title: Long-term treatment with low doses of interleukin-2 and interferon-alpha: immunological effects in advanced renal cell cancer.
abstract: OBJECTIVE
  We aimed to determine the immunological effects of low doses of recombinant interleukin-2 (rIL-2) and recombinant interferon-alpha (rIFN-alpha) in patients bearing advanced renal cell carcinoma.
  
  
  METHODS
  Twenty-seven patients received therapeutic cycles consisting of subcutaneous rIL-2 for 5 days per week and intramuscular rIFN-alpha twice weekly, for 4 consecutive weeks. The cycle was repeated indefinitely at regular 4-month intervals, for all patients. rIL-2 (1 x 10(6) IU/m2) was administered every 12 h on days 1 and 2 and once a day on days 3-5 of each week; rIFN-alpha (1.8 x 10(6) IU/m2) was given on days 3 and 5. In the enrolled patients, total and differential white blood cell counts, phenotypic analysis of some lymphocyte subsets, and soluble IL-2 receptor (sIL-2R), were investigated before and after each of the first six cycles of therapy (about 24 months of follow-up).
  
  
  RESULTS
  The cycles of immunotherapy induced a significant increase of total lymphocytes (37%, P < 0.001), eosinophils (222%, P < 0.001), CD25+ cells (27%, P=0.004), sIL-2R (174%, P < 0.001) and natural killer (NK) cells (CD3-CD56+) (61%, P < 0.001); the subset that expresses CD56 with high density (CD56+ bright) expanded more (233%, P < 0.001) than the subset expressing the same marker with low density (CD56+ dimmer) (15%, P = 0.043). Unlike the previous subsets, the treatment decreased significantly T-lymphocytes with NK cell marker (CD3+ CD56+) (28%, P = 0.011). No significant differences of effectiveness were found among the subsequent treatment cycles, except for CD25+ cells and sIL-2R (P = 0.036 and P = 0.005, respectively): the increase induced by immunotherapy was maximum after the first cycle and decreased progressively thereafter.
  
  
  CONCLUSIONS
  Long-term repeated cycles of low-dose immunotherapy induced repeated and significant expansion of one of the most important lymphocyte subsets for the non-MHC-restricted immune response to the tumour mass: CD3-CD56+ cells.
authors.affiliation: Dipartimento di Clinica Medica, Nefrologia e Scienze della Prevenzione, Università di Parma, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Pavone
authors.forename: S
authors.initials: S
authors.lastname: Andrulli
authors.forename: R
authors.initials: R
authors.lastname: Santi
authors.forename: M
authors.initials: M
authors.lastname: Majori
authors.forename: C
authors.initials: C
authors.lastname: Buzio
mesh_terms: D000328:Adult; D000368:Aged; D017252:CD3 Complex / Q000032:analysis; D019002:CD56 Antigen / Q000032:analysis; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage*; D007376:Interleukin-2 / Q000008:administration & dosage*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins
chemical_list: D017252:CD3 Complex; D019002:CD56 Antigen; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D007376:Interleukin-2; D011994:Recombinant Proteins