Your browser doesn't support javascript.
loading
Novel EGFRvIII-CAR transgenic mice for rigorous preclinical studies in syngeneic mice.
Chuntova, Pavlina; Hou, Yafei; Naka, Ryosuke; Yamamichi, Akane; Chen, Tiffany; Goretsky, Yitzhar; Hatae, Ryusuke; Nejo, Takahide; Kohanbash, Gary; Mende, Abigail L; Montoya, Megan; Downey, Kira M; Diebold, David; Skinner, Jayne; Liang, Hong-Erh; Schwer, Bjoern; Okada, Hideho.
Afiliação
  • Chuntova P; Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
  • Hou Y; Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
  • Naka R; Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
  • Yamamichi A; Japanese Red Cross Osaka Hospital, Osaka City, Japan.
  • Chen T; Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
  • Goretsky Y; Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
  • Hatae R; Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
  • Nejo T; Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
  • Kohanbash G; Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
  • Mende AL; Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
  • Montoya M; Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
  • Downey KM; Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
  • Diebold D; Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
  • Skinner J; Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
  • Liang HE; Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
  • Schwer B; Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.
  • Okada H; Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
Neuro Oncol ; 24(2): 259-272, 2022 02 01.
Article em En | MEDLINE | ID: mdl-34347086
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.
Assuntos
Palavras-chave
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Imunoterapia Adotiva / Glioblastoma / Receptores ErbB / Receptores de Antígenos Quiméricos Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2022 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Imunoterapia Adotiva / Glioblastoma / Receptores ErbB / Receptores de Antígenos Quiméricos Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2022 Tipo de documento: Article