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Immunotherapy with Histamine Dihydrochloride and Interleukin-2 in Acute Myeloid Leukaemia
Table 1: Pre-clinical Pharmacodynamics of Histamine Dihydrochloride (HDC) and Interleukin-2 (IL-2) Protection by IL-2’s Target Cells
by HDC and Synergy Between HDC and IL-2
Reference Focus of Study Main Result(s)
Hellstrand et al., 1990
28
Human NK-cell regulation Synergy between HDC and IL-2 regarding NK-cell-mediated killing of cultured human
and lymphoma cells leukaemic in vitro.
Defines myeloid histamine H
2
receptors mediating effects of HDC.
Hellstrand et al., 1990
29
Growth of NK-cell-sensitive tumours in mice Synergy between HDC and IL-2 in inducing NK-cell-mediated destruction
of melanoma cells in vivo.
Hellstrand et al., 1991
30
Human NK-cell regulation HDC potentiates IL-2-induced cell-cycle proliferation of human NK cells in vitro by
countering a myeloid-cell-derived suppressive signal.
Hellstrand et al., 1994
20
Human NK-cell regulation Synergy between HDC and IL-2 regarding NK-cell-mediated killing of cultured
human leukaemic and lymphoma cells in vitro.
Defines the role of myeloid suppressor cells.
Hellstrand et al.,1994
31
Human NK-cell regulation Synergy between HDC and IL-2 in inducing antibody-dependent
cellular cytotoxicity in NK-cells in vitro.
Asea et al., 1996
32
Growth of NK-cell-sensitive tumours in mice Synergy between HDC and IL-2 in inducing NK-cell-mediated destruction
of YAC-1 lymphoma in vivo.
Asea et al., 1996
33
Human NK-cell regulation Synergy between HDC and IL-2 in inducing production of interferon-γ
by NK cells in vitro.
Brune et al. 1996
27
Human NK-cell regulation Synergy between HDC and IL-2 in inducing NK-cell-mediated destruction of
freshly recovered AML blasts in vitro.
Defines the role of myeloid-cell-derived oxygen radicals.
Hansson et al., 1996
34
Protection of NK cells HDC-induced protection of NK-cells and T-cells against myeloid-cell-induced
apoptosis in vitro.
Hansson et al., 1999
23
Human T- and N-cell regulation Synergy between HDC and IL-2 in inducing activation antigen expression
(CD69) in T cells and NK cells in vitro.
Mellqvist et al., 2000
35
Human T- and NK-cell regulation and protection Synergy between HDC and IL-2 in inducing NK-cell-mediated destruction of
of antileukaemic lymphocytes cultured leukaemic cells using polymorphnuclear myeloid cells or malignant CML
cells as suppressor cells in vitro.
Betten et al., 2001
36
Protection of T- and NK-cells against myeloid- HDC protects T and NK cells against myeloid-cell-induced
cell-induced apoptosis oxygen-radical-mediated apoptosis in vitro.
Kozar et al., ,2002
37
Mouse NK-cell regulation Potentiation by HDC of IL-2 induced activation of murine NK-cells in vitro.
Romero et al., 2006
38
Human NK-cell regulation HDC-induced preservation of activating NK-cell receptors (NKp46/NKG2D) in vitro.
Thorén et al., 2006
39
Protection of antileukaemic lymphocytes HDC-induced protection of NK cells and T cells against myeloid-cell-induced
apoptosis in vitro.
Defines the role of the PARP-1/AIF axis in myeloid cell-induced apoptosis.
Figure 2: Schematic Representation of Immunostimulatory Properties of Histamine Dihydrochloride
A B
Phagocyte
CD3
Phagocyte
ξ expression
Cytotoxic
NK-activating receptors
lymphocyte
IFN- Cytotoxicγ
NADPH
Cytotoxicity
lymphocyte
oxidase
O
2
IL-2 response
NADPH Cytotoxicity
oxidase
Lysed
ROS
leukaemic
cells
H
2
receptor
HDC IL-2
IL-2
receptor
Cell death
Leukaemic cells
Panel A schematically describes how myeloid-cell-derived oxygen radicals inactivate antileukaemic lymphocytes and trigger apoptosis in these cells. Panel B shows the same scheme of events in
the presence of histamine dihydrochloride (HDC), which inhibits oxygen radical production in myeloid cells and prevents these suppressive events. By maintaining the function and viability of
antileukaemic lymphocytes, HDC synergises with the T- and NK-cell-activating cytokine interleukin (IL)-2 to induce killing of sensitive target cells, including human acute myeloid leukaemia blasts.
Clinical Pharmacodynamics of Histamine Dihydrochloride patients receiving HDC/IL-2 showed improved induction of IFN-γ in several
During the course of the study using HDC/IL-2 in cancers other than AML, types of T cell,
24
and in renal cell carcinoma, treatment with HDC/IL-2 was
the effect of treatment with HDC/IL-2 on T- and NK-cell functions was associated with improved functional status of cytotoxic lymphocytes in
monitored and compared with that of IL-2 monotherapy. In melanoma, peripheral blood and at the site of malignant tumour growth.
25
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