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).
OBJECTIVE
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.


METHODS
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.
Asemissen
Anne Marie
AM
Medizinische Klinik III, Hämatologie, Onkologie und Transfusionsmedizin, Charité Campus Benjamin Franklin, Berlin, Germany.
Scheibenbogen
Carmen
C
Letsch
Anne
A
Hellstrand
Kristoffer
K
Thorén
Fredrik
F
Gehlsen
Kurt
K
Schmittel
Alexander
A
Thiel
Eckhard
E
Keilholz
Ulrich
U
D017252:CD3 Complex / Q000096:biosynthesis; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D016207:Cytokines / Q000096:biosynthesis; D005434:Flow Cytometry; D006632:Histamine / Q000627:therapeutic use*; D006650:Histocompatibility Testing; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D018793:Interleukin-13 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism / Q000627:therapeutic use*; D020014:K562 Cells; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000556:secondary; D008213:Lymphocyte Activation; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism; D009362:Neoplasm Metastasis; D010455:Peptides / Q000737:chemistry; D017382:Reactive Oxygen Species; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors; D016896:Treatment Outcome
D017252:CD3 Complex; D016207:Cytokines; D018793:Interleukin-13; D007376:Interleukin-2; D010455:Peptides; D017382:Reactive Oxygen Species; D006632:Histamine; D007371:Interferon-gamma