IL13RA2-integrated genetically engineered mouse model allows for CAR T cells targeting pediatric high-grade gliomas

Area of Science:

• Neuro-oncology
• Immunotherapy
• Genetically Engineered Mouse Models (GEMM)

Background:

• Pediatric high-grade gliomas (pHGG) and diffuse midline gliomas (pDMG) lack effective treatments.
• Current immunotherapy research is hindered by the absence of immunocompetent animal models.

Purpose of the Study:

• To develop a fully immunocompetent, genetically engineered mouse model (GEMM) for pHGG and pDMG.
• To incorporate the glioma-associated antigen, interleukin 13 receptor alpha 2 (IL13RA2), for targeted therapy evaluation.
• To assess the preclinical efficacy of IL13RA2-targeted immunotherapies.

Main Methods:

• Utilized the RCAS-Tva delivery system in Nestin-Tva mice for gliomagenesis.
• Induced tumors by overexpressing PDGFB and deleting p53 and/or PTEN, with or without IL13RA2.
• Administered CAR T-cell treatment targeting IL13RA2 in the developed mouse model.

Main Results:

• De novo gliomas formed with and without IL13RA2 expression, showing similar onset.
• Tumors exhibited high-grade glioma characteristics, including infiltration and necrosis.
• IL13RA2-targeted CAR T-cell therapy significantly improved survival (46 days vs. 28 days) and achieved 25% long-term survival.

Conclusions:

• The developed GEMM is suitable for studying pDMG and pHGG in an immunocompetent setting.
• This model enables effective preclinical evaluation of IL13RA2-directed immunotherapies.
• The model shows promise for advancing the clinical application of targeted glioma therapies.