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Granulocyte Macrophage Colony-stimulating Factor and Interleukin 4 Enhance the Number and Antigen-presenting Activity of Circulating CD14⁺ and CD83⁺ Cells in Cancer Patients¹

Divisions of Pulmonary and Critical Care Medicine [M. D. R., S. M. K., A. N. P., M. M.] and Hematology/Oncology [B. J. G., N. M., R. A. F.] and the Jonsson Comprehensive Cancer Center [M. D. R., R. A. F.], University of California at Los Angeles School of Medicine, Los Angeles, California 90095

Antigen-presenting cells (APCs) are essential for stimulating antigen-specific immunity, including immunity against tumor cells. We hypothesized that systemic administration of granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4, which promote monocytes to differentiate into dendritic cells in vitro, might enhance the number and antigen-presenting activity of CD14⁺ cells in vivo. Patients with metastatic solid malignancies were treated with daily s.c. injections of either GM-CSF alone (2.5 µg/kg/day) or GM-CSF in combination with IL-4 (0.5–6.0 µg/kg/day) in a multicohort study. When given alone, GM-CSF increased the number of CD14⁺ cells but did not enhance the cells’ expression of APC markers or antigen-presenting activity. In contrast, combination therapy with GM-CSF and IL-4 stimulated CD14⁺ cells to acquire several APC characteristics including increased expression of HLA-DR and CD11c, decreased CD14, increased endocytotic activity, and the ability to stimulate T cells in a mixed leukocyte reaction. Combination therapy also induced a dose-dependent increase in the number of CD14^-/CD83⁺ cells with APC activity. Clinically significant and sustained tumor regression was observed in one patient. Systemic therapy with GM-CSF and IL-4 may provide a mechanism for increasing the number and function of APCs in patients with cancer.

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