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Flt3-Ligand: Just Another Cytokine?
-Bruce G. Redman, D.O.,
Associate Professor of Medicine,
Division of Hematology/Oncology,
Associate Director, Tumor Immunotherapy Program
Background
Flt3-Ligand (flt3-L) is a new cytokine that not only increases
dendritic cells, it also mobilizes early hematopoietic progenitor
cells. Flt3-L is short for fms-like tyrosine-kinase 3 ligand
— a naturally occurring glycoprotein that can stimulate
the proliferation and differentiation of hematopoietic progenitor
cells. The receptor for flt3-L belongs to a class of growth
factor receptors involved in early hematopoiesis.
This group of receptors is identified by their intrinsic kinase
activity and, when stimulated by the appro-priate ligand,
by their tyrosine phosphorylation activity. Other ligands
that share this group of receptors include Kit Ligand (KL)
and platelet derived growth factor. Flt3-L has been shown
in vitro to enhance the survival of primitive hematopoietic
progenitors and facilitate limited self renewal of more mature
hematopoietic cells. It differs from KL in that it has no
effect on mast cells or melanocytes. Flt3-L has been produced
by Immunex Corporation using recombinant DNA technology in
a Chinese Hamster Ovary cell line.
Pre-clinical: Hematopoiesis
The hematological effects of flt3-L have been evaluated in
the mouse and non-human primate model. In the mouse model,
the administration of flt3-L resulted in increases in Colony-Forming
Units (CFU) in the bone marrow, spleen and peripheral blood
(1). Increases were seen in CFU-Granulocyte-Macrophage (CFU-GM)
and CFU-Granulocyte-Erythrocyte-Monocyte-Megakaryocyte (CFU-GEMM).
More than a 100-fold increase was seen in CFU-GM and CFU-GEMM
in the spleen after 8 days of flt3-L administration, and over
a 500-fold increase was seen in the peripheral blood that
was maximal after 10 days of administration. Evaluation of
flt3-L in non-human primates also revealed significant increases
in peripheral blood CFUs after 13 days of once-daily subcutaneous
administration (2). Total white blood count (WBC) also was
increased in non-human primates to approximately two and a
half times normal. In these experiments the administration
of Granulocyte-Colony Stimulating Factor (G-CSF) with flt3-L
was synergistic in the mobilization of hematopoietic progenitors
into the peripheral blood. Overall, in pre-clinical evaluations,
flt3-L has been shown to have a significant effect on the
proliferation and mobilization of hematopoietic progenitors.
Pre-clinical: Immunologic Effects
Dendritic cells (DC) have been shown to be the most potent
antigen-presenting cells in the immune system repertoire and
are especially adapted to initiating primary immune responses
of naïve T cells (3). The effect of flt3-L administration
on DC number and activity has been evaluated in the mouse
(4). Flt3-L administered to mice resulted in a significant
increase in DC number in peripheral blood, spleen, liver,
lymph nodes and lung. These DC remained functional in their
ability to stimulate allogeneic T cell proliferation and in
their ability to prime an antigen-specific immune response
in vivo.
Flt3-L administration to tumor-bearing mice has shown significant
antitumor activity in various models. In a methylcholanthrene
(MCA)-induced fibrosarcoma, the administration of flt3-L resulted
in complete tumor regression in a significant number of mice
and a decreased tumor growth rate in others (5). Evaluation
of the mechanism of antitumor activity in this model revealed
it was dependent on CD8+ effector cell population. Histologic
evaluation of regressing tumor masses in flt3-L-treated mice
showed infiltration of lymphocytes and cells that morphologically
resembled DC, as compared to the untreated controls.
Flt3-L also has been evaluated in the spontaneously arising,
poorly immunogenic B16 melanoma and EL-4 lymphoma, as well
as the immunogenic CL8-1 melanoma model (6). These studies
show significant tumor growth inhibition in all three models.
Specific immunohistochemical staining for DC showed a significant
increase in DC infiltration in treated B16 melanoma and EL-4
lymphoma, as compared to the untreated controls. Authors did
not find a significant difference in the staining intensity
for CD8+ cells between treated and control animals.
Clinical Evaluations
Flt3-L administration to healthy volunteers for 14 days has
been shown to be well tolerated (7). These initial studies
also confirm the pre-clinical studies in that the subcutaneous
administration of flt3-L resulted in a significant increase
in CD34+ cells and functional DCs in the peripheral blood
of the volunteers (8).
Due to flt3-L’s effect on hematopoietic progenitors and
on the immune system through its effect on dendritic cells,
it is currently undergoing clinical evaluations in the treatment
of cancer patients. Flt3-L is being evaluated as a mobilizer
of peripheral blood progenitor cells either with GM-CSF or
G-CSF in patients undergoing peripheral blood stem cell transplant.
Based on its ability to expand DCs, increase uptake and presentation
of tumor-associated antigens, and stimulate tumor-specific
cytotoxic T-lymphocytes, flt3-L is also undergoing evaluation
at various centers with non-Hodgkin’s lymphoma and prostate
cancer patients. At the University of Michigan Comprehensive
Cancer Center, we are evaluating flt3-L administration in
the treatment of patients with metastatic melanoma as a part
of our Tumor Immmunology Program. Flt3-L has the promise of
being clinically useful as both a hematopoietic growth factor,
as well as a useful immunotherapeutic agent against cancer.
However, only ongoing clinical evaluations will define the
ultimate role of this cytokine.
References
- Brasel K, McKenna HJ, Morrissey PJ, et al. Hematological
effects of flt3-Ligand in vivo in mice. Blood. 88:2004-2012,1996.
- Papayannopoulou T, Nakamoto B, Andrews RG, et al. In vivo
effects of flt3/flk2-Ligand on mobilization of hematopoietic
progenitors in primates and potent synergistic enhancement
with granulocyte colony-stimulating factor. Blood. 90:620-629,1997.
- Steinman RM. The dendritic cell system and its role in
immunogenicity. Ann Rev Immunol. 9:271-297,1991.
- Maraskovsky E, Brasel K, Teepe M, et al. Dramatic increase
in the numbers of functionally mature dendritic cells in
flt3-Ligand treated mice: Multiple dendritic cell subpopulations
identified. J Exp Med. 184:1953-1962,1996.
- Lynch DH, Andreasen A, Maraskovsky E, et al. Flt3- Ligand
induces tumor regression and antitumor immune responses
in vivo. Nature Med. 3:625-631,1997.
- Esche C, Subbotin VM, Maliszewski C, et al. Flt3- Ligand
administration inhibits tumor growth in murine melanoma
and lymphoma. Cancer Res. 58: 380-383,1998.
- Lebsack ME, McKenna HJ, Hoek JA, et al. Safety of flt3-Ligand
in healthy volunteers. Blood 90 (suppl 1):751a, 1997.
- Maraskovsky E, Roux E, Teepe M, et al. Flt3-Ligand increases
peripheral blood dendritic cells in healthy volunteers.
Blood 90 (suppl 1):2585a, 1997.
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