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.
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: Regina Berger; Heidi Fiegl; Georg Goebel; Petra Obexer; Michael Ausserlechner; Wolfgang Doppler; Cornelia Hauser-Kronberger; Roland Reitsamer; Daniel Egle; Daniel Reimer; Elisabeth Müller-Holzner; Allison Jones; Martin Widschwendter Journal: Cancer Sci Date: 2010-01-12 Impact factor: 6.716
Authors: Jonathan W Friedberg; Jennifer L Kelly; Donna Neuberg; Derick R Peterson; Jeffery L Kutok; Rabih Salloum; Thomas Brenn; David C Fisher; Elizabeth Ronan; Virginia Dalton; Lynn Rich; Diana Marquis; Paul Sims; Paul G Rothberg; Jane Liesveld; Richard I Fisher; Robert Coffman; Tim Mosmann; Arnold S Freedman Journal: Br J Haematol Date: 2009-06-10 Impact factor: 6.998
Authors: Robert J Hopkins; Nancy F Daczkowski; Paulina E Kaptur; Derek Muse; Eric Sheldon; Craig LaForce; Suha Sari; Thomas L Rudge; Edward Bernton Journal: Vaccine Date: 2013-05-10 Impact factor: 3.641