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

Cancer Immunol Immunother. 2007 Mar;56(3):381-9. doi: 10.1007/s00262-006-0197-8. Epub 2006 Jul 8.

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.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • Peptides / immunology
  • Phenotype
  • Phytohemagglutinins / pharmacology
  • Structure-Activity Relationship
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • Th2 Cells / drug effects
  • Th2 Cells / immunology

Substances

  • Cancer Vaccines
  • Cytokines
  • Peptides
  • Phytohemagglutinins
  • Granulocyte Colony-Stimulating Factor