The Effectiveness of Bivalent CAR T-Cell Therapy Targeting EGFR and IL13Rα2 in Treating Recurrent Glioblastoma

In recent years, the treatment of recurrent glioblastoma (RGBM) has been continually explored and improved, yet overall survival rates remain less than one year, presenting a significant challenge. The limitations of existing treatments and the complexity of recurrent glioblastoma have led scientists to continuously explore different treatment methods. This article reports the mid-term results of a clinical trial published in the journal Nature Medicine, focusing on the application of dual-target chimeric antigen receptor T-cell (CAR-T) therapy targeting EGFR and IL13Rα2 in patients with recurrent glioblastoma.

Study Background and Motivation

Recurrent glioblastoma is a highly malignant brain tumor, with conventional radiotherapy and chemotherapy showing limited efficacy in recurrent cases, and currently, there is no standard treatment method. Therefore, developing more effective treatments has become an important goal in medical research. Chimeric antigen receptor T-cell therapy (CAR-T therapy) has shown significant efficacy in various hematologic tumors, but how to apply this technology to solid tumors, especially brain tumors, remains a major scientific challenge.

Study Source and Author Information

This article was published in the March 13, 2024 issue of Nature Medicine. The research team, consisting of Stephen J. Bagley, Meghan Logun, Joseph A. Fraietta, and others, came from various departments of the Perelman School of Medicine at the University of Pennsylvania. The trial reported in this paper was funded by Kite Pharma, a subsidiary of Gilead Sciences, with the clinical trial registration number NCT05168423.

Research Methods and Processes

This study is a single-center, open-label Phase I clinical trial involving patients aged 18 and above with recurrent glioblastoma. Patients must have had tumor recurrence after prior radiation therapy, and EGFR amplification in tumor tissue confirmed by fluorescence in situ hybridization (FISH). The article focuses on the following contents:

1. Study Design and Patient Selection

Patients were divided into three dose groups, each receiving 1×10^7, 2.5×10^7, or 5×10^7 CAR-T cells. CAR-T cells were injected directly into the cerebrospinal fluid via lumbar puncture through an Ommaya reservoir implanted via cranial surgery. The primary endpoint of the study was to assess the safety of CAR-T cells by evaluating the incidence of dose-limiting toxicity (DLT) and determining the tolerated dose. Secondary endpoints included the frequency of manufacturing failures and the objective imaging response rate (ORR).

2. Patient Treatment and Evaluation

During cell manufacturing, patients needed to ensure sufficient white blood cell count to extract T-cells for gene transduction. CAR expression was detected by flow cytometry, using CD3, CD45 markers, and terminal amino acid identification. Patients underwent maximal safe tumor resection and confirmation of EGFR amplification status in recurrent tissue before CAR-T cell injection, with each patient monitored for a minimum of 7 days.

3. Adverse Events and Safety

The study showed that all six patients exhibited early moderate to severe neurotoxicity after treatment, such as immune effector cell-associated neurotoxicity syndrome (ICANS), consistent with tumor inflammation-related neurotoxicity. Some patients required high-dose dexamethasone and Anakinra co-administration. Only one patient in the high-dose group (2.5×10^7 cells) experienced Grade 3 toxicity, such as anorexia, generalized muscle weakness, and fatigue, but no Grade 4 or Grade 5 toxicity was observed.

4. Preliminary Efficacy Evaluation

MRI scans of all patients during the early post-treatment period showed signs of tumor shrinkage, but none reached the objective imaging response criterion (i.e., tumor volume reduction ≥50% sustained for at least four weeks). However, three out of six patients showed a tumor volume reduction of at least 30%, and three patients with over two months of follow-up maintained stable disease, ruling out the phenomenon of pseudo-response.

5. Tumor Target Expression, Pharmacokinetics, and Cytokine Analysis

Immunofluorescence detection of pre-treated tumor tissue, peripheral blood, and cerebrospinal fluid was conducted before and after CAR-T cell injection. Various cytokines (such as IFNγ, IL-2, TNFα, and IL-6) were measured to evaluate the amplification and migration of CAR-T cells in cerebrospinal fluid and peripheral blood.

Experimental Results and Discussion

Preliminary data suggest that this CAR-T cell therapy shows good safety and bioactivity in treating recurrent glioblastoma. Although the sample size is small and the follow-up time is short, the study indicates potential disease control, particularly in early responses to multifocal lesions. Tumor burden reduction was observed within 24-48 hours, with significant changes in cytokine levels, consistent with CAR-T cell activation and antitumor response.

Significance of the Study

This study demonstrates the potential prospect of applying dual-target CAR-T cell therapy in recurrent glioblastoma. Despite challenges, this therapy, through complex target design and popular gene transduction technology, promises to change the ineffective treatment landscape. Future studies should continue to optimize dosage and treatment regimens to achieve more long-term and stable antitumor effects.

Future Outlook

Next, the research team plans to expand the sample size to further validate the preliminary efficacy. Through more correlative studies such as single-cell sequencing, cell function, and immune microenvironment analysis, there will be a deeper understanding of the mechanism of action and long-term effects of CAR-T cells in vivo. Therefore, this study not only provides new hope for treating recurrent glioblastoma but also lays the foundation for trying new cellular immunotherapies.