CpG oligodeoxynucleotides alter lymphocyte and dendritic cell trafficking in humans.

Abstract

PURPOSE:

CpG oligodeoxynucleotides (CpG-ODN) are being investigated as cancer vaccine adjuvants because they mature plasmacytoid dendritic cells (PDC) into potent antigen-presenting cells. CpG-ODN also induce PDC to secrete chemokines that alter lymphocyte migration. Whether CpG-ODN TLR signals enhance antigen-specific immunity and/or trafficking in humans is unknown.

EXPERIMENTAL DESIGN:

We conducted a phase I study of CpG-ODN (1018 ISS) given as a vaccine adjuvant with granulocyte-macrophage colony-stimulating factor (GM-CSF) to induce T-cell immunity to a peptide vaccine from the tumor-associated antigen hTERT.

RESULTS:

The adjuvant effect was limited; only 1 of 16 patients showed a high-frequency hTERT-specific tetramer CD8(+) T-cell response. However, CpG-ODN induced marked, transient peripheral blood lymphopenia. Biopsies showed dense lymphocytic infiltration at the vaccine site clustered around activated PDC. In vitro, CpG-ODN-treated PDC induced T-cell migration, showing that CpG-ODN stimulation of human PDC was sufficient to chemoattract T cells.

CONCLUSIONS:

Our results show that (a) CpG-ODN with GM-CSF may not be an effective adjuvant strategy for hTERT peptide vaccines but (b) GM-CSF/CpG-ODN causes a PDC-mediated chemokine response that recruits T-cell migration to the peripheral tissues. These findings suggest a novel therapeutic role for targeted injections of CpG-ODN to direct lymphocyte migration to specific sites such as the tumor bed.

• Authors: W Nicholas Haining, Jeffrey Davies, Holger Kanzler, Linda Drury, Thomas Brenn, John Evans, Jill Angelosanto, Steven Rivoli, Kate Russell, Suzanne George, Paul Sims, Donna Neuberg, Xiaochun Li, Jeffrey Kutok, Jeffrey Morgan, Patrick Wen, George Demetri, Robert L Coffman, Lee M Nadler
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 14 Issue 17 Pg. 5626-34 (Sep 01 2008) ISSN: 1078-0432 [Print] United States
• PMID: 18765557 (Publication Type: Clinical Trial, Phase I, Journal Article)

Chemical References

• Adjuvants, Immunologic
• CPG-oligonucleotide
• Cancer Vaccines
• Oligodeoxyribonucleotides
• TLR9 protein, human
• Toll-Like Receptor 9
• Vaccines, Subunit
• Granulocyte-Macrophage Colony-Stimulating Factor
• TERT protein, human
• Telomerase

Topics

• Adjuvants, Immunologic
• Cancer Vaccines (adverse effects, therapeutic use)
• Cell Movement
• Dendritic Cells (immunology)
• Granulocyte-Macrophage Colony-Stimulating Factor (immunology)
• Humans
• Oligodeoxyribonucleotides (immunology, therapeutic use)
• T-Lymphocytes (immunology)
• Telomerase (immunology)
• Toll-Like Receptor 9 (antagonists & inhibitors)
• Vaccines, Subunit (therapeutic use)