title: Flt3 ligand as a vaccine adjuvant in association with HER-2/neu peptide-based vaccines in patients with HER-2/neu-overexpressing cancers.
abstract: Dendritic cells (DCs) are potent antigen-presenting cells and have shown promise to function as "natural" vaccine adjuvants. Currently, most cancer vaccine trials using DCs generate autologous DCs ex vivo for each patient. Systemic treatment with Flt3 ligand (FL) results in a marked increase of DCs in tissues such as spleen and lymph nodes in mice and in the peripheral blood and skin of humans. In light of these observations, we questioned whether FL could be used systemically as a vaccine adjuvant to stimulate DC mobilization in vivo, circumventing the need to generate DCs ex vivo. Ten patients with HER-2/neu-overexpressing cancer were enrolled in a phase 1 study to receive a HER-2/neu peptide-based vaccine targeting the intracellular domain of the HER-2/neu protein. All patients received 20 microg/kg FL per day subcutaneously for 14 days. Five patients received the HER-2/neu peptide-based vaccine alone on day 7 of the 14-day cycle, and 5 patients received the vaccine admixed with 150 microg granulocyte macrophage-colony-stimulating factor (GM-CSF) on day 7 of the FL cycle. T-cell proliferative responses to HER-2/neu peptides and intracellular domain protein suggest that vaccine regimens including FL as an adjuvant were not effective in eliciting a significant HER-2/neu protein-specific T-cell proliferative response. However, including FL as a vaccine adjuvant was effective in boosting the precursor frequency of interferon-gamma-secreting HER-2/neu-specific T cells. The small sample size of each group, however, did not allow a statistically significant comparison of immune responses between the FL alone and FL with GM-CSF arms. Finally, vaccine regimens including FL as a vaccine adjuvant were associated with the development of apparent autoimmune phenomena in some patients.
authors.affiliation: Division of Oncology, University of Washington, Seattle, WA 98195-6527, USA. ndisis@u.washington.edu
authors.forename: Mary L
authors.initials: ML
authors.lastname: Disis
authors.forename: Kristine
authors.initials: K
authors.lastname: Rinn
authors.forename: Keith L
authors.initials: KL
authors.lastname: Knutson
authors.forename: Donna
authors.initials: D
authors.lastname: Davis
authors.forename: Dania
authors.initials: D
authors.lastname: Caron
authors.forename: Corazon
authors.initials: C
authors.lastname: dela Rosa
authors.forename: Kathy
authors.initials: K
authors.lastname: Schiffman
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology; D001327:Autoimmune Diseases / Q000139:chemically induced; D001943:Breast Neoplasms / Q000150:complications / Q000378:metabolism / Q000628:therapy; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000494:pharmacology*; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008565:Membrane Proteins / Q000008:administration & dosage* / Q000276:immunology / Q000494:pharmacology; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000150:complications / Q000378:metabolism / Q000628:therapy; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000008:administration & dosage* / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma; D008565:Membrane Proteins; D010446:Peptide Fragments; D018719:Erb-b2 Receptor Tyrosine Kinases; C084881:flt3 ligand protein