Related Experiment Video
Updated: Feb 28, 2026
Generation of CAR T Cells for Adoptive Therapy in the Context of Glioblastoma Standard of Care
Published on: February 16, 2015
Antigen Specificity and Cell Engineering Determine CAR T Cell Efficacy in Group 3 Medulloblastoma
Giedre Krenciute1, Meghan Ward1, Justine Fouliard2
1St. Jude Children's Research Hospital.
Abstract:
Group 3 medulloblastoma (G3MB) is a devastating disease of the central nervous system (CNS) that primarily affects infants and children. Chimeric antigen receptor (CAR) T cell therapy holds the promise to improve outcomes for CNS malignancies, but few studies have focused specifically on G3MB. We used publicly available datasets to demonstrate EphA2 and B7-H3 expression in primary G3MB and validated expression in patient-derived cell lines. EphA2-CAR T cells had greater cytolytic activity, persistence, and TH1 cytokine production than B7-H3-CAR T cells in coculture assays with MYC-driven G3MB cell lines in vitro. In vivo, EphA2-CAR T cells demonstrated superior tumor control and improved survival compared to B7-H3-CAR T cells in 2 of 3 orthotopic G3MB models. B7-H3-CAR T cells outperformed EphA2-CAR T cells in one model in which the antigen density of EphA2 was 5-fold lower than for B7-H3. The limited antitumor activity of EphA2-CAR T cells could be overcome with second genetic modifications that increase T cell functionality including deletion of DNMT3A or the expression of a constitutively active IL-18 chimeric cytokine receptor. Thus, our study nominates EphA2-CAR T cells as a promising alternative to B7-H3-CAR T cells, which are actively being explored in clinical studies for medulloblastoma.
Insights
EphA2-CAR T cells show promise for treating Group 3 medulloblastoma (G3MB) in children. Enhancements can overcome limitations, offering an alternative to B7-H3-CAR T cells for CNS malignancies.
Area of Science:
- Oncology
- Immunotherapy
- Pediatric Cancer
Background:
- Group 3 medulloblastoma (G3MB) is a high-risk pediatric central nervous system (CNS) cancer.
- Chimeric antigen receptor (CAR) T cell therapy is a potential treatment for CNS malignancies.
- Limited research exists on CAR T cell therapy specifically for G3MB.
Purpose of the Study:
- To evaluate EphA2 and B7-H3 as targets for CAR T cell therapy in G3MB.
- To compare the efficacy of EphA2-CAR T cells versus B7-H3-CAR T cells against G3MB.
- To explore strategies for enhancing CAR T cell activity in G3MB.
Main Methods:
- Publicly available datasets were analyzed for EphA2 and B7-H3 expression in G3MB.
- Patient-derived G3MB cell lines were used for validation.
- In vitro coculture assays assessed CAR T cell cytolytic activity, persistence, and cytokine production.
- In vivo orthotopic G3MB models were used to evaluate tumor control and survival.
Main Results:
- EphA2 and B7-H3 are expressed in primary G3MB and cell lines.
- EphA2-CAR T cells demonstrated superior in vitro activity and in vivo tumor control in most models.
- B7-H3-CAR T cells were more effective when EphA2 expression was low.
- Genetic modifications, such as DNMT3A deletion or IL-18 receptor expression, improved EphA2-CAR T cell function.
Conclusions:
- EphA2-CAR T cells represent a promising alternative to B7-H3-CAR T cells for G3MB treatment.
- Targeting EphA2 warrants further investigation for pediatric CNS malignancies.
- Strategies to enhance CAR T cell functionality can overcome antigen-specific limitations.
