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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)

Artikel i vetenskaplig tidskrift
Författare Anne Marie Asemissen
Carmen Scheibenbogen
Anne Letsch
Kristoffer Hellstrand
Fredrik Bergh Thorén
Kurt Gehlsen
Alexander Schmittel
Eckhard Thiel
Ulrich Keilholz
Publicerad i Clin Cancer Res
Volym 11
Nummer/häfte 1
Sidor 290-7
ISSN 1078-0432 (Print)
Publiceringsår 2005
Publicerad vid Institutionen för laboratoriemedicin, Avdelningen för klinisk virologi
Sidor 290-7
Språk en
Ämnesord 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
Ämneskategorier Medicin och Hälsovetenskap


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.

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