EGFRvIII mCAR-modified T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss

Journal Article

Purpose: 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. Experimental Design: 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 EGFRvIIImCART 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 EGFRvIIINEG tumors, suggesting generation of host immunity against additional tumor antigens. Conclusion: 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. © 2014 American Association for Cancer Research.

Full Text

Duke Authors

Cited Authors

  • Sampson, JH; Choi, BD; Sanchez-Perez, L; Suryadevara, CM; Snyder, DJ; Flores, CT; Schmittling, RJ; Nair, SK; Reap, EA; Norberg, PK; Herndon, JE; Kuan, CT; Morgan, RA; Rosenberg, SA; Johnson, LA

Published Date

  • February 26, 2014

Published In

Volume / Issue

  • 20 / 4

Start / End Page

  • 972 - 984

Electronic International Standard Serial Number (EISSN)

  • 1557-3265

International Standard Serial Number (ISSN)

  • 1078-0432

Digital Object Identifier (DOI)

  • 10.1158/1078-0432.CCR-13-0709

Citation Source

  • Scopus