PMID- 24722266
OWN - NLM
STAT- MEDLINE
DCOM- 20150115
LR  - 20231120
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 9
IP  - 4
DP  - 2014
TI  - EGFRvIII-specific chimeric antigen receptor T cells migrate to and kill tumor 
      deposits infiltrating the brain parenchyma in an invasive xenograft model of 
      glioblastoma.
PG  - e94281
LID - 10.1371/journal.pone.0094281 [doi]
LID - e94281
AB  - Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and 
      is uniformly lethal. T-cell-based immunotherapy offers a promising platform for 
      treatment given its potential to specifically target tumor tissue while sparing 
      the normal brain. However, the diffuse and infiltrative nature of these tumors in 
      the brain parenchyma may pose an exceptional hurdle to successful immunotherapy 
      in patients. Areas of invasive tumor are thought to reside behind an intact blood 
      brain barrier, isolating them from effective immunosurveillance and thereby 
      predisposing the development of "immunologically silent" tumor peninsulas. 
      Therefore, it remains unclear if adoptively transferred T cells can migrate to 
      and mediate regression in areas of invasive GBM. One barrier has been the lack of 
      a preclinical mouse model that accurately recapitulates the growth patterns of 
      human GBM in vivo. Here, we demonstrate that D-270 MG xenografts exhibit the 
      classical features of GBM and produce the diffuse and invasive tumors seen in 
      patients. Using this model, we designed experiments to assess whether T cells 
      expressing third-generation chimeric antigen receptors (CARs) targeting the 
      tumor-specific mutation of the epidermal growth factor receptor, EGFRvIII, would 
      localize to and treat invasive intracerebral GBM. EGFRvIII-targeted CAR 
      (EGFRvIII+ CAR) T cells demonstrated in vitro EGFRvIII antigen-specific 
      recognition and reactivity to the D-270 MG cell line, which naturally expresses 
      EGFRvIII. Moreover, when administered systemically, EGFRvIII+ CAR T cells 
      localized to areas of invasive tumor, suppressed tumor growth, and enhanced 
      survival of mice with established intracranial D-270 MG tumors. Together, these 
      data demonstrate that systemically administered T cells are capable of migrating 
      to the invasive edges of GBM to mediate antitumor efficacy and tumor regression.
FAU - Miao, Hongsheng
AU  - Miao H
AD  - Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of 
      Surgery, Duke University Medical Center, Durham, North Carolina, United States of 
      America.
FAU - Choi, Bryan D
AU  - Choi BD
AD  - Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of 
      Surgery, Duke University Medical Center, Durham, North Carolina, United States of 
      America; Department of Pathology, Duke University Medical Center, Durham, North 
      Carolina, United States of America.
FAU - Suryadevara, Carter M
AU  - Suryadevara CM
AD  - Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of 
      Surgery, Duke University Medical Center, Durham, North Carolina, United States of 
      America.
FAU - Sanchez-Perez, Luis
AU  - Sanchez-Perez L
AD  - Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of 
      Surgery, Duke University Medical Center, Durham, North Carolina, United States of 
      America.
FAU - Yang, Shicheng
AU  - Yang S
AD  - Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of 
      Surgery, Duke University Medical Center, Durham, North Carolina, United States of 
      America.
FAU - De Leon, Gabriel
AU  - De Leon G
AD  - Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of 
      Surgery, Duke University Medical Center, Durham, North Carolina, United States of 
      America; Department of Molecular Cancer Biology, Duke University Medical Center, 
      Durham, North Carolina, United States of America.
FAU - Sayour, Elias J
AU  - Sayour EJ
AD  - Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of 
      Surgery, Duke University Medical Center, Durham, North Carolina, United States of 
      America; Department of Pathology, Duke University Medical Center, Durham, North 
      Carolina, United States of America.
FAU - McLendon, Roger
AU  - McLendon R
AD  - Department of Pathology, Duke University Medical Center, Durham, North Carolina, 
      United States of America; The Preston Robert Tisch Brain Tumor Center, Duke 
      University Medical Center, Durham, North Carolina, United States of America.
FAU - Herndon, James E 2nd
AU  - Herndon JE 2nd
AD  - Department of Biostatistics and Bioinformatics, Duke University Medical Center, 
      Durham, North Carolina, United States of America.
FAU - Healy, Patrick
AU  - Healy P
AD  - Department of Biostatistics and Bioinformatics, Duke University Medical Center, 
      Durham, North Carolina, United States of America.
