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Addition of histamine to interleukin 2 treatment augments type 1 T-cell responses in patients with melanoma in vivo: immunologic results from a randomized clinical trial of interleukin 2 with or without histamine (MP 104)

Journal article
Authors Anne Marie Asemissen
Carmen Scheibenbogen
Anne Letsch
Kristoffer Hellstrand
Fredrik Bergh Thorén
Kurt Gehlsen
Alexander Schmittel
Eckhard Thiel
Ulrich Keilholz
Published in Clin Cancer Res
Volume 11
Issue 1
Pages 290-7
ISSN 1078-0432 (Print)
Publication year 2005
Published at Institute of Laboratory Medicine, Dept of Clinical Virology
Pages 290-7
Language en
Keywords Antigens, CD3/biosynthesis, Cell Line, Tumor, Chromatography, High Pressure Liquid, Cytokines/biosynthesis, Flow Cytometry, Histamine/ therapeutic use, Histocompatibility Testing, Humans, Interferon Type II/metabolism, Interleukin-13/metabolism, Interleukin-2/metabolism/ therapeutic use, K562 Cells, Leukocytes, Mononuclear/metabolism, Liver Neoplasms/ drug therapy/secondary, Lymphocyte Activation, Melanoma/ drug therapy/metabolism, Monocytes/metabolism, Neoplasm Metastasis, Peptides/chemistry, Reactive Oxygen Species, T-Lymphocytes/immunology/ metabolism, Time Factors, Treatment Outcome
Subject categories Medical and Health Sciences


PURPOSE: Preclinical investigations suggest that histamine dihydrochloride (HDC) protects T cells and natural killer cells from inhibition by monocyte-derived reactive oxygen metabolites and synergizes with interleukin (IL) 2 in inducing T-cell activation. Here, we investigate whether this mechanism is operational in patients with melanoma treated with HDC as an adjunct to IL-2. EXPERIMENTAL DESIGN: Melanoma patients having liver metastases were treated with IL-2 with or without HDC within a randomized, multicenter, phase III trial. The effect of HDC on type 1 and type 2 T-cell cytokine production was investigated in peripheral blood samples from 19 patients with the use of intracellular cytokine flow cytometry. Melanoma-specific T-cell responses were analyzed in eight HLA-A2-positive patients. RESULTS: Frequencies of CD3+ T cells producing IFN-gamma (type 1 T cells) in response to phorbol myristate acetate/ionomycin increased (median, 1.8-fold) in patients receiving IL-2 plus HDC but not in those receiving IL-2 alone (P < 0.01 for comparison between arms). In contrast, the number of IL-13-producing type 2 T cells that increased in patients after treatment with IL-2 was not modulated by HDC. Melanoma- and tyrosinase-specific IFN-gamma and IL-13-producing T cells were detected in two of four HLA-A2-positive patients with melanoma following treatment with HDC + IL-2. CONCLUSIONS: Treatment of patients with stage IV melanoma with HDC in combination with IL-2 increases type 1 T-cell responses and may promote induction of melanoma-specific T cells. These effects are of relevance for tumor immunotherapy and provide a potential mechanism for the clinical efficacy of HDC added to IL-2.

Page Manager: Webmaster|Last update: 9/11/2012

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