Mobilization of Dendritic Cell Precursors in Patients With Cancer by Flt3 Ligand Allows the Generation of Higher Yields of Cultured Dendritic Cells

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Abstract
Flt3 ligand (Flt3L) stimulates the proliferation and differentiation of hematopoietic cells. Subcutaneous Flt3L administration has been shown to effectively manage some murine cancers and in humans, to lead to an increase in peripheral blood monocyte and dendritic cell (DC) counts. In the current study, we determined the effects of Flt3L therapy on patients with melanoma and renal cancer, and in particular, if Flt3L could be used either by enhancing the immunization of patients with melanoma to tumor antigen peptides in vivo, or by mobilizing DC precursors to allow the production of larger numbers of cultured DC. Flt3 ligand administration resulted in a 19-fold increase in DC counts in the peripheral blood of patients. The DC generated in vivo appeared only partially activated, expressing increased levels of CD86, CD33, and major histocompatibility complex class II, but no or low levels of CD80 and CD83. This partial activation may account for the lack of enhanced immune responses to melanoma antigens and absence of clinical responses in the patients even in combination with antigen immunization. Flt3 ligand administration did result, however, in a 7-fold increased yield of monocytes per liter of blood from leukapheresed patients. Dendritic cells were as readily generated from monocytes collected before and after Flt3L therapy, and they stimulated allogeneic T-cell proliferation in a mixed leukocyte reaction to a similar magnitude. Thus, the use of Flt3L may be an important method to mobilize DC precursors to allow patient therapy with larger numbers of cultured DC.