CAR T Cell Therapy for Glioblastoma: A Review of the First Decade of Clinical Trials.

in Molecular therapy : the journal of the American Society of Gene Therapy by Sabrina L Begley, Donald M O'Rourke, Zev A Binder

TLDR

  • Researchers analyzed the results of 10 phase I clinical trials of CAR T cell therapy for glioblastoma and found that while the treatment has shown promise, it's still a developing field with many challenges to overcome.
  • The study highlighted the need for continued research and refinement of CAR T cell therapy to improve its effectiveness and durability.

Abstract

Glioblastoma (GBM) is an aggressive primary brain tumor with a poor prognosis and few effective treatment options. Focus has shifted towards using immunotherapies, such as chimeric antigen receptor (CAR) T cells, to selectively target tumor antigens and mediate cytotoxic activity within an otherwise immunosuppressive tumor microenvironment. Between 2015-2024, the results of eight completed and two ongoing phase I clinical trials have been published. The majority of studies have treated recurrent GBM patients, although the inter- and intra-patient tumor heterogeneity has been historically challenging to overcome. Molecular targets have included EGFR, HER2, and IL13Rα2 and there has been continued development in improving receptor constructs, identifying novel targets, and adding adjuvant enhancers to increase efficacy. CAR T cells have been safely administered through both peripheral and locoregional routes but with variable clinical and radiographic efficacy. Most trials utilized autologous T cell products to avoid immune rejection yet were unable to consistently show robust engraftment and persistence within patients. Nonetheless, targeted immunotherapies such as CAR T cell therapy remain the next frontier for GBM treatment, and the popularity and complexity of this undertaking is evident in the past, present, and future landscape of clinical trials.

Overview

  • The study focuses on the use of immunotherapies, specifically chimeric antigen receptor (CAR) T cells, to target glioblastoma (GBM) tumors.
  • The study analyzed the results of 10 phase I clinical trials published between 2015-2024, with a focus on recurrent GBM patients and molecular targets such as EGFR, HER2, and IL13Rα2.
  • The primary objective of the study is to explore the potential of CAR T cell therapy as a treatment for GBM, with a focus on improving receptor constructs, identifying novel targets, and adding adjuvant enhancers to increase efficacy.

Comparative Analysis & Findings

  • The study found that most trials utilized autologous T cell products to avoid immune rejection, but were unable to consistently show robust engraftment and persistence within patients.
  • The results of the trials showed variable clinical and radiographic efficacy, with some patients showing significant responses while others experienced minimal or no responses.
  • Despite challenges, the study concluded that targeted immunotherapies, such as CAR T cell therapy, remain the next frontier for GBM treatment.

Implications and Future Directions

  • The study highlights the need for continued development and refinement of CAR T cell therapy, including the identification of novel targets and the use of adjuvant enhancers to increase efficacy.
  • Future studies should focus on overcoming inter- and intra-patient tumor heterogeneity and improving the durability of T cell persistence and engraftment.
  • Additional research is also needed to address the challenges of immune rejection and to develop strategies to enhance the effectiveness of CAR T cell therapy.
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