Glioblastoma (GBM) is the most common and aggressive type of malignant brain tumor in adults, with patients typically surviving only 12-18 months after diagnosis. Despite decades of research, there is currently no cure for glioblastoma, and approved treatments such as surgery, radiotherapy, and chemotherapy have limited effectiveness in extending patients' lives.
Even after aggressive treatment, most glioblastoma patients will relapse, and the median survival of patients with recurrent glioblastoma (rGBM) is only 6-10 months. Currently, no specific therapeutic intervention has been shown to prolong the survival of patients with recurrent glioblastoma. Therefore, effective treatment for recurrent glioblastoma remains one of the largest unmet medical needs in the field of oncology.
In March 2024, researchers from the Perelman School of Medicine at the University of Pennsylvania published a paper in the journal Nature Medicine. The paper reported early results of a phase 1 clinical trial, which showed that dual-target CAR-T cells targeting epidermal growth factor receptor (EGFR) and interleukin-13 receptor α2 (IL13Rα2) may be an effective strategy to reduce the growth of solid tumors in the brain of patients with recurrent glioblastoma (rGBM).
In June 2025, the team published another paper in the journal Nature Medicine, further reporting the results of a phase 1 clinical trial of the above dual-target CAR-T cell therapy, entitled "Intracerebroventricular bivalent CAR T cells targeting EGFR and IL-13Rα2 in recurrent glioblastoma: a phase 1 trial". The results of this phase 1 clinical trial showed that dual-target CAR-T cell therapy targeting EGFR and IL13Rα2 slowed tumor growth in nearly two-thirds of patients with recurrent glioblastoma (rGBM).
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The research team developed a dual-target CAR-T cell therapy targeting two common proteins in glioblastoma, EGFR and IL13Rα2, CART-EGFR-IL3Rα2 cell therapy. The EGFR epitope is present on the surface of tumor cells in 50%-60% of glioblastoma patients, while IL13Rα2 is expressed in 50-75% of glioblastoma patients and has been shown to be a potential therapeutic target. The research team delivered CAR-T cells to the cerebrospinal fluid via intrathecal injection, allowing them to reach brain tumors more directly.
The study included 18 patients with recurrent glioblastoma (rGBM) who underwent surgery to remove as much of the tumor as possible, followed by the delivery of dual-target CAR-T cells directly to the cerebrospinal fluid via intrathecal injection. The primary endpoints of this single-center, phase 1 open-label clinical trial included dose-limiting toxicity, determination of the maximum tolerated dose and recommended dose, and the occurrence of adverse events; secondary endpoints included objective imaging response, duration of response, progression-free survival, and overall survival.
Figure 1. CAR T cell pharmacokinetics and cytokines in the CSF of all patients. (Bagley, Stephen J., et al. 2025)
The results showed that the maximum tolerated dose was determined to be 2.5×107 CAR-T cells. Among the 18 patients, 10 (56%) experienced grade 3 neurotoxicity; no grade 4-5 neurotoxicity occurred. Among the 13 patients with measurable disease, 8 (62%) experienced tumor regression after receiving CAR-T cell treatment, of which 1 patient was confirmed as a partial response and 1 patient had sustained stable disease for more than 16 months. The median progression-free survival was 1.9 months, and the median overall survival had not been reached at the time of data cutoff (median follow-up time was 8.1 months).
The research team said that it was unusual to see tumors shrink like this in patients with recurrent glioblastoma, and no immunotherapy drugs tried in the past could do this. Most of these patients had rapidly growing tumors when they received CAR-T treatment, and the treatment changed the course of their disease, which is of great significance to glioblastoma patients. After treatment, several patients with recurrent glioblastoma survived for 12 months or more, while the median survival of this patient group was less than one year, which is a remarkable treatment result. In addition, 7 patients were still alive after one year, and one of them had no tumor growth for more than 16 months, despite the fact that the disease had spread widely and the tumor had grown rapidly when he was enrolled.
These results show that intraventricular infusion of dual-target CART-EGFR-IL13Rα2 is feasible and generally safe. CART-EGFR-IL13Rα2 cells infused into the patient's brain are biologically active and show signals of anti-tumor effects in recurrent glioblastoma (rGBM). The research team aims to further improve the therapy so that more patients can achieve more lasting results.
References
- Bagley, Stephen J., et al. Intrathecal bivalent CAR T cells targeting EGFR and IL13Rα2 in recurrent glioblastoma: phase 1 trial interim results. Nature Medicine 30.5 (2024): 1320-1329.
- Bagley, Stephen J., et al. Intracerebroventricular bivalent CAR T cells targeting EGFR and IL-13Rα2 in recurrent glioblastoma: a phase 1 trial. Nature Medicine (2025): 1-10.