A groundbreaking dual-target CAR T cell therapy has demonstrated significant tumor shrinkage in patients with recurrent glioblastoma, offering new hope for treating the most aggressive and deadly form of brain cancer in adults. The experimental treatment achieved tumor reduction in 62% of patients, marking a notable advance in a disease where traditional immunotherapies have largely failed.
The findings, presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting and simultaneously published in Nature Medicine, represent a significant milestone in the fight against glioblastoma (GBM), which typically carries a median survival of just 6-10 months for recurrent cases.
Novel Dual-Target Approach Shows Promise
The Penn-developed CAR T cell therapy stands apart from conventional treatments by simultaneously targeting two proteins commonly found in brain tumors: epidermal growth factor receptor (EGFR) and interleukin-13 receptor alpha 2 (IL13Rα2). Unlike traditional CAR T therapies, this treatment is administered directly into the cerebrospinal fluid, allowing for targeted delivery to brain tumors.
"Seeing recurrent GBM tumors shrink like this is extraordinary because the immunotherapy drugs that we've tried in the past have been unable to do that," said principal investigator Stephen Bagley, MD, MSCE, an assistant professor of Hematology-Oncology and Neurosurgery at Penn's Perelman School of Medicine.
The dual-target CAR was developed in the laboratory of Donald M. O'Rourke, MD, the John Templeton, Jr., MD Professor in Neurosurgery and director of the Glioblastoma Translational Center of Excellence in the Abramson Cancer Center at Penn Medicine.
Clinical Trial Results Exceed Expectations
The phase I clinical trial enrolled 18 patients with recurrent GBM who underwent surgical tumor removal followed by infusion of the dual-target CAR T cell therapy. Among the 13 patients who had at least 1cm of tumor remaining after surgery, eight patients (62%) experienced tumor shrinkage following CAR T cell therapy.
While tumors regrew after one to three months in most patients, the study revealed several encouraging survival signals:
- Two patients (11%) remain alive with stable disease continuing beyond six months
- Of seven patients with at least 12 months of follow-up, three (43%) survived beyond one year
- One patient has maintained stable disease with no tumor growth for more than 16 months, despite having advanced disease spread and rapid growth at enrollment
These survival outcomes are particularly significant given that the typical survival for recurrent GBM patients ranges from 6 to 10 months, while newly diagnosed patients face average life expectancies of 12-18 months despite aggressive treatment.
Evidence of Sustained Immune Response
The researchers discovered compelling evidence that the therapy continues working within the immune system after infusion. In one patient who required repeat surgery due to tumor regrowth, analysis of the removed tissue revealed positive treatment effects, including T cell infiltration throughout the tumor and clearance by immune cells called macrophages.
Spinal fluid samples from other patients showed similar signals of immune system stimulation, with one patient maintaining detectable CAR T cells in spinal fluid one year after treatment.
"These results reaffirm that we're onto something with our dual target therapy, and that we have a good template that we can begin refining for even better outcomes," O'Rourke said. "Periods of stability, when tumors shrink or don't grow, vastly improve the quality of a patient's life."
Safety Profile Established for Future Trials
The therapy demonstrated an acceptable safety profile, with ten of 18 patients (56%) experiencing grade 3 neurotoxicity. No new or unexpected side effects were reported beyond the known side effects of other FDA-approved CAR T cell therapies. The neurotoxicity was successfully managed, and researchers determined the therapy to be safe and feasible.
Based on these results, the research team has established the maximum tolerated dose level for upcoming clinical trials, with the first trial planned for patients with newly diagnosed GBM.
Moving Forward with Enhanced Treatment Strategy
The final cohort of the current study will test multiple doses of CAR T cell therapy to determine if repeat dosing can extend the time before tumor regrowth occurs.
"By the time GBM recurs, it has become even more challenging to treat, and the patient has already been through a lot," Bagley explained. "We're hopeful that by moving quickly to test this CAR T cell therapy in the newly diagnosed setting, the cancer will be more vulnerable to therapy and more patients will see a benefit."
The study received funding from Kite, a Gilead Company, the Abramson Cancer Center Glioblastoma Translational Center of Excellence, the Templeton Family Initiative in Neuro-Oncology, and the Maria and Gabriele Troiano Brain Cancer Immunotherapy Fund.
