PMID- 25762141
OWN - NLM
STAT- MEDLINE
DCOM- 20150407
LR  - 20230413
IS  - 1476-4687 (Electronic)
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 519
IP  - 7543
DP  - 2015 Mar 19
TI  - Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma 
      patients.
PG  - 366-9
LID - 10.1038/nature14320 [doi]
AB  - 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.
FAU - Mitchell, Duane A
AU  - Mitchell DA
AD  - 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.
FAU - Batich, Kristen A
AU  - Batich KA
AD  - 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.
FAU - Gunn, Michael D
AU  - Gunn MD
AD  - 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.
FAU - Huang, Min-Nung
AU  - Huang MN
AD  - Department of Immunology, Duke University Medical Center, Durham, North Carolina 
      27710, USA.
FAU - Sanchez-Perez, Luis
AU  - Sanchez-Perez L
AD  - Division of Neurosurgery, Department of Surgery, Duke University Medical Center, 
      Durham, North Carolina 27710, USA.
FAU - Nair, Smita K
AU  - Nair SK
AD  - Division of Surgical Sciences, Department of Surgery, Duke University Medical 
      Center, Durham, North Carolina 27710, USA.
FAU - Congdon, Kendra L
AU  - Congdon KL
AD  - Division of Neurosurgery, Department of Surgery, Duke University Medical Center, 
      Durham, North Carolina 27710, USA.
FAU - Reap, Elizabeth A
AU  - Reap EA
AD  - Division of Neurosurgery, Department of Surgery, Duke University Medical Center, 
      Durham, North Carolina 27710, USA.
FAU - Archer, Gary E
AU  - Archer GE
AD  - 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.
FAU - Desjardins, Annick
AU  - Desjardins A
AD  - 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.
FAU - Friedman, Allan H
AU  - Friedman AH
AD  - 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.
FAU - Friedman, Henry S
AU  - Friedman HS
AD  - 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.
FAU - Herndon, James E 2nd
AU  - Herndon JE 2nd
AD  - Department of Biostatistics and Bioinformatics, Duke University Medical Center, 
      Durham, North Carolina 27710, USA.
FAU - Coan, April
AU  - Coan A
AD  - Department of Biostatistics and Bioinformatics, Duke University Medical Center, 
      Durham, North Carolina 27710, USA.
FAU - McLendon, Roger E
AU  - McLendon RE
AD  - 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.
FAU - Reardon, David A
AU  - Reardon DA
AD  - 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.
FAU - Vredenburgh, James J
AU  - Vredenburgh JJ
AD  - 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.
FAU - Bigner, Darell D
AU  - Bigner DD
AD  - 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.
FAU - Sampson, John H
AU  - Sampson JH
AD  - 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.
LA  - eng
GR  - R01 NS067037/NS/NINDS NIH HHS/United States
GR  - P50 CA108786/CA/NCI NIH HHS/United States
GR  - P50 NS020023/NS/NINDS NIH HHS/United States
GR  - R01-CA134844/CA/NCI NIH HHS/United States
GR  - P01 CA154291/CA/NCI NIH HHS/United States
GR  - R01 CA235612/CA/NCI NIH HHS/United States
GR  - R01 CA134844/CA/NCI NIH HHS/United States
GR  - P01-CA154291-01A1/CA/NCI NIH HHS/United States
GR  - UL1 RR024128/RR/NCRR NIH HHS/United States
GR  - P50-CA108786/CA/NCI NIH HHS/United States
GR  - 1UL2 RR024128-01/RR/NCRR NIH HHS/United States
GR  - P50-NS20023/NS/NINDS NIH HHS/United States
GR  - R01-CA177476-01/CA/NCI NIH HHS/United States
GR  - T32 GM007171/GM/NIGMS NIH HHS/United States
GR  - UL1 TR001427/TR/NCATS NIH HHS/United States
GR  - R01-NS067037/NS/NINDS NIH HHS/United States
GR  - T32 AI052077/AI/NIAID NIH HHS/United States
GR  - R01 CA177476/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20150311
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (CCL3 protein, human)
RN  - 0 (Cancer Vaccines)
RN  - 0 (Ccl3 protein, mouse)
RN  - 0 (Chemokine CCL3)
RN  - 0 (Phosphoproteins)
RN  - 0 (Tetanus Toxoid)
RN  - 0 (Viral Matrix Proteins)
RN  - 0 (cytomegalovirus matrix protein 65kDa)
SB  - IM
CIN - Nature. 2015 Mar 19;519(7543):300-1. PMID: 25762139
CIN - Nat Rev Cancer. 2015 May;15(5):258-9. PMID: 25833215
CIN - Cancer Discov. 2015 Jun;5(6):571. PMID: 25877510
CIN - Nat Rev Drug Discov. 2015 May;14(5):312. PMID: 25907340
MH  - Animals
MH  - Antigens, Neoplasm/immunology
MH  - CD4-Positive T-Lymphocytes/drug effects/immunology
MH  - Cancer Vaccines/administration & dosage/*immunology/therapeutic use
MH  - Cell Movement/drug effects
MH  - Chemokine CCL3/*immunology
MH  - Dendritic Cells/cytology/*drug effects/immunology
MH  - Female
MH  - Glioblastoma/drug therapy/*immunology/pathology/*therapy
MH  - Humans
MH  - Immunotherapy/methods
MH  - Lymph Nodes/cytology/drug effects/immunology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Phosphoproteins/chemistry/genetics/immunology
MH  - Substrate Specificity
MH  - Survival Rate
MH  - Tetanus Toxoid/*administration & dosage/*pharmacology/therapeutic use
MH  - Treatment Outcome
MH  - Viral Matrix Proteins/chemistry/genetics/immunology
PMC - PMC4510871
MID - NIHMS664586
COIS- The authors declare the following competing financial interests: D.A.M., K.A.B., 
      and J.H.S. have filed provisional patents related to the use of Td 
      pre-conditioning as a method to improve immunization efficacy. D.A.M. has served 
      as a paid member of the Schering Plough North American Investigators Advisory 
      Board. S.K.N. is a co-inventor on a patent that describes the use of DCs 
      transfected with tumor antigen encoding RNA that has been licensed by Argos 
      Therapeutics (Durham, NC) through Duke University. S.K.N. has no financial 
      interests in Argos Therapeutics and is not compensated by Argos Therapeutics. 
      D.A.R. has served as paid speaker for Schering/Merck and Genentech/Roche. The 
      remaining authors declare no competing financial interests.
EDAT- 2015/03/13 06:00
MHDA- 2015/04/08 06:00
PMCR- 2015/09/19
CRDT- 2015/03/13 06:00
PHST- 2013/12/06 00:00 [received]
PHST- 2015/02/13 00:00 [accepted]
PHST- 2015/03/13 06:00 [entrez]
PHST- 2015/03/13 06:00 [pubmed]
PHST- 2015/04/08 06:00 [medline]
PHST- 2015/09/19 00:00 [pmc-release]
AID - nature14320 [pii]
AID - 10.1038/nature14320 [doi]
PST - ppublish
SO  - Nature. 2015 Mar 19;519(7543):366-9. doi: 10.1038/nature14320. Epub 2015 Mar 11.