title: Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients.
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.
authors.affiliation: 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.
authors.forename: Duane A
authors.initials: DA
authors.lastname: Mitchell
authors.affiliation: 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.
authors.forename: Kristen A
authors.initials: KA
authors.lastname: Batich
authors.affiliation: 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.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Gunn
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Min-Nung
authors.initials: MN
authors.lastname: Huang
authors.affiliation: Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Luis
authors.initials: L
authors.lastname: Sanchez-Perez
authors.affiliation: Division of Surgical Sciences, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Smita K
authors.initials: SK
authors.lastname: Nair
authors.affiliation: Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Kendra L
authors.initials: KL
authors.lastname: Congdon
authors.affiliation: Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Reap
authors.affiliation: 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.
authors.forename: Gary E
authors.initials: GE
authors.lastname: Archer
authors.affiliation: 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.
authors.forename: Annick
authors.initials: A
authors.lastname: Desjardins
authors.affiliation: 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.
authors.forename: Allan H
authors.initials: AH
authors.lastname: Friedman
authors.affiliation: 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.
authors.forename: Henry S
authors.initials: HS
authors.lastname: Friedman
authors.affiliation: Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Herndon
authors.affiliation: Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: April
authors.initials: A
authors.lastname: Coan
authors.affiliation: 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.
authors.forename: Roger E
authors.initials: RE
authors.lastname: McLendon
authors.affiliation: 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.
authors.forename: David A
authors.initials: DA
authors.lastname: Reardon
authors.affiliation: 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.
authors.forename: James J
authors.initials: JJ
authors.lastname: Vredenburgh
authors.affiliation: 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.
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.affiliation: 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.
authors.forename: John H
authors.initials: JH
authors.lastname: Sampson
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology* / Q000627:therapeutic use; D002465:Cell Movement / Q000187:drug effects; D054405:Chemokine CCL3 / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D008198:Lymph Nodes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D013379:Substrate Specificity; D015996:Survival Rate; D013745:Tetanus Toxoid / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome; D014763:Viral Matrix Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; C515429:CCL3 protein, human; D019496:Cancer Vaccines; C496534:Ccl3 protein, mouse; D054405:Chemokine CCL3; D010750:Phosphoproteins; D013745:Tetanus Toxoid; D014763:Viral Matrix Proteins; C065418:cytomegalovirus matrix protein 65kDa