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)

Clin Cancer Res. 2005 Jan 1;11(1):290-7.


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.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD3 Complex / biosynthesis
  • Cell Line, Tumor
  • Chromatography, High Pressure Liquid
  • Cytokines / biosynthesis
  • Flow Cytometry
  • Histamine / therapeutic use*
  • Histocompatibility Testing
  • Humans
  • Interferon-gamma / metabolism
  • Interleukin-13 / metabolism
  • Interleukin-2 / metabolism
  • Interleukin-2 / therapeutic use*
  • K562 Cells
  • Leukocytes, Mononuclear / metabolism
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / secondary
  • Lymphocyte Activation
  • Melanoma / drug therapy*
  • Melanoma / metabolism
  • Monocytes / metabolism
  • Neoplasm Metastasis
  • Peptides / chemistry
  • Reactive Oxygen Species
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism*
  • Time Factors
  • Treatment Outcome


  • CD3 Complex
  • Cytokines
  • Interleukin-13
  • Interleukin-2
  • Peptides
  • Reactive Oxygen Species
  • Histamine
  • Interferon-gamma