Prostaglandin F2 receptor negative regulator as a potential target for chimeric antigen receptor-T cell therapy for glioblastoma.

in Cancer immunology, immunotherapy : CII by Hideki Kuroda, Noriyuki Kijima, Tetsuro Tachi, Shunya Ikeda, Koki Murakami, Tomoyoshi Nakagawa, Moto Yaga, Kanji Nakagawa, Reina Utsugi, Ryuichi Hirayama, Yoshiko Okita, Naoki Kagawa, Naoki Hosen, Haruhiko Kishima

TLDR

  • The study identified a novel glioblastoma-specific antigen, PTGFRN, and generated CAR-T cells that target it, showing promising results in an orthotopic xenograft murine model.
  • The findings suggest that PTGFRN may be a valuable target for intracranial CAR-T cell therapy to treat glioblastoma.

Abstract

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. 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. 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. 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.

Overview

  • The study aimed to identify novel glioblastoma (GBM)-specific cell surface antigens as targets for chimeric antigen receptor (CAR)-T cell therapy.
  • The researchers generated a library of monoclonal antibodies (mAbs) against tumor cell lines derived from patients with GBM and selected mAbs that reacted with tumor cells but not with non-malignant human brain cells.
  • The primary objective of the study was to identify a candidate antigen and generate CAR-T cells that target it to treat GBM.

Comparative Analysis & Findings

  • The study identified a monoclonal antibody, 5E17, that reacted with tumor cells in six of seven patients with GBM but not with non-malignant human brain cells.
  • The antigen recognized by 5E17 was identified as prostaglandin F2 receptor negative regulator (PTGFRN).
  • CAR-T cells derived from 5E17 showed cytokine production and cytotoxicity upon co-culture with tumor cells from patients with GBM and demonstrated antitumor effects in an orthotopic xenograft murine model.

Implications and Future Directions

  • Cell surface PTGFRN is a candidate target for intracranial CAR-T cell therapy for GBM, and further studies are needed to assess the safety and efficacy of this approach.
  • On-target off-tumor toxicity in alternative normal tissues needs to be carefully tested to minimize adverse effects.
  • Further research is needed to explore the potential of CAR-T cell therapy targeting PTGFRN in combination with other therapies for GBM treatment.
Read Full Article