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B7-H3 CAR T Cells Are Effective against Ependymomas but Limited by Tumor Size and Immune Response
Sanya Mehta1,2,3,4,5, Siri Ippagunta2,3,4, Srinidhi Varadharajan2,3,4
1Department of Bone Marrow Transplantation and Cellular Therapy (BMTCT), St. Jude Children's Research Hospital, Memphis, Tennessee.
Purpose:
Targeted treatments are desperately needed for ependymomas. Chimeric antigen receptor (CAR) T cells have immense potential to transform patient outcomes. However, CAR T-cell therapy for ependymomas has been largely understudied. In this study, we explore the potential of targeting B7 homolog 3 (B7-H3/CD276) with CAR T cells to treat pediatric ependymomas.
Experimental Design:
We profiled B7-H3 protein expression in 44 pediatric ependymoma samples by IHC. We generated second-generation human B7-H3.CAR T cells and examined their anti-ependymoma activity in six in vitro and two in vivo xenograft models. We validated findings using HER2-targeted CAR T cells. In addition, we used murine B7-H3.CAR T cells to evaluate in vivo antitumor activity in a fully syngeneic supratentorial ependymoma model.
Results:
The majority of clinical ependymoma samples (29/44) stained positive for B7-H3, indicating high but heterogeneous expression across patients. In vitro, human B7-H3.CAR T cells had potent anti-ependymoma cytolytic activity, expansion, and persistence, which was inversely correlated with the upregulation of B7-H3 on CAR T cells. We found that CAR T cells favor type 2 cytokines phenotypes after repeated exposure to ependymoma cell lines, which may be driven by C-C motif chemokine ligand 2 secretion by ependymomas. In vivo, there was potent and significant antitumor activity in human xenograft ependymoma models. However, response durability was limited and significantly correlated with the degree of tumor burden. In the syngeneic setting, murine B7-H3.CAR T-cell efficacy against ependymomas was limited and did not extend survival.
Conclusions:
Our results support ongoing clinical evaluation of B7-H3.CAR T cells for ependymomas and provide model systems for further studying determinants of anti-ependymoma CAR T-cell treatment efficacy and resistance.
Insights
Chimeric antigen receptor (CAR) T-cell therapy targeting B7-H3 shows promise for pediatric ependymomas. While effective in models, further research is needed to overcome resistance and improve durability for this targeted treatment.
Area of Science:
- Oncology
- Immunotherapy
- Pediatric Cancer Research
Background:
- Ependymomas require novel targeted treatments.
- Chimeric antigen receptor (CAR) T-cell therapy offers transformative potential.
- CAR T-cell therapy for ependymomas remains understudied.
Purpose of the Study:
- To explore the potential of targeting B7 homolog 3 (B7-H3) with CAR T cells for pediatric ependymomas.
- To assess the efficacy and limitations of B7-H3.CAR T-cell therapy in preclinical ependymoma models.
Main Methods:
- Immunohistochemistry (IHC) to profile B7-H3 expression in pediatric ependymoma samples.
- Generation of human B7-H3.CAR T cells and assessment of anti-ependymoma activity in vitro and in vivo xenograft models.
- Validation using HER2-targeted CAR T cells and evaluation in a syngeneic ependymoma model with murine B7-H3.CAR T cells.
Main Results:
- B7-H3 was highly but heterogeneously expressed in most ependymoma samples (29/44).
- Human B7-H3.CAR T cells demonstrated potent in vitro cytolytic activity, expansion, and persistence.
- In vivo, significant antitumor activity was observed in xenograft models, but response durability was limited and correlated with tumor burden. Syngeneic models showed limited efficacy.
Conclusions:
- Results support clinical evaluation of B7-H3.CAR T cells for ependymomas.
- Preclinical models provide a platform for studying CAR T-cell treatment efficacy and resistance mechanisms.
- Further investigation is needed to enhance durability and overcome resistance in CAR T-cell therapy for ependymomas.
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