Chimeric antigen receptor T-cell therapy in patients with malignant glioma-From neuroimmunology to clinical trial design considerations

Neuro Oncol. 2025 Feb 10;27(2):352-368. doi: 10.1093/neuonc/noae203.

Abstract

Clinical trials evaluating chimeric antigen receptor (CAR) T-cell therapy in patients with malignant gliomas have shown some early promise in pediatric and adult patients. However, the long-term benefits and safety for patients remain to be established. The ultimate success of CAR T-cell therapy for malignant glioma will require the integration of an in-depth understanding of the immunology of the central nervous system (CNS) parenchyma with strategies to overcome the paucity and heterogeneous expression of glioma-specific antigens. We also need to address the cold (immunosuppressive) microenvironment, exhaustion of the CAR T-cells, as well as local and systemic immunosuppression. Here, we discuss the basics and scientific considerations for CAR T-cell therapies and highlight recent clinical trials. To help identify optimal CAR T-cell administration routes, we summarize our current understanding of CNS immunology and T-cell homing to the CNS. We also discuss challenges and opportunities related to clinical trial design and patient safety/monitoring. Finally, we provide our perspective on future prospects in CAR T-cell therapy for malignant gliomas by discussing combinations and novel engineering strategies to overcome immuno-regulatory mechanisms. We hope this review will serve as a basis for advancing the field in a multiple discipline-based and collaborative manner.

Keywords: T lymphocytes; chimeric antigen receptor (CAR); clinical trial; geneTherapy; malignant glioma.

Publication types

  • Review

MeSH terms

  • Brain Neoplasms* / immunology
  • Brain Neoplasms* / therapy
  • Clinical Trials as Topic*
  • Glioma* / immunology
  • Glioma* / therapy
  • Humans
  • Immunotherapy, Adoptive* / methods
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell / therapeutic use
  • Receptors, Chimeric Antigen* / immunology
  • Research Design
  • T-Lymphocytes / immunology
  • Tumor Microenvironment / immunology

Substances

  • Receptors, Chimeric Antigen
  • Receptors, Antigen, T-Cell