title: A phase I trial of continuous infusion interleukin-4 (IL-4) alone and following interleukin-2 (IL-2) in cancer patients.
abstract: 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.
  
  
  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.
authors.affiliation: Division of Hematology/Oncology, Loyola University Medical Center, Maywood, Ill.
authors.forename: J A
authors.initials: JA
authors.lastname: Sosman
authors.forename: S G
authors.initials: SG
authors.lastname: Fisher
authors.forename: C
authors.initials: C
authors.lastname: Kefer
authors.forename: R I
authors.initials: RI
authors.lastname: Fisher
authors.forename: T M
authors.initials: TM
authors.lastname: Ellis
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000032:analysis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D019002:CD56 Antigen; D004334:Drug Administration Schedule; D004487:Edema / Q000209:etiology; D004802:Eosinophilia / Q000209:etiology; D004804:Eosinophils; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000009:adverse effects; D015847:Interleukin-4 / Q000008:administration & dosage* / Q000009:adverse effects; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000276:immunology / Q000628:therapy*
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D019002:CD56 Antigen; D007376:Interleukin-2; D015847:Interleukin-4