Treatment with tumor necrosis factor-α and granulocyte-macrophage colony-stimulating factor increases epidermal Langerhans' cell numbers in cancer patients

Dendritic cells (DCs) initiate primary and stimulate secondary T-cell responses. We conducted a phase I trial of tumor necrosis factor (TNF-α) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with cancer to increase DCs in peripheral blood or skin based on in vitro data that showed that CD34⁺ hematopoietic precursors require these cytokines to mature into functional antigen-presenting DCs. Eleven patients were treated for 7 days with GM-CSF, 125 μg/m² twice daily as subcutaneous injections, and TNF-α as a continuous infusion at dose levels of 25, 50, or 100 μg/m²/day. The maximum tolerated dose of TNF-α was 50 μg/m²/day with this dose of GM-CSF; dose-limiting toxicities occurred in both patients treated with 100 μg/m²/day. One became thrombocytopenic and the other had transient confusion. Epidermal Langerhans' cells were quantitated by S100 staining of skin biopsies and DC precursors in peripheral blood by colony- forming unit dendritic (CFU-dendritic) assays. S100-positive cells in the epidermis doubled after treatment (2.55 S100⁺ cells/high-power field before treatment to 6.05 after treatment, p = 0.029). CFUdendritic in peripheral blood increased after treatment in 3 colorectal cancer patients but not in 3 patients with melanoma. CD11c⁺ or CD123⁺. HLADR(bright), lineage-negative dendritic cell precursors were not increased in peripheral blood mononuclear cells. This trial demonstrates that treatment with TNF-α and GM-CSF can increase the number of DCs in the skin and the number of dendritic cell precursors in the blood of some patients with cancer. This approach may increase the efficacy of vaccination to tumor antigens in cancer patients.