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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)

¹ Medizinische Klinik III, Hämatologie, Onkologie und Transfusionsmedizin, Charité Campus Benjamin Franklin, Berlin, Germany; ² Department of Virology, University of Goteborg, Goteborg, Sweden; and ³ Maxim Pharmaceuticals, San Diego, California

Requests for reprints: Ulrich Keilholz, Department of Medicine III, Hematology, Oncology and Transfusion Medicine, Charité, Campus Benjamin Franklin, Hindenburgdamm 30, D012200 Berlin, Germany. Fax: 49-30-8445-4021; E-mail: ulrich.keilholz{at}charite.de.

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- (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- 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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