HISTAMINE IN CANCER-IMMUNOTHERAPY

A novel strategy for enhancing the efficacy of immunotherapy with inte rleukin-2 (IL-2) and interferon-alpha (IFN-alpha) in human neoplasia i s presented. IL-2 and IFN-alpha are potent activators of the antitumou r activity of natural killer (NK) cells but only rarely reduce the tum our burden in treated patients. Recent studies suggest that a reason w hy these cytokines are insufficiently effective in human cancer is tha t phagocytes inhibit the tumour-killing activity of NK cells at the si te of the tumour. Histamine prevents the phagocyte-induced, NK cell-in hibiting signal; thus, histamine and IL-2 or histamine and IFN-alpha s ynergize to induce NK cell-mediated killing of human tumour cells in v itro. Further, treatment of tumour-bearing mice with histamine enhance s IL-2- and IFN-alpha-induced destruction of NK cell-sensitive tumour cells in vivo. More than 50 patients with neoplastic disease have been treated with histamine, given in subcutaneous injections, together wi th IL-2 or IFN-alpha. The results of two pilot trials in metastatic me lanoma suggest that the addition of histamine to IL-2 and IFN-alpha pr olongs survival time and induces regression of tumours, such as Ever m elanoma, which are otherwise considered refractory to immunotherapy. T he results of a trial in acute myelogenous leukaemia (AML) suggest tha t histamine and IL-2 protects AML patients against relapse of leukaemi c disease. Histamine is well tolerated: for example, AML patients in r emission have treated themselves with histamine at home without superv ision for a total of >300 weeks with only a handful of therapy-related hospital contacts. Controlled trials in melanoma and AML are under wa y to further investigate the putative benefit of histamine in neoplast ic disease.