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Prostaglandin F2 receptor negative regulator as a potential target for chimeric antigen receptor-T cell therapy for
Hideki Kuroda1, Noriyuki Kijima2, Tetsuro Tachi1
1Department of Neurosurgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, 5650871, Japan.
Background:
Chimeric antigen receptor (CAR)-T cell therapy targeting novel glioblastoma (GBM)-specific cell surface antigens is a promising approach. However, transcriptome analyses have revealed few GBM-specific target antigens.
Methods:
A library of monoclonal antibodies (mAbs) against tumor cell lines derived from patients with GBM was generated. mAbs reacting with tumor cells in resected tissues from patients with GBM but not with nonmalignant human brain cells were detected. The antigens that were recognized were identified through expression cloning. CAR-T cells derived from a candidate mAb were generated, and their functionality was tested in vitro and in vivo.
Results:
Approximately 3,200 clones were established. Among them, 5E17 reacted with tumor cells in six of seven patients with GBM, but not with nonmalignant human brain cells. Prostaglandin F2 receptor negative regulator (PTGFRN) was identified as an antigen recognized by 5E17. CAR-T cells derived from 5E17 produced cytokines and exerted cytotoxicity upon co-culture with tumor cells from patients with GBM. Furthermore, intracranial injection of 5E17-CAR-T cells demonstrated antitumor effects in an orthotopic xenograft murine model with patient-derived GBM cells.
Conclusions:
Cell surface PTGFRN is a candidate target for intracranial CAR-T cell therapy for GBM. On-target off-tumor toxicity in alternative normal tissues needs to be carefully tested.
Insights
Chimeric antigen receptor (CAR)-T cell therapy shows promise for glioblastoma (GBM). Researchers identified Prostaglandin F2 receptor negative regulator (PTGFRN) as a GBM-specific target, demonstrating CAR-T cell effectiveness in preclinical models.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Biology
Background:
- Chimeric antigen receptor (CAR)-T cell therapy is a promising strategy for glioblastoma (GBM).
- Identifying GBM-specific cell surface antigens for CAR-T targeting remains a challenge due to limited transcriptome data.
Purpose of the Study:
- To identify novel glioblastoma (GBM)-specific cell surface antigens for CAR-T cell therapy.
- To evaluate the therapeutic potential of CAR-T cells targeting a newly identified antigen.
Main Methods:
- Generated a library of monoclonal antibodies (mAbs) against GBM tumor cell lines.
- Screened mAbs for reactivity against patient-derived GBM tissues and specificity against nonmalignant brain cells.
- Identified target antigen using expression cloning and generated CAR-T cells for in vitro and in vivo testing.
Main Results:
- Identified Prostaglandin F2 receptor negative regulator (PTGFRN) as a target antigen recognized by mAb 5E17.
- 5E17-derived CAR-T cells demonstrated specific cytokine production and cytotoxicity against GBM cells in vitro.
- Intracranial administration of 5E17-CAR-T cells showed significant antitumor effects in a patient-derived GBM xenograft model.
Conclusions:
- Cell surface PTGFRN is a viable target for intracranial CAR-T cell therapy in glioblastoma (GBM).
- Further investigation is required to assess potential on-target, off-tumor toxicities in normal tissues.
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