CpG oligodeoxynucleotides alter lymphocyte and dendritic cell trafficking in humans

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

Research output: Contribution to journalArticle

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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 chemoattractTcells. 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 rolefor targeted injections of CpG-ODN to direct lymphocyte migration to specific sites suchas the tumor bed.

Original languageEnglish (US)
Pages (from-to)5626-5634
Number of pages9
JournalClinical Cancer Research
Volume14
Issue number17
DOIs
StatePublished - Sep 1 2008
Externally publishedYes

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Human Trafficking
Oligodeoxyribonucleotides
Dendritic Cells
Lymphocytes
Granulocyte-Macrophage Colony-Stimulating Factor
T-Lymphocytes
Subunit Vaccines
Chemokines
Cell Movement
Immunity
Vaccines
Lymphopenia
Cancer Vaccines
Neoplasm Antigens
Antigen-Presenting Cells

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Haining, W. N., Davies, J., Kanzler, H., Drury, L., Brenn, T., Evans, J., ... Nadler, L. M. (2008). CpG oligodeoxynucleotides alter lymphocyte and dendritic cell trafficking in humans. Clinical Cancer Research, 14(17), 5626-5634. https://doi.org/10.1158/1078-0432.CCR-08-0526

CpG oligodeoxynucleotides alter lymphocyte and dendritic cell trafficking in humans. / Haining, W. Nicholas; Davies, Jeffrey; Kanzler, Holger; Drury, Linda; Brenn, Thomas; Evans, John; Angelosanto, Jill; Rivoli, Steven; Russell, Kate; George, Suzanne; Sims, Paul; Neuberg, Donna; Li, Xiaochun; Kutok, Jeffrey; Morgan, Jeffrey; Wen, Patrick; Demetri, George; Coffman, Robert L.; Nadler, Lee M.

In: Clinical Cancer Research, Vol. 14, No. 17, 01.09.2008, p. 5626-5634.

Research output: Contribution to journalArticle

Haining, WN, Davies, J, Kanzler, H, Drury, L, Brenn, T, Evans, J, Angelosanto, J, Rivoli, S, Russell, K, George, S, Sims, P, Neuberg, D, Li, X, Kutok, J, Morgan, J, Wen, P, Demetri, G, Coffman, RL & Nadler, LM 2008, 'CpG oligodeoxynucleotides alter lymphocyte and dendritic cell trafficking in humans', Clinical Cancer Research, vol. 14, no. 17, pp. 5626-5634. https://doi.org/10.1158/1078-0432.CCR-08-0526
Haining, W. Nicholas ; Davies, Jeffrey ; Kanzler, Holger ; Drury, Linda ; Brenn, Thomas ; Evans, John ; Angelosanto, Jill ; Rivoli, Steven ; Russell, Kate ; George, Suzanne ; Sims, Paul ; Neuberg, Donna ; Li, Xiaochun ; Kutok, Jeffrey ; Morgan, Jeffrey ; Wen, Patrick ; Demetri, George ; Coffman, Robert L. ; Nadler, Lee M. / CpG oligodeoxynucleotides alter lymphocyte and dendritic cell trafficking in humans. In: Clinical Cancer Research. 2008 ; Vol. 14, No. 17. pp. 5626-5634.
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T1 - CpG oligodeoxynucleotides alter lymphocyte and dendritic cell trafficking in humans

AU - Haining, W. Nicholas

AU - Davies, Jeffrey

AU - Kanzler, Holger

AU - Drury, Linda

AU - Brenn, Thomas

AU - Evans, John

AU - Angelosanto, Jill

AU - Rivoli, Steven

AU - Russell, Kate

AU - George, Suzanne

AU - Sims, Paul

AU - Neuberg, Donna

AU - Li, Xiaochun

AU - Kutok, Jeffrey

AU - Morgan, Jeffrey

AU - Wen, Patrick

AU - Demetri, George

AU - Coffman, Robert L.

AU - Nadler, Lee M.

PY - 2008/9/1

Y1 - 2008/9/1

N2 - 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 chemoattractTcells. 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 rolefor targeted injections of CpG-ODN to direct lymphocyte migration to specific sites suchas the tumor bed.

AB - 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 chemoattractTcells. 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 rolefor targeted injections of CpG-ODN to direct lymphocyte migration to specific sites suchas the tumor bed.

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