Glioblastoma (GBM) is an aggressive and common brain cancer in adults with average life expectancies of 12–18 months after diagnosis and median survival rate for recurrent GBM ranging from 6–10 months.
In a new study presented at the 2025 American Society of Clinical Oncology (ASCO) annual meeting, researchers from the University of Pennsylvania (Penn) Perelman School of Medicine have developed a dual-target CAR-T cell therapy that has slowed GBM tumor growth in nearly two-thirds of patients based on results from a Phase I clinical trial.
The study was published as a paper in Nature Medicine, titled “Intracerebroventricular bivalent CAR T cells targeting EGFR and IL-13Rα2 in recurrent glioblastoma: a Phase I trial,” and builds on an early report from the same Phase I clinical trial published last year.
Researchers from the lab of Donald M. O’Rourke, MD, professor in neurosurgery and director of the Glioblastoma Translational Center of Excellence in the Abramson Cancer Center at Penn Medicine, developed the CAR-T product that targets two proteins commonly found in brain tumors, epidermal growth factor receptor (EGFR) and interleukin-13 receptor alpha 2 (IL13Rα2). O’Rourke is also a scientific advisor to the trial.
The study enrolled 18 patients with recurrent GBM who underwent surgery to remove as much of the tumor as possible, followed by infusion of the dual-target CAR-T cell therapy directly into the cerebrospinal fluid. The tumors became smaller after CAR-T cell therapy in eight of the 13 patients who still had at least 1 cm of tumor remaining after surgery.
“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, an assistant professor of hematology-oncology at Penn. “Before the trial, many of these patients had tumors that were growing rapidly, and the treatment changed the trajectory of their disease, which is very meaningful to patients with GBM.”
Several patients lived 12 months or longer after receiving the investigational therapy, a notable result given that the typical survival prognosis for this patient population is less than a year. Two patients remain alive with stable disease that has continued beyond six months. Additionally, seven patients were still alive after a year, with one individual experiencing no tumor growth for more than 16 months, despite advanced disease spread and rapid growth at the time of enrollment.
The results also showed signs that the therapy remained in the immune system after the infusion to prevent tumor growth over time. Researchers detected infiltration of T cells throughout the tumor and clearance of the tumor by macrophages in the removed tissue in one patient who experienced tumor regrowth after the CAR-T cell therapy.
Spinal fluid samples from other patients displayed similar signs of immune system stimulation, with one patient’s spinal fluid showing detectable CAR-T cells one year after receiving the 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. Our goal is to refine the treatment so that more patients experience longer-lasting results.”
