Monocytes and neutrophils as 'bad guys' for the outcome of interleukin-2 with and without histamine in metastatic renal cell carcinoma - results from a randomised phase II trial

Histamine (HDC) inhibits formation and release of phagocyte-derived reactive oxygen species, and thereby protects natural killer (NK) and T cells against oxidative damage. Thus, the addition of histamine may potentially improve the efficacy of interleukin-2 ( IL-2). We have explored this potential mechanism clinically in two randomised phase II trials in metastatic renal cell carcinoma (mRCC). In parallel with the clinical trial in Denmark (n = 63), we obtained serial blood samples and tumour biopsies searching for a potential histamine effect in situ. At baseline and on-treatment weeks 3 and 8, we monitored the 'good guys' ( i.e. NK and T cells) and 'bad guys' ( i.e. monocytes/ macrophages and neutrophils) simultaneously in blood ( n 59) and tumour tissue ( n 44). Patients with high number of monocytes and neutrophils in peripheral blood had very poor survival, with apparently no benefit from either IL-2 alone or IL-2/HDC treatment. Blood monocytes ( r = -0.36, P = 0.01) and neutrophils ( r = -0.46, P = 0.001) were negatively correlated with cytotoxicity, whereas blood NK cells were positively correlated with cytotoxicity ( r = 0.39, P = 0.002). Treatment with IL-2 alone resulted in a significantly higher number of circulating monocytes ( P 0.037) and intratumoral macrophages ( P = 0.005) compared with baseline. In contrast, IL-2/HDC resulted in an unchanged number of circulating monocytes and intratumoral macrophages, and in addition, a significantly increased number of intratumoral CD56(+) NK cells ( P = 0.008) and CD8(+) T cells ( P = 0.019) compared with baseline. The study provides evidence that circulating monocytes and neutrophils are powerful negative prognostic factors for IL-2-based immunotherapy and establishes a biological rationale for the potential use of histamine in conjunction with IL-2 in mRCC.