title: Successful induction of clinically competent dendritic cells from granulocyte colony-stimulating factor-mobilized monocytes for cancer vaccine therapy.
abstract: Recent studies have suggested that dendritic cell (DC)-based immunotherapy is one promising approach for the treatment of cancer. We previously studied the clinical toxicity, feasibility, and efficacy of cancer vaccine therapy with peptide-pulsed DCs. In that study, we used granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood monocytes as a cell source of DCs. However, previous investigations have suggested that G-CSF-mobilized peripheral blood monocytes produce reduced levels of proinflammatory cytokines such as interleukin (IL)-12 and tumor necrosis factor (TNF)-alpha. These T helper (Th)-1-type cytokines are thought to promote antitumor immune response. In this study, we assessed the functional abilities of DCs generated from G-CSF-mobilized monocytes obtained from 13 patients with CEA-positive advanced solid cancers. Peripheral blood mononuclear cells were obtained from leukapheresis products collected before and after systemic administration of G-CSF (subcutaneous administration of high-dose [5-10 microg/kg] human recombinant G-CSF for five consecutive days). In vitro cytokine production profiles after stimulation with lipopolysaccharide (LPS) were compared between monocytes with and without G-CSF mobilization. DCs generated from monocytes were also examined with respect to cytokine production and the capacity to induce peptide-specific T cell responses. Administration of G-CSF was found to efficiently mobilize peripheral blood monocytes. Although G-CSF-mobilized monocytes (G/Mo) less effectively produced Th-1-type cytokines than control monocytes (C/Mo), DCs generated from G/Mo restored the same level of IL-12 production as that seen in DCs generated from C/Mo. T cell induction assay using recall antigen peptide and phenotypic analyses also demonstrated that DCs generated from G/Mo retained characteristics identical to those generated from C/Mo. Our results suggest that G-CSF mobilization can be used to collect monocytes as a cell source for the generation of DCs for cancer immunotherapy. DCs generated in this fashion were pulsed with HLA-A24-restricted CEA epitope peptide and administered to patients safely; immunological responses were induced in some patients.
authors.affiliation: Department of Surgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan. yueda@koto.kpu-m.ac.jp
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ueda
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Itoh
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Fuji
authors.forename: Sachio
authors.initials: S
authors.lastname: Harada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fujiki
authors.forename: Keiji
authors.initials: K
authors.lastname: Shimizu
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shiozaki
authors.forename: Arihiro
authors.initials: A
authors.lastname: Iwamoto
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimizu
authors.forename: Osam
authors.initials: O
authors.lastname: Mazda
authors.forename: Takafumi
authors.initials: T
authors.lastname: Kimura
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Sonoda
authors.forename: Masafumi
authors.initials: M
authors.lastname: Taniwaki
authors.forename: Hisakazu
authors.initials: H
authors.lastname: Yamagishi
mesh_terms: D000328:Adult; D000368:Aged; D019496:Cancer Vaccines / Q000276:immunology* / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000187:drug effects / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000276:immunology* / Q000494:pharmacology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy*; D010455:Peptides / Q000276:immunology; D010641:Phenotype; D010835:Phytohemagglutinins / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology
chemical_list: D019496:Cancer Vaccines; D016207:Cytokines; D010455:Peptides; D010835:Phytohemagglutinins; D016179:Granulocyte Colony-Stimulating Factor