EGFRvIII-specific chimeric antigen receptor T cells migrate to and kill tumor deposits infiltrating the brain parenchyma in an invasive xenograft model of glioblastoma.

dc.contributor.author

Miao, Hongsheng

dc.contributor.author

Choi, Bryan D

dc.contributor.author

Suryadevara, Carter M

dc.contributor.author

Sanchez-Perez, Luis

dc.contributor.author

Yang, Shicheng

dc.contributor.author

De Leon, Gabriel

dc.contributor.author

Sayour, Elias J

dc.contributor.author

McLendon, Roger

dc.contributor.author

Herndon, James E

dc.contributor.author

Healy, Patrick

dc.contributor.author

Archer, Gary E

dc.contributor.author

Bigner, Darell D

dc.contributor.author

Johnson, Laura A

dc.contributor.author

Sampson, John H

dc.contributor.editor

Castro, Maria G

dc.coverage.spatial

United States

dc.date.accessioned

2018-03-01T14:24:05Z

dc.date.available

2018-03-01T14:24:05Z

dc.date.issued

2014

dc.description.abstract

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.

dc.identifier

https://www.ncbi.nlm.nih.gov/pubmed/24722266

dc.identifier

PONE-D-13-51021

dc.identifier.eissn

1932-6203

dc.identifier.uri

https://hdl.handle.net/10161/16108

dc.language

eng

dc.publisher

Public Library of Science (PLoS)

dc.relation.ispartof

PLoS One

dc.relation.isversionof

10.1371/journal.pone.0094281

dc.subject

Adoptive Transfer

dc.subject

Animals

dc.subject

Antigens, Neoplasm

dc.subject

Brain

dc.subject

Brain Neoplasms

dc.subject

Cell Membrane

dc.subject

Cell Movement

dc.subject

Female

dc.subject

Glioblastoma

dc.subject

Green Fluorescent Proteins

dc.subject

Humans

dc.subject

Immunotherapy

dc.subject

Lentivirus

dc.subject

Mice

dc.subject

Neoplasm Invasiveness

dc.subject

Neoplasm Transplantation

dc.subject

Receptor, Epidermal Growth Factor

dc.subject

Receptors, Antigen, T-Cell

dc.subject

T-Lymphocytes

dc.title

EGFRvIII-specific chimeric antigen receptor T cells migrate to and kill tumor deposits infiltrating the brain parenchyma in an invasive xenograft model of glioblastoma.

dc.type

Journal article

duke.contributor.orcid

McLendon, Roger|0000-0001-6682-4588

duke.contributor.orcid

Bigner, Darell D|0000-0001-5548-4899

duke.contributor.orcid

Sampson, John H|0000-0002-0104-7658

pubs.author-url

https://www.ncbi.nlm.nih.gov/pubmed/24722266

pubs.begin-page

e94281

pubs.issue

4

pubs.organisational-group

Basic Science Departments

pubs.organisational-group

Biostatistics & Bioinformatics

pubs.organisational-group

Clinical Science Departments

pubs.organisational-group

Duke

pubs.organisational-group

Duke Cancer Institute

pubs.organisational-group

Immunology

pubs.organisational-group

Institutes and Centers

pubs.organisational-group

Neurosurgery

pubs.organisational-group

Orthopaedics

pubs.organisational-group

Pathology

pubs.organisational-group

Radiation Oncology

pubs.organisational-group

School of Medicine

pubs.organisational-group

Surgery

pubs.publication-status

Published online

pubs.volume

9

Files

Original bundle

Now showing 1 - 1 of 1
Loading...
Thumbnail Image
Name:
EGFRvIII-specific chimeric antigen receptor T cells migrate to and kill tumor deposits infiltrating the brain parenchyma in an invasive xenograft model of glioblastoma.pdf
Size:
942.58 KB
Format:
Adobe Portable Document Format