Successful induction of clinically competent dendritic cells from granulocyte colony-stimulating factor-mobilized monocytes for cancer vaccine therapy

• Published in: Cancer Immunology, Immunotherapy Immunotherapy, 2007-03, Vol.56 (3), p.381-389
• Main Authors: Ueda, Yuji, Itoh, Tsuyoshi, Fuji, Nobuaki, Harada, Sachio, Fujiki, Hiroshi, Shimizu, Keiji, Shiozaki, Atsushi, Iwamoto, Arihiro, Shimizu, Takeshi, Mazda, Osam, Kimura, Takafumi, Sonoda, Yoshiaki, Taniwaki, Masafumi, Yamagishi, Hisakazu
• Format: Article
• Language: English
• Subjects: Adult; Aged; Cancer Vaccines - immunology; Cancer Vaccines - therapeutic use; Cell Proliferation - drug effects; Cytokines - drug effects; Cytokines - immunology; Dendritic Cells - cytology; Dendritic Cells - immunology; Female; Granulocyte Colony-Stimulating Factor - immunology; Granulocyte Colony-Stimulating Factor - pharmacology; Humans; Male; Middle Aged; Monocytes - drug effects; Monocytes - immunology; Neoplasms - immunology; Neoplasms - therapy; Original; Peptides - immunology; Phenotype; Phytohemagglutinins - pharmacology; Structure-Activity Relationship; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Th2 Cells - drug effects; Th2 Cells - immunology
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-006-0197-8

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.