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Updated: Jun 17, 2025
Generation of CAR T Cells for Adoptive Therapy in the Context of Glioblastoma Standard of Care
Published on: February 16, 2015
EphA3-targeted chimeric antigen receptor T cells are effective in glioma and generate curative memory T cell
Leesa Lertsumitkul1,2, Melinda Iliopoulos1, Stacie S Wang1,3
1Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
Background:
High-grade gliomas including glioblastoma (GBM) and diffuse midline gliomas (DMG) represent the most lethal and aggressive brain cancers where current treatment modalities offer limited efficacy. Chimeric antigen receptor (CAR) T cell therapies have emerged as a promising strategy, boasting tumor-specific targeting and the unique ability to penetrate the blood-brain barrier. However, the effective clinical application hinges on the optimal choice of antigen, with a limited number, currently under investigation.
Methods:
We employed cell surface proteomic analysis of primary human high-grade glioma samples from both adult and pediatric patients. This led to the identification of Ephrin type-A receptor 3 (EphA3) as a prevalently expressed target. We engineered a second-generation EphA3-targeted CAR T cell and assessed function using in vitro and in vivo models of GBM and DMG.
Results:
EphA3-targeted CAR T cells demonstrated robust antigen-specific killing of human GBM and DMG cell lines in vitro. In an orthotopic xenograft NSG mouse model, EphA3-targeted CAR T cells not only effectively eradicated tumors but also established a functional T cell population protective on rechallenge. Remarkably, mice rechallenged with a second contralateral orthotopic tumor implantation achieved complete tumor clearance and maintained a sustained complete response 6 months following initial treatment.
Conclusion:
Building on the proven safety profile of EphA3 antibodies in clinical settings, our study provides compelling preclinical evidence supporting the efficacy of EphA3-targeted CAR T cells against high-grade gliomas. These findings underscore the potential for transitioning this innovative therapy into clinical trials, aiming to revolutionize the treatment landscape for patients afflicted with these formidable brain cancers.
Insights
Chimeric antigen receptor (CAR) T cell therapy targeting Ephrin type-A receptor 3 (EphA3) shows promise for treating aggressive brain cancers like glioblastoma (GBM) and diffuse midline gliomas (DMG). Preclinical studies demonstrate EphA3-targeted CAR T cells effectively eliminate tumors and provide long-term protection.
Area of Science:
- Neuro-oncology
- Immunotherapy
- Cellular therapy
Background:
- High-grade gliomas (GBM, DMG) are lethal brain cancers with limited treatment options.
- Chimeric antigen receptor (CAR) T cell therapy offers targeted treatment and blood-brain barrier penetration.
- Identifying optimal tumor antigens is crucial for CAR T cell therapy's clinical success.
Purpose of the Study:
- To identify novel cell surface targets for CAR T cell therapy in high-grade gliomas.
- To evaluate the efficacy of Ephrin type-A receptor 3 (EphA3)-targeted CAR T cells against GBM and DMG.
Main Methods:
- Cell surface proteomic analysis of primary human glioma samples.
- Engineering of a second-generation EphA3-targeted CAR T cell.
- In vitro and in vivo assessment of CAR T cell function in GBM and DMG models.
Main Results:
- EphA3-targeted CAR T cells demonstrated specific killing of GBM and DMG cell lines in vitro.
- In vivo studies showed tumor eradication and protective immunity upon rechallenge.
- Sustained complete response observed in mice rechallenged with contralateral tumors.
Conclusions:
- EphA3 is a promising target for CAR T cell therapy in high-grade gliomas.
- Preclinical data support the efficacy and potential for clinical translation of EphA3-targeted CAR T cells.
- This therapy could revolutionize treatment for aggressive brain cancers.
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