title: Treatment with tumor necrosis factor-alpha and granulocyte-macrophage colony-stimulating factor increases epidermal Langerhans' cell numbers in cancer patients.
abstract: Dendritic cells (DCs) initiate primary and stimulate secondary T-cell responses. We conducted a phase I trial of tumor necrosis factor (TNF-alpha) 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 microg/m(2) twice daily as subcutaneous injections, and TNF-alpha as a continuous infusion at dose levels of 25, 50, or 100 microg/m(2)/day. The maximum tolerated dose of TNF-alpha was 50 microg/m(2)/day with this dose of GM-CSF; dose-limiting toxicities occurred in both patients treated with 100 microg/m(2)/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). CFU-dendritic in peripheral blood increased after treatment in 3 colorectal cancer patients but not in 3 patients with melanoma. CD11c(+) or CD123(+), HLA-DR(bright), lineage-negative dendritic cell precursors were not increased in peripheral blood mononuclear cells. This trial demonstrates that treatment with TNF-alpha 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.
authors.affiliation: Biological Response Modifiers Program, NCI-FCRDC, 501 W. Seventh Street, Suite 3, Frederick, Maryland 21701-4507, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Janik
authors.forename: L L
authors.initials: LL
authors.lastname: Miller
authors.forename: W C
authors.initials: WC
authors.lastname: Kopp
authors.forename: D D
authors.initials: DD
authors.lastname: Taub
authors.forename: H
authors.initials: H
authors.lastname: Dawson
authors.forename: D
authors.initials: D
authors.lastname: Stevens
authors.forename: P
authors.initials: P
authors.lastname: Kostboth
authors.forename: B D
authors.initials: BD
authors.lastname: Curti
authors.forename: K C
authors.initials: KC
authors.lastname: Conlon
authors.forename: B K
authors.initials: BK
authors.lastname: Dunn
authors.forename: S E
authors.initials: SE
authors.lastname: Donegan
authors.forename: R
authors.initials: R
authors.lastname: Ullrich
authors.forename: W G
authors.initials: WG
authors.lastname: Alvord
authors.forename: B L
authors.initials: BL
authors.lastname: Gause
authors.forename: D L
authors.initials: DL
authors.lastname: Longo
mesh_terms: D000328:Adult; D001706:Biopsy; D002272:Carcinoembryonic Antigen / Q000097:blood; D002452:Cell Count; D003110:Colonic Neoplasms / Q000097:blood; D003114:Colony-Forming Units Assay; D004359:Drug Therapy, Combination; D005260:Female; D005434:Flow Cytometry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use*; D006801:Humans; D007801:Langerhans Cells / Q000187:drug effects*; D007958:Leukocyte Count; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology*; D011994:Recombinant Proteins / Q000627:therapeutic use; D012867:Skin / Q000473:pathology; D013921:Thrombocytopenia / Q000139:chemically induced; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use*
chemical_list: D002272:Carcinoembryonic Antigen; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor