HISTAMINE AND CYTOKINE THERAPY

Interleukin-2 (IL-2) and interferon-alpha (IFN-alpha) are potent activ ators of natural killer (NK) cells and other anti-tumor effector cells , but the results obtained in clinical trials with these cytokines hav e proved disappointing in many forms of cancer. It may be that IL-2 an d IFN-alpha are often not sufficiently effective because intratumoral monocytes/macrophages (MO) inhibit the cytokine-induced activation of cytotoxic effector lymphocytes such as NK-cells at the site of tumor g rowth. An essential parr of this inhibitory signal is conveyed by MO-d erived reactive oxygen species (ROS), which potently inhibit NK-cell-r elated functions, including the constitutive and cytokine-induced cyto toxicity against tumor cells. Histamine, a biogenic amine, inhibits RO S formation iii MO; thereby, histamine synergizes with IL-2, and with IFN-alpha to induce killing of NK-cell-sensitive human tumor cells in vitro. Furthermore, treatment of tumor-bearing mice with histamine pot entiates cytokine-induced killing of NK-cell-sensitive murine tumor ce lls in vivo. In ongoing clinical trials, histamine has been added to I L-2 or IFN-alpha in immunotherapy of human neoplastic disease. The res ults of two pilot trials in metastatic melanoma suggest that the addit ion of histamine to IL-2/IFN-alpha prolongs survival time and induces regression of turners, such as liver melanoma, which are considered re fractory to immunotherapy with IL-2 or IFN-alpha. In acute myelogenous leukemia (AML), histamine and IL-2 have been given in order to protec t patients in remission against relapse of leukemic disease. The poten tial benefit of histamine therapy in melanoma and AML will be evaluate d in randomized trials.