title: EGFRvIII mCAR-modified T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss.
abstract: OBJECTIVE
  Chimeric antigen receptor (CAR) transduced T cells represent a promising immune therapy that has been shown to successfully treat cancers in mice and humans. However, CARs targeting antigens expressed in both tumors and normal tissues have led to significant toxicity. Preclinical studies have been limited by the use of xenograft models that do not adequately recapitulate the immune system of a clinically relevant host. A constitutively activated mutant of the naturally occurring epidermal growth factor receptor (EGFRvIII) is antigenically identical in both human and mouse glioma, but is also completely absent from any normal tissues.
  
  
  METHODS
  We developed a third-generation, EGFRvIII-specific murine CAR (mCAR), and performed tests to determine its efficacy in a fully immunocompetent mouse model of malignant glioma.
  
  
  RESULTS
  At elevated doses, infusion with EGFRvIII mCAR T cells led to cures in all mice with brain tumors. In addition, antitumor efficacy was found to be dependent on lymphodepletive host conditioning. Selective blockade with EGFRvIII soluble peptide significantly abrogated the activity of EGFRvIII mCAR T cells in vitro and in vivo, and may offer a novel strategy to enhance the safety profile for CAR-based therapy. Finally, mCAR-treated, cured mice were resistant to rechallenge with EGFRvIII(NEG) tumors, suggesting generation of host immunity against additional tumor antigens.
  
  
  CONCLUSIONS
  All together, these data support that third-generation, EGFRvIII-specific mCARs are effective against gliomas in the brain and highlight the importance of syngeneic, immunocompetent models in the preclinical evaluation of tumor immunotherapies.
authors.affiliation: Authors' Affiliations: Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of Surgery; Department of Pathology; The Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical Center; Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina; and Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: John H
authors.initials: JH
authors.lastname: Sampson
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Choi
authors.forename: Luis
authors.initials: L
authors.lastname: Sanchez-Perez
authors.forename: Carter M
authors.initials: CM
authors.lastname: Suryadevara
authors.forename: David J
authors.initials: DJ
authors.lastname: Snyder
authors.forename: Catherine T
authors.initials: CT
authors.lastname: Flores
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schmittling
authors.forename: Smita K
authors.initials: SK
authors.lastname: Nair
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Reap
authors.forename: Pamela K
authors.initials: PK
authors.lastname: Norberg
authors.forename: James E
authors.initials: JE
authors.lastname: Herndon
authors.forename: Chien-Tsun
authors.initials: CT
authors.lastname: Kuan
authors.forename: Richard A
authors.initials: RA
authors.lastname: Morgan
authors.forename: Steven A
authors.initials: SA
authors.lastname: Rosenberg
authors.forename: Laura A
authors.initials: LA
authors.lastname: Johnson
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001254:Astrocytoma / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D001932:Brain Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D057127:Single-Chain Antibodies / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation
chemical_list: D011948:Receptors, Antigen, T-Cell; D057127:Single-Chain Antibodies; C410723:epidermal growth factor receptor VIII; D066246:ErbB Receptors