Long-term treatment with low doses of interleukin-2 and interferon-alpha: immunological effects in advanced renal cell cancer

Purpose: We aimed to determine the immunological effects of low doses of re combinant interleukin-2 (rIL-2) and recombinant interferon-alpha (rIFN-alph a) in patients bearing advanced renal cell carcinoma. Methods: Twenty-seven patients received therapeutic cycles consisting of su bcutaneous rIL-2 for 5 days per week and intramuscular rIFN-a twice weekly, for 4 consecutive weeks. The cycle was repeated indefinitely at regular dr -month intervals, for all patients, rIL-2 (1 x 10(6) IU/m(2)) was administe red 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/m(2)) was given on days 3 and 5. In the enrolled pat ients, total and differential white blood cell counts, phenotypic analysis of some lymphocyte subsets, and soluble IL-2 receptor (sIL-2R), were invest igated before and after each of the first six cycles of therapy (about 24 m onths of follow-up). Results: The cycles of immunotherapy induced a significant increase of tota l 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 (CD 3-CD56 +) (61%, P ( 0.001); the subset that expresses CD56 with high densit y (CD56 + bright) expanded more (233%, P < 0.001) than the subset expressin g the same marker with low density (CD56+ dimmer) (15%, P = 0.043). Unlike the previous subsets. the treatment decreased significantly T-lymphocytes w ith 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 re peated and significant expansion of one of the most important lymphocyte su bsets for the non-MHC-restricted immune response to the tumour mass: CD3-CD 56 + cells.