU/m2/day followed by 3 days rest, and then a second 7 day course of CI i.v. IL-4. IL-4 dose escalation included 40 micrograms/m2/day (6 pts.), 120 micrograms/m2/day (3 pts.), 360 micrograms/m2/day (5 pts.), and 600 micrograms/m2/day (3 pts.).

Results: Dose limiting toxicity occurred at 600 micrograms/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 micrograms 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 micrograms) 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 CD56+ (NK/LAK marker) lymphocytes (mean increase = 6.8%), above levels induced by the preceding IL-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 micrograms/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 CD56+ 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.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antigens, CD / analysis
  • Antigens, Differentiation, T-Lymphocyte / analysis
  • CD56 Antigen
  • Drug Administration Schedule
  • Edema / etiology
  • Eosinophilia / etiology
  • Eosinophils
  • Female
  • Humans
  • Infusions, Intravenous
  • Interleukin-2 / administration & dosage*
  • Interleukin-2 / adverse effects
  • Interleukin-4 / administration & dosage*
  • Interleukin-4 / adverse effects
  • Killer Cells, Lymphokine-Activated / immunology
  • Killer Cells, Natural / immunology
  • Leukocyte Count
  • Male
  • Middle Aged
  • Neoplasms / blood
  • Neoplasms / immunology
  • Neoplasms / therapy*


  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • CD56 Antigen
  • Interleukin-2
  • Interleukin-4