EGFRvIII-specific chimeric antigen receptor T cells migrate to and kill tumor deposits infiltrating the brain parenchyma in an invasive xenograft model of glioblastoma.
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.
Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States of America.
Hongsheng
H
Miao
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.
Bryan D
BD
Choi
Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States of America.
Carter M
CM
Suryadevara
Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States of America.
Luis
L
Sanchez-Perez
Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States of America.
Shicheng
S
Yang
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.
Gabriel
G
De Leon
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.
Elias J
EJ
Sayour
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.
Roger
R
McLendon
Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina, United States of America.
James E
JE
Herndon
Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina, United States of America.
Patrick
P
Healy
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.
Gary E
GE
Archer
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.
Darell D
DD
Bigner
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.
Laura A
LA
Johnson
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.
John H
JH
Sampson
D019264:Adoptive Transfer; D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D001921:Brain / Q000276:immunology / Q000378:metabolism*; D001932:Brain Neoplasms / Q000276:immunology* / Q000628:therapy; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D005909:Glioblastoma / Q000276:immunology* / Q000628:therapy; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*
D000951:Antigens, Neoplasm; D011948:Receptors, Antigen, T-Cell; C410723:epidermal growth factor receptor VIII; D049452:Green Fluorescent Proteins; D066246:ErbB Receptors