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Updated: Jun 4, 2025
Intracranial Cannula Implantation for Serial Locoregional Chimeric Antigen Receptor CAR T Cell Infusions in Mice
Published on: February 24, 2023
IL13RA2-integrated genetically engineered mouse model allows for CAR T cells targeting pediatric high-grade gliomas
Maggie Seblani1, Markella Zannikou2, Joseph Duffy2
1Lurie Children's Hospital.
Abstract:
Pediatric high-grade gliomas (pHGG) and pediatric diffuse midline gliomas (pDMG) are devastating diseases without durable and curative options. Although targeted immunotherapy has shown promise, the field lacks immunocompetent animal models to study these processes in detail. To achieve this, we developed a fully immunocompetent, genetically engineered mouse model (GEMM) for pDMG and pHGG that incorporates the glioma-associated antigen, interleukin 13 receptor alpha 2 (IL13RA2). Utilizing the RCAS-Tva delivery system in Nestin-Tva mice, we induced gliomagenesis by overexpressing PDGFB and deleting p53 (p53fl/fl) or both p53 and PTEN (p53fl/fl PTENfl/fl), with or without IL13RA2 in neonatal mice. De novo tumors developed in models with and without IL13RA2, showing no statistical difference in onset (n = 33, 38 days, p = 0.62). The p53fl/fl PTENfl/fl tumors displayed more aggressive characteristics (n = 12, 31 days). Tumors exhibited features typical of high-grade glioma, including infiltration, pseudopalisading necrosis, and microvascular proliferation. They also showed a high Ki-67 index, variable IL13RA2 expression, a high frequency of CD11b + macrophages, and a low proportion of CD3 + T cells. The model proved effective for evaluating IL13RA2-targeted immunotherapies, with a significant response to CAR T-cell treatment that extended survival (46 days vs. 28 days control; p < 0.0001) and achieved 25% long-term survival in mice. This model facilitates the preclinical assessment of IL13RA2-directed therapies and holds potential for clinical application.
Insights
Researchers developed a new immunocompetent mouse model for pediatric gliomas (pDMG/pHGG) incorporating IL13RA2. This model successfully evaluated IL13RA2-targeted immunotherapy, significantly improving survival in preclinical studies.
Area of Science:
- Neuro-oncology
- Immunotherapy
- Genetically Engineered Mouse Models
Background:
- Pediatric high-grade gliomas (pHGG) and diffuse midline gliomas (pDMG) lack effective treatments.
- Targeted immunotherapies show promise but require suitable preclinical models.
- Existing models often lack a fully functional immune system for studying immunotherapy.
Purpose of the Study:
- To develop a fully immunocompetent, genetically engineered mouse model (GEMM) for pDMG and pHGG.
- To incorporate the glioma-associated antigen, interleukin 13 receptor alpha 2 (IL13RA2), for targeted therapy evaluation.
- To assess the efficacy of IL13RA2-targeted immunotherapy in this novel preclinical model.
Main Methods:
- Utilized the RCAS-Tva system in Nestin-Tva mice for gliomagenesis.
- Induced tumors by overexpressing PDGFB and deleting p53 or both p53 and PTEN.
- Incorporated IL13RA2 expression in some models for targeted therapy studies.
Main Results:
- Developed de novo pDMG/pHGG models with or without IL13RA2, exhibiting aggressive glioma features.
- Observed no significant difference in tumor onset between models with or without IL13RA2.
- Demonstrated significant survival extension (p < 0.0001) and 25% long-term survival with CAR T-cell therapy targeting IL13RA2.
Conclusions:
- The developed GEMM is a valuable tool for preclinical evaluation of IL13RA2-targeted therapies for pediatric gliomas.
- This model recapitulates key features of human gliomas and the tumor microenvironment.
- The findings support the potential clinical application of IL13RA2-directed immunotherapies in pediatric glioma patients.