FAU - Archer, Gary E
AU  - Archer GE
AD  - Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of 
      Surgery, Duke University Medical Center, Durham, North Carolina, United States of 
      America; Department of Pathology, Duke University Medical Center, Durham, North 
      Carolina, United States of America; The Preston Robert Tisch Brain Tumor Center, 
      Duke University Medical Center, Durham, North Carolina, United States of America.
FAU - Bigner, Darell D
AU  - Bigner DD
AD  - Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of 
      Surgery, Duke University Medical Center, Durham, North Carolina, United States of 
      America; Department of Pathology, Duke University Medical Center, Durham, North 
      Carolina, United States of America; The Preston Robert Tisch Brain Tumor Center, 
      Duke University Medical Center, Durham, North Carolina, United States of America.
FAU - Johnson, Laura A
AU  - Johnson LA
AD  - Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of 
      Surgery, Duke University Medical Center, Durham, North Carolina, United States of 
      America; The Preston Robert Tisch Brain Tumor Center, Duke University Medical 
      Center, Durham, North Carolina, United States of America.
FAU - Sampson, John H
AU  - Sampson JH
AD  - Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of 
      Surgery, Duke University Medical Center, Durham, North Carolina, United States of 
      America; Department of Pathology, Duke University Medical Center, Durham, North 
      Carolina, United States of America; The Preston Robert Tisch Brain Tumor Center, 
      Duke University Medical Center, Durham, North Carolina, United States of America.
LA  - eng
GR  - 1R01CA177476-01/CA/NCI NIH HHS/United States
GR  - 5P50-NS020023-30/NS/NINDS NIH HHS/United States
GR  - P50 NS020023/NS/NINDS NIH HHS/United States
GR  - R01 CA135272/CA/NCI NIH HHS/United States
GR  - 5R01-CA135272-05/CA/NCI NIH HHS/United States
GR  - R01 CA177476/CA/NCI NIH HHS/United States
GR  - DP2 CA174502/CA/NCI NIH HHS/United States
GR  - P30 CA016520/CA/NCI NIH HHS/United States
GR  - 3R25-NS065731-03S1/NS/NINDS NIH HHS/United States
GR  - T32 GM007171/GM/NIGMS NIH HHS/United States
GR  - 1F30CA177152-01/CA/NCI NIH HHS/United States
GR  - R25 NS065731/NS/NINDS NIH HHS/United States
GR  - F30 CA177152/CA/NCI NIH HHS/United States
GR  - P30 CA014236/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20140410
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (Receptors, Antigen, T-Cell)
RN  - 0 (epidermal growth factor receptor VIII)
RN  - 147336-22-9 (Green Fluorescent Proteins)
RN  - EC 2.7.10.1 (ErbB Receptors)
SB  - IM
MH  - Adoptive Transfer
MH  - Animals
MH  - Antigens, Neoplasm/metabolism
MH  - Brain/immunology/*metabolism
MH  - Brain Neoplasms/*immunology/therapy
MH  - Cell Membrane/metabolism
MH  - Cell Movement
MH  - ErbB Receptors/*metabolism
MH  - Female
MH  - Glioblastoma/*immunology/therapy
MH  - Green Fluorescent Proteins/metabolism
MH  - Humans
MH  - Immunotherapy
MH  - Lentivirus/genetics
MH  - Mice
MH  - Neoplasm Invasiveness
MH  - Neoplasm Transplantation
MH  - Receptors, Antigen, T-Cell/metabolism
MH  - T-Lymphocytes/*metabolism
PMC - PMC3983153
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2014/04/12 06:00
MHDA- 2015/01/16 06:00
PMCR- 2014/04/10
CRDT- 2014/04/12 06:00
PHST- 2013/12/17 00:00 [received]
PHST- 2014/03/14 00:00 [accepted]
PHST- 2014/04/12 06:00 [entrez]
PHST- 2014/04/12 06:00 [pubmed]
PHST- 2015/01/16 06:00 [medline]
PHST- 2014/04/10 00:00 [pmc-release]
AID - PONE-D-13-51021 [pii]
AID - 10.1371/journal.pone.0094281 [doi]
PST - epublish
SO  - PLoS One. 2014 Apr 10;9(4):e94281. doi: 10.1371/journal.pone.0094281. eCollection 
      2014.