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Nature. 2015 Mar 19;519(7543):366-9. doi: 10.1038/nature14320. Epub 2015 Mar 11.

Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients.

Author information

1
1] Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina 27710, USA [2] Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA [3] Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA.
2
1] Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA [2] Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA.
3
1] Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA [2] Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710, USA.
4
Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710, USA.
5
Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
6
Division of Surgical Sciences, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
7
1] Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina 27710, USA [2] Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
8
Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina 27710, USA.
9
1] Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina 27710, USA [2] Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA.
10
1] Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina 27710, USA [2] Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA [3] Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA [4] Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710, USA [5] Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA.

Abstract

After stimulation, dendritic cells (DCs) mature and migrate to draining lymph nodes to induce immune responses. As such, autologous DCs generated ex vivo have been pulsed with tumour antigens and injected back into patients as immunotherapy. While DC vaccines have shown limited promise in the treatment of patients with advanced cancers including glioblastoma, the factors dictating DC vaccine efficacy remain poorly understood. Here we show that pre-conditioning the vaccine site with a potent recall antigen such as tetanus/diphtheria (Td) toxoid can significantly improve the lymph node homing and efficacy of tumour-antigen-specific DCs. To assess the effect of vaccine site pre-conditioning in humans, we randomized patients with glioblastoma to pre-conditioning with either mature DCs or Td unilaterally before bilateral vaccination with DCs pulsed with Cytomegalovirus phosphoprotein 65 (pp65) RNA. We and other laboratories have shown that pp65 is expressed in more than 90% of glioblastoma specimens but not in surrounding normal brain, providing an unparalleled opportunity to subvert this viral protein as a tumour-specific target. Patients given Td had enhanced DC migration bilaterally and significantly improved survival. In mice, Td pre-conditioning also enhanced bilateral DC migration and suppressed tumour growth in a manner dependent on the chemokine CCL3. Our clinical studies and corroborating investigations in mice suggest that pre-conditioning with a potent recall antigen may represent a viable strategy to improve anti-tumour immunotherapy.

PMID:
25762141
PMCID:
PMC4510871
DOI:
10.1038/nature14320
[Indexed for MEDLINE]
Free PMC Article

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