Novel EGFRvIII-CAR transgenic mice for rigorous preclinical studies in syngeneic mice
| Autor: | Pavlina Chuntova, Kira Downey, Ryusuke Hatae, Tiffany A Chen, Abigail L Mende, Megan Montoya, Bjoern Schwer, Jayne Skinner, Hideho Okada, Gary Kohanbash, Takahide Nejo, Yitzhar E. Goretsky, Yafei Hou, Hong-Erh Liang, David Diebold, Akane Yamamichi, Ryosuke Naka |
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| Rok vydání: | 2021 |
| Předmět: |
EGFRvIII
Genetically modified mouse Cancer Research Transgene medicine.medical_treatment Adoptive Oncology and Carcinogenesis Mice Transgenic Biology Inbred C57BL Immunotherapy Adoptive Transgenic Cell Line Viral vector Vaccine Related Mice Rare Diseases In vivo Cell Line Tumor Receptors Genetics medicine Animals Cytotoxic T cell Oncology & Carcinogenesis Epidermal growth factor receptor Cancer Receptors Chimeric Antigen Tumor CART cells glioblastoma Neurosciences Chimeric Antigen Gene Therapy Immunotherapy Chimeric antigen receptor Brain Disorders Mice Inbred C57BL ErbB Receptors Brain Cancer Oncology Basic and Translational Investigations Cancer research biology.protein Immunization immunotherapy Neurology (clinical) Glioblastoma |
| Zdroj: | Neuro-oncology, vol 24, iss 2 Neuro Oncol |
| ISSN: | 1523-5866 1522-8517 |
| DOI: | 10.1093/neuonc/noab182 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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