REVIEW article

Front. Immunol.

Sec. Cancer Immunity and Immunotherapy

Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1596499

This article is part of the Research TopicStrategies Aimed at Improving the Effectiveness of Immunotherapies in Pediatric Brain CancerView all 6 articles

CAR-T Cell Therapy in Brain Malignancies: Obstacles in the Face of Cellular Trafficking and Persistence

Provisionally accepted
Serge YaacoubSerge Yaacoub1Stefanyda MaslovaStefanyda Maslova2Elton VanNoyElton VanNoy1Abigail HaffeyAbigail Haffey1Khatereh KhorsandiKhatereh Khorsandi1Natasha SheybaniNatasha Sheybani2,3Dalia HaydarDalia Haydar1*
  • 1Children’s National Hospital, Washington D.C., United States
  • 2University of Virginia, Charlottesville, Virginia, United States
  • 3Focused Ultrasound Foundation, Charlottesville, Virginia, United States

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Chimeric Antigen Receptor T (CAR-T) cell therapy offers substantial promise for the treatment of brain malignancies, yet its clinical translation remains limited. Tumors such as Glioblastoma Multiforme (GBM), Diffuse Intrinsic Pontine Glioma (DIPG), and Medulloblastoma (MB) are associated with poor prognoses and exhibit limited responsiveness to conventional treatment modalities, including radiotherapy, chemotherapy, and surgical resection. The application of CAR-T cell therapy in these contexts faces significant challenges, primarily in terms of efficient cellular trafficking into the tumor microenvironment and access to heterogeneous tumor regions. Furthermore, CAR-T cell persistence, defined by the long-term survival and functionality of infused cells, remains a critical hurdle in achieving durable therapeutic responses and preventing tumor relapses. This review aims to address the two predominant barriers, trafficking and persistence, by discussing the underlying mechanisms that limit CAR-T cell efficacy in brain tumors, reviewing current strategies aimed at overcoming these challenges, and evaluating novel approaches to enhance the effectiveness of CAR-T therapies in this setting.

Keywords: CAR-T cells, brain tumors, trafficking, Persistence, Tumor Microenvironment, Cellular Exhaustion, Cell Delivery, targeted therapy

Received: 19 Mar 2025; Accepted: 29 May 2025.

Copyright: © 2025 Yaacoub, Maslova, VanNoy, Haffey, Khorsandi, Sheybani and Haydar. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dalia Haydar, Children’s National Hospital, Washington D.C., United States

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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