Abstract | BACKGROUND: 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.
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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 |
Journal | Neuro-oncology
(Neuro Oncol)
Vol. 24
Issue 2
Pg. 259-272
(02 01 2022)
ISSN: 1523-5866 [Electronic] England |
PMID | 34347086
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | © The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected]. |
Chemical References |
- Receptors, Chimeric Antigen
- epidermal growth factor receptor VIII
- ErbB Receptors
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Topics |
- Animals
- Cell Line, Tumor
- ErbB Receptors
- Glioblastoma
(pathology)
- Immunotherapy, Adoptive
(methods)
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Receptors, Chimeric Antigen
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