IngentaConnect Treatment with Tumor Necrosis Factor-alpha and Granulocyte-Macrop...

Authors: Janik J.E.¹; Miller L.L.¹; Kopp W.C.²; Taub D.D.⁴; Dawson H.⁴; Stevens D.⁵; Kostboth P.²; Curti B.D.¹; Conlon K.C.¹; Dunn B.K.¹; Donegan S.E.⁶; Ullrich R.⁷; Alvord W.G.³; Gause B.L.¹; Longo D.L.^{1, 4}

Source: Clinical Immunology, Volume 93, Number 3, December 1999 , pp. 209-221(13)

Publisher: Academic Press

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 g/m² twice daily as subcutaneous injections, and TNF- alpha as a continuous infusion at dose levels of 25, 50, or 100 g/m²/day. The maximum tolerated dose of TNF- alpha was 50 g/m²/day with this dose of GM-CSF; dose-limiting toxicities occurred in both patients treated with 100 g/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). 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.

Language: English

Document Type: Research article

Affiliations: 1: Biological Response Modifiers Program, NCI-FCRDC, 501 W. Seventh Street, Suite 3, Frederick, Maryland, 21701-4507 2: Clinical Services Program 3: Clinical Services Program, Data Management Services, Inc., SAIC Frederick, NCI-FCRDC, Frederick, Maryland, 21702-1201 4: National Institute on Aging, NIH, 5600 Nathan Shock Drive, Baltimore, Maryland, 21224-6825 5: Reeders Memorial Home, Boonsboro, Maryland 6: Frederick Memorial Hospital, 400 W. Seventh Street, Frederick, Maryland, 21701 7: Department of Immunology and Molecular Biology, USAMRIID, 1425 Porter Street, Frederick, Maryland, 21702

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Treatment with Tumor Necrosis Factor- and Granulocyte–Macrophage Colony-Stimulating Factor Increases Epidermal Langerhans' Cell Numbers in Cancer Patients