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Publications

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Ppublish 11 citations

PubMed: 34347086 DOI: 10.1093/neuonc/noab182

Novel EGFRvIII-CAR transgenic mice for rigorous preclinical studies in syngeneic mice.

Neuro Oncol 24(2):259-272

Authors: Pavlina Chuntova, Yafei Hou, Ryosuke Naka, Akane Yamamichi, Tiffany Chen, Yitzhar Goretsky, Ryusuke Hatae, Takahide Nejo, Gary Kohanbash, Abigail L Mende, Megan Montoya, Kira M Downey, David Diebold, Jayne Skinner, Hong-Erh Liang, Bjoern Schwer, Hideho Okada

Affiliations

  • Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
  • Japanese Red Cross Osaka Hospital, Osaka City, Japan.
  • Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
  • Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
  • Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.
  • The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, California, USA.
  • Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, California, USA.
  • The Parker Institute for Cancer Immunotherapy, San Francisco, California, USA.

Abstract

BACKGROUND

Rigorous preclinical studies of chimeric antigen receptor (CAR) immunotherapy will require large quantities of consistent and high-quality CAR-transduced T (CART) cells that can be used in syngeneic mouse glioblastoma (GBM) models. To this end, we developed a novel transgenic (Tg) mouse strain with a fully murinized CAR targeting epidermal growth factor receptor variant III (EGFRvIII).

METHODS

We first established the murinized version of EGFRvIII-CAR and validated its function using a retroviral vector (RV) in C57BL/6J mice bearing syngeneic SB28 GBM expressing EGFRvIII. Next, we created C57BL/6J-background Tg mice carrying the anti-EGFRvIII-CAR downstream of a Lox-Stop-Lox cassette in the Rosa26 locus. We bred these mice with CD4-Cre Tg mice to allow CAR expression on T cells and evaluated the function of the CART cells both in vitro and in vivo. To inhibit immunosuppressive myeloid cells within SB28 GBM, we also evaluated a combination approach of CART and an anti-EP4 compound (ONO-AE3-208).

RESULTS

Both RV- and Tg-CART cells demonstrated specific cytotoxic activities against SB28-EGFRvIII cells. A single intravenous infusion of EGFRvIII-CART cells prolonged the survival of glioma-bearing mice when preceded by a lymphodepletion regimen with recurrent tumors displaying profound EGFRvIII loss. The addition of ONO-AE3-208 resulted in long-term survival in a fraction of CART-treated mice and those survivors demonstrated delayed growth of subcutaneously re-challenged both EGFRvIII+ and parental EGFRvIII- SB28.

CONCLUSION

Our new syngeneic CAR Tg mouse model can serve as a useful tool to address clinically relevant questions and develop future immunotherapeutic strategies.

MeSH

Brain Neoplasms, Cells, Growth, Immunotherapy, Glioblastoma

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