Natural killer cell cytotoxicity is enhanced by very low doses of rIL-2 and rIFN-α in patients with renal cell carcinoma

Very low doses of recombinant interleukin-2 (rIL-2) and interferon-α (rIFN-α) induce, in patients with advanced renal cell carcinoma (RCC) clinical response rate and median survival time comparable to other protocols, other than immunological response in terms of expansion of NK cells and cT lymphocytes. The aim of this pilot study was to verify whether very low dose immunotherapy can enhance NK cell cytotoxicity against tumoral target cells. Eight patients with advanced and 13 patients with localised disease received 4-week cycles of rIL-2 (total dose per week 7 MIU/m², s.c.) and rIFN-α (total dose per week 3.6 MUI/m², i.m.) according to the scheme proposed by Buzio et al. Neutrophils, monocytes, eosinophils, NK cells (CD56+bright, CD56+dimmer, CD3-CD56 +), NK-T cells (CD3+CD56+), Th-lymphocytes, cT-lymphocytes, HLA-DR+ and CD25+  lymphocytes and NK cell cytotoxicity were evaluated before and after cycle. The treatment led to the significant expansion of eosinophils (P < 0.001), NK cells (P < 0.001), CD56+bright (P < 0.001), CD56+dimmer (P < 0.001), Th-lymphocytes (P = 0.001), cT-lymphocytes (P = 0.014), HLA-DR+ (P = 0.007) and CD25+(P = 0.002) cells. Neutrophils significantly decreased (P = 0.001), whereas no significant effect was observed on monocytes (P = 0.22) or NK-T cells (P = 0.20). Patients with localised disease responded significantly better to treatment than metastatic patients in terms of the expansion of CD56+bright (P = 0.038), DR+ (P = 0.021), CD25+ (P = 0.006) and Th-lymphocytes (P = 0.014). The NK cell cytotoxicity was significantly increased by the immunotherapy in the whole population (P = 0.021) and similarly in the two groups of patients (P = 0.860); a reverse relation, even if not significant, was seen between the variation of NK-T cells and NK cells cytotoxicity (r = −0.39; P = 0.074).