title: Immune response in blood and tumour tissue in patients with metastatic malignant melanoma treated with IL-2, IFN alpha and histamine dihydrochloride.
abstract: Interleukin-2 and interferon-alpha are pleiotropic immuno-activating cytokines with clinical efficacy in malignant melanoma. The anti-melanoma activity of these cytokines is believed to result from the triggering of lymphocyte-mediated killing of tumour cells. In ongoing clinical trials, histamine dihydrochloride is used as an adjuvant to IL-2 and IFN-alpha with a view to protecting lymphocytes from oxidative inhibition induced by tumour-infiltrating monocyte/macrophages. In this study, we have serially monitored mononuclear cells in peripheral blood and tumour biopsies from 13 patients with metastatic malignant melanoma treated under a protocol comprising histamine, IFN-alpha and low-dose IL-2. One complete and 3 partial responses were observed, while 3 patients had stable disease and 6 progressed. A trend towards a gradual increase in the absolute number of circulating CD56+/CD3- NK cells in patients maintaining stable disease during therapy was noted. In tumour tissues, the extent of leukocyte infiltration prior to treatment correlated with tumour response. Additional infiltration by NK cells (CD56+) and monocytes during treatment was seen only in responding patients. Patients with progressive disease exhibited a low density of leukocytes infiltrating tumour tissues at the onset of treatment as compared to the surrounding tissues. Our data indicate that the degree and localization of mononuclear infiltration before and during immunotherapy under this protocol may determine therapeutic anti-tumour responses.
authors.affiliation: Department of Medical Microbiology and Immunology, University of Aarhus, Denmark.
authors.forename: Andreas Schjellerup
authors.initials: AS
authors.lastname: Jørkov
authors.forename: Frede
authors.initials: F
authors.lastname: Donskov
authors.forename: Torben
authors.initials: T
authors.lastname: Steiniche
authors.forename: Annika
authors.initials: A
authors.lastname: Ternesten-Bratel
authors.forename: Peter
authors.initials: P
authors.lastname: Naredi
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Hellstrand
authors.forename: Marianne
authors.initials: M
authors.lastname: Hokland
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017252:CD3 Complex / Q000276:immunology; D018959:CD57 Antigens / Q000276:immunology; D005260:Female; D006632:Histamine / Q000627:therapeutic use*; D017442:Histamine Agonists / Q000627:therapeutic use*; D006801:Humans; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage; D007376:Interleukin-2 / Q000008:administration & dosage; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000628:therapy*; D008875:Middle Aged; D011994:Recombinant Proteins; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: D017252:CD3 Complex; D018959:CD57 Antigens; D017442:Histamine Agonists; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D007376:Interleukin-2; D011994:Recombinant Proteins; D006632:Histamine; D017493:Leukocyte Common Antigens