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

Miao, Hongsheng

Choi, Bryan D

Suryadevara, Carter M

Sanchez-Perez, Luis

Yang, Shicheng

De Leon, Gabriel

Sayour, Elias J

McLendon, Roger

Herndon, James E

Healy, Patrick

Archer, Gary E

Bigner, Darell D

Johnson, Laura A

Sampson, John H

Castro, Maria G

United States

2018-03-01T14:24:05Z

2018-03-01T14:24:05Z

2014

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.

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

PONE-D-13-51021

1932-6203

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

eng

Public Library of Science (PLoS)

PLoS One

10.1371/journal.pone.0094281

Adoptive Transfer

Animals

Antigens, Neoplasm

Brain

Brain Neoplasms

Cell Membrane

Cell Movement

Female

Glioblastoma

Green Fluorescent Proteins

Humans

Immunotherapy

Lentivirus

Mice

Neoplasm Invasiveness

Neoplasm Transplantation

Receptor, Epidermal Growth Factor

Receptors, Antigen, T-Cell

T-Lymphocytes

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

Journal article

McLendon, Roger|0000-0001-6682-4588

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

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

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

e94281

4

Basic Science Departments

Biostatistics & Bioinformatics

Clinical Science Departments

Duke

Duke Cancer Institute

Immunology

Institutes and Centers

Neurosurgery

Orthopaedics

Pathology

Radiation Oncology

School of Medicine

Surgery

Published online

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