An investigational dual-target chimeric antigen receptor (CAR) T-cell therapy approach could slow tumor growth in patients with recurrent glioblastoma, according to new findings presented by Bagley et al at the 2025 ASCO Annual Meeting (Abstract 102) and simultaneously published in Nature Medicine.
Background
Glioblastoma is the most common and deadliest type of brain cancer in adult patients. Patients with the disease often survive for 12 to 18 months following diagnosis, despite decades of focused research efforts. Even after aggressive treatment, the cancer recurs in nearly all patients. The median survival rate for recurrent glioblastoma ranges from 6 to 10 months.
CAR T-cell therapy is a type of personalized immunotherapy that uses a patient’s own immune cells to treat their cancer. Although widely successful in hematologic malignancies, CAR T-cell therapy has yet to make significant inroads against solid tumors.
“Seeing recurrent [glioblastoma] tumors shrink like this is extraordinary, because the immunotherapy drugs that we’ve tried in the past have been unable to do that,” highlighted lead study author Stephen Bagley, MD, MSCE, Assistant Professor of Hematology-Oncology and Neurosurgery at the University of Pennsylvania Perelman School of Medicine. “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 [glioblastoma],” he added.
Study Methods and Results
In the study, researchers developed a novel CAR T-cell therapy that was designed to target two proteins commonly found in brain tumors—epidermal growth factor receptor and interleukin-13 receptor alpha 2. They recruited 18 patients with recurrent glioblastoma who underwent surgical resection of as much of the tumor as possible prior to the administration of the novel CAR T-cell therapy through an injection into the cerebrospinal fluid.
The tumors became smaller following CAR T-cell therapy in 62% (n = 8) of the 13 patients who still had at least 1 cm of tumor remaining postsurgery. While the tumors grew back after 1 to 3 months in most of the patients, the researchers noted encouraging signals. Eleven percent of the patients (n = 2) remained alive with stable disease that continued beyond 6 months. Among the seven patients with at least 12 months’ follow-up time, 43% (n = 3) of them were still alive after 1 year. This included one patient whose cancer remained stable, with no tumor growth for more than 16 months, despite presenting with advanced disease metastasis and rapid growth at the time of enrollment.
The researchers also found indicators that the therapy remained in the immune system postinfusion to prevent tumor growth over time. In one of the patients who underwent surgery again as a result of tumor regrowth following the administration of the novel CAR T-cell therapy, the researchers detected positive effects of the treatment in the removed tissue—including infiltration of T cells throughout the tumor and clearance of the tumor by macrophages. The researchers observed similar signals of the therapy stimulating the immune system through spinal fluid samples from the other patients, including one patient whose spinal fluid still had detectable CAR T cells 1 year posttreatment.
The researchers reported that 56% (n = 10) of the patients experienced grade 3 neurotoxicity, with no new or unexpected adverse effects noted beyond the known adverse effects of other U.S. Food and Drug Administration–approved CAR T-cell therapies. The neurotoxicity was managed successfully, and the therapy was determined to be safe and feasible.
Conclusions
“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,” emphasized senior study author 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. “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,” he indicated.
In the final cohort of this study, the researchers plan to administer more than one dose of the novel CAR T-cell therapy in patients to determine whether repeat dosing may extend the time before recurrence. Based on their results, the researchers determined the maximum tolerated dose level to carry forward in upcoming clinical trials, the first of which will include patients with newly diagnosed glioblastoma.
“By the time [glioblastoma] recurs, it has become even more challenging to treat, and the patient has already been through a lot,” Dr. Bagley underscored. “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,” he concluded.
Disclosure: The research in this study was funded by 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. For full disclosures of the study authors, visit meetings.asco.org and nature.com.
