Histamine dihydrochloride: inhibiting oxidants and synergising IL-2-mediated immune activation in the tumour microenvironment

Abstract

The potential role of histamine in cancer immunotherapy has been a subject of interest for more than a decade. A significant body of research has elucidated the action of histamine in a model system that mimics the tumour microenvironment. In vitro evidence indicates that histamine inhibits the generation and release of reactive oxygen species (ROS) by monocytes/macrophages (MO) during respiratory burst. Since ROS have been shown to abrogate peritumoural and intratumoural cytokine activation of natural killer (NK) and T-cells and induce apoptosis of these cells in vitro, inhibition of ROS may enable cytokines to activate NK and T-cells and restore their antineoplastic, cytotoxic capabilities. Experimental data indicate that histamine and interleukin-2 (IL-2) act synergistically to activate NK cell cytotoxicity (NKCC). Although IL-2, a regulator of immune responses, has been shown to promote NKCC in monotherapy for metastatic melanoma (MM), renal cell carcinoma (RCC) and acute myeloid leukaemia (AML), objective responses occur in a minority of patients and survival is not significantly extended, except for a minority of patients with MM using high-dose regimens which have not been widely adopted. In vitro findings suggest that the addition of histamine to IL-2 therapy might improve response rates and disease-free survival by protecting the cells of the immune system from oxidative stress and inducing natural endogenous immune cytotoxicity. An IL-2/histamine Phase III trial is in progress in a population of AML patients. A recently completed Phase III trial of IL-2 vs. IL-2/histamine in patients with MM demonstrated a trend towards a superior survival benefit from IL-2/histamine for all patients entered, and a statistically significant survival benefit for patients with hepatic metastases.