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  • Open Access

Addition of histamine to IL-2 treatment augments T1 cell-function in melanoma patients in vivo: results from a randomized clinical trial of IL-2 with or without histamine (MP 104)

  • 1Email author,
  • 1,
  • 1,
  • 2,
  • 3,
  • 1 and
  • 1
Cancer Cell International20044 (Suppl 1) :S47

https://doi.org/10.1186/1475-2867-4-S1-S47

  • Received: 28 April 2004
  • Published:

Keywords

  • Melanoma
  • Histamine
  • Melanoma Patient
  • Melanoma Cell Line
  • Liver Involvement

Histamine is used as an adjunct to interleukin-2 (IL-2) in tumor immunotherapy due to its protective effect on NK and T cell inhibition by monocyte-derived reactive oxygen metabolites in vitro. Results from a first randomized phase III trial showed an increase in survival in stage IV melanoma patients with liver involvement (Agarwala SS, J Clin Oncol 2002, 20). Here we have analyzed the effect of histamine on T cell cytokine production in patients treated with IL-2 without or with histamine within a second randomized multicenter phase III trial. A significant increase (mean 2.2-fold) in frequencies of CD3+ T cells producing IFN-γ (T1 cells) in response to mitogen stimulation was detected in patients treated with histamine plus IL-2 (n = 7 patients) while IL-2 alone (n = 10 patients) had no effect on the frequency of IFNγ-producing CD3+ T cells. In contrast, frequencies of CD3+ T cells producing IL-13 (T2 cells) significantly increased in patients receiving IL-2 (mean 2.7-fold) and this effect was not modulated by histamine (mean increase 2.9-fold). These effects were observed for both CD3+CD8+ as well as CD3+CD4+ T cells. In vitro experiments using separated T cells and monocytes from healthy subjects show that while histamine does not induce IFN-γ production in T cells it protects T cells from monocyte-induced down-regulation of IFN-γ. Melanoma-specific T cell responses were analyzed in the 9 HLA-A2+ patients (IL2 + histamine, n = 4; IL-2, n = 5) against HLA-A2+ melanoma cell lines using intra-cellular cytokine staining. Induction or augmentation of melanoma-reactive IFN-γ and IL-13-producing T cells could be shown in 2 HLA-A2-positive melanoma patients treated with histamine and IL-2, but in none of the patients in the IL-2 arm. Both patients had received previous vaccination with HLA-A*0201 binding tyrosinase peptide and also tyrosinase-specific T cell responses were detected after IL-2 plus histamine treatment. In summary, treatment with histamine in combination with IL-2 increases T1 responses and stimulates melanoma-specific T cells.

Authors’ Affiliations

(1)
Med. Klinik III, Hämatologie, Onkologie u.Transfusionsmedizin, Charité Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany
(2)
Department of Virology, University of Göteborg, Göteborg, Sweden
(3)
MAXIM, San Diego, USA

Copyright

© Author(s); licensee BioMed Central Ltd. 2004

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