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News Archive: Michigan Oncology Journal Summer 98

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

  1. Brasel K, McKenna HJ, Morrissey PJ, et al. Hematological effects of flt3-Ligand in vivo in mice. Blood. 88:2004-2012,1996.
  2. 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.
  3. Steinman RM. The dendritic cell system and its role in immunogenicity. Ann Rev Immunol. 9:271-297,1991.
  4. 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.
  5. 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.
  6. 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.
  7. Lebsack ME, McKenna HJ, Hoek JA, et al. Safety of flt3-Ligand in healthy volunteers. Blood 90 (suppl 1):751a, 1997.
  8. 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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Please note: The articles listed in the Cancer Center's News Archive are here for historical purposes. The information and links may no longer be up-to-date.