title: Pilot study of interleukin-2 and lymphokine-activated killer cells combined with immunomodulatory doses of chemotherapy and sequenced with interferon alfa-2a in patients with metastatic melanoma and renal cell carcinoma.
abstract: BACKGROUND
  Experiments in animal tumor models suggest that the antitumor effects of interleukin-2 (IL-2) or IL-2 in combination with lymphokine-activated killer (LAK) cells can be enhanced by chemotherapy agents such as cyclophosphamide or doxorubicin or by the biologic agent interferon alpha.
  
  
  OBJECTIVE
  We determined the toxicity and clinical response rate of an IL-2-LAK cell regimen modified by the addition of moderate, immunomodulatory doses of chemotherapy and sequenced with interferon alfa-2a (IFN alpha-2a) in patients with metastatic melanoma and renal cell carcinoma.
  
  
  METHODS
  IL-2 (3-6 million units/m2 per day) was administered by continuous infusion on days 0-5 and days 11-16. LAK cells were infused on days 11 and 12 or on days 11, 12, and 14. Low doses of cyclophosphamide (300 mg/m2) and doxorubicin (25 mg/m2) were given on day 9 before the LAK cell infusions. Following the IL-2-LAK cell infusion, IFN alpha-2a (12 million units/m2) was administered for a total of nine doses to complete a cycle of treatment. A total of 89 patients were enrolled in the study.
  
  
  RESULTS
  For each histology, there were eight partial responses in 40 assessable patients, for an overall response rate of 20% (90% confidence interval = 10%-33%). The median response duration was 5 months, although two patients with renal cell carcinoma and one patient with metastatic melanoma had almost complete disappearance of tumor and are still responding after 26+, 22+, and 26+ months, respectively. Toxic effects were severe in patients receiving the highest dose of IL-2 administered in this study and similar to those reported with other high-dose IL-2-LAK cell regimens. Although toxic effects were completely reversible in most patients, there were four treatment-related deaths.
  
  
  CONCLUSIONS
  This regimen is active in patients with metastatic melanoma and renal cell carcinoma and produces meaningful responses in a small percentage of these patients; however, it is not clear whether cyclophosphamide, doxorubicin, and IFN alpha-2a as used in this protocol appreciably augmented the antitumor activity of the IL-2-LAK cell regimen.
authors.affiliation: Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: M
authors.initials: M
authors.lastname: Sznol
authors.forename: J W
authors.initials: JW
authors.lastname: Clark
authors.forename: J W
authors.initials: JW
authors.lastname: Smith
authors.forename: R G
authors.initials: RG
authors.lastname: Steis
authors.forename: W J
authors.initials: WJ
authors.lastname: Urba
authors.forename: L V
authors.initials: LV
authors.lastname: Rubinstein
authors.forename: L A
authors.initials: LA
authors.lastname: VanderMolen
authors.forename: J
authors.initials: J
authors.lastname: Janik
authors.forename: W H
authors.initials: WH
authors.lastname: Sharfman
authors.forename: R G
authors.initials: RG
authors.lastname: Fenton
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000628:therapy*; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects; D004334:Drug Administration Schedule; D005260:Female; D006321:Heart / Q000187:drug effects; D006801:Humans; D007107:Immune System / Q000187:drug effects; D007167:Immunotherapy; D007262:Infusions, Intravenous; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000009:adverse effects / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000009:adverse effects / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000628:therapy*; D015979:Killer Cells, Lymphokine-Activated / Q000637:transplantation*; D008168:Lung / Q000187:drug effects; D008297:Male; D008545:Melanoma / Q000628:therapy*; D008875:Middle Aged; D010865:Pilot Projects; D011994:Recombinant Proteins
chemical_list: D000077190:Interferon alpha-2; D016898:Interferon-alpha; D007376:Interleukin-2; D011994:Recombinant Proteins; D004317:Doxorubicin; D003520:Cyclophosphamide