Novel Dual-Target CAR T-Cell Therapy for Recurrent Glioblastoma

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Targeting two brain tumor–associated proteins with chimeric antigen receptor (CAR) T-cell therapy may reduce solid tumor growth in patients with recurrent glioblastoma, according to results from a phase I trial published by Bagley et al in Nature Medicine. The findings suggest that the new dual-target approach represents an encouraging step toward the development of effective, long-lasting therapies for solid tumors like glioblastoma.


Patients with glioblastoma—the most common and aggressive type of brain cancer in adults—typically survive 12 to 18 months following diagnosis. Despite decades of research, there is currently no cure for the disease, and approved therapies such as surgery, radiation, and chemotherapy have limited effect in prolonging survival. Even after aggressive treatment, many patients with glioblastoma experience cancer recurrence.

In CAR T-cell therapy, the patient’s own immune system is used to attack cancer cells. Their T cells are removed for reprogramming to recognize antigens characteristic of a specific type of cancer and then returned to the body to eliminate the cancer cells. CAR T-cell therapy is currently U.S. Food and Drug Administration (FDA) approved to treat hematologic malignancies such as leukemia; however, previous studies have demonstrated the significant challenges of engineering cells to target and kill solid tumors.

“The challenge with [glioblastoma] and other solid tumors is tumor heterogeneity, meaning not all cells within a [glioblastoma] tumor are the same or have the same antigen that a CAR T cell is engineered to attack, and every [patient’s] [tumor] is unique to them. [Therefore], a treatment that works for one patient might not be as effective for another,” stressed lead study author Stephen Bagley, MD, MSCE, Assistant Professor of Hematology-Oncology and Neurosurgery at Penn Medicine. “What’s more, [glioblastoma] tumors can evade a patient’s immune system and block immune cells—both engineered CAR T cells and a patient’s own immune cells—that might otherwise fight the tumor. Our challenge is getting our treatment around the tumor’s defenses so we can kill it,” he added.

Study Methods and Results

In an ongoing phase I clinical trial ( identifier NCT05168423), researchers assigned six patients with glioblastoma to receive CAR T cells targeting two proteins commonly found in brain tumors: epidermal growth factor receptor (EGFR) and interleukin-13 receptor alpha 2, present in about 60% and 75% of glioblastoma, respectively. Although CAR T-cell therapy for hematologic malignancies is usually administered intravenously, the researchers utilized a technique to deliver the dual-target CAR T cells intrathecally into the cerebrospinal fluid so that the engineered cells could reach the glioblastoma more directly.

After 24 to 48 hours following administration of the dual-target CAR T-cell therapy, the researchers discovered that the tumors of all six patients reduced in size and that the reductions were sustained several months later in a subset of the patients.

The researchers emphasized that all six of the patients involved in the trial experienced substantial but manageable neurotoxicity.


“This is the first time CAR T-cell therapy with two targets, rather than just one, has been administered to patients with glioblastoma,” explained Dr. Bagley. “Our results suggest that this is a step in the right direction, and this method, when delivered through a patient’s spinal fluid, could be the key to developing therapies that outsmart the complicated defense systems of [glioblastoma],” he added.

“We are energized by these results and are eager to continue our trial, which will give us a better understanding of how this dual-target CAR T-cell therapy affects a wider range of [patients] with recurrent [glioblastoma],” underscored 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 at the Abramson Cancer Center at Penn Medicine. “This cancer [type] is unique in each individual, so a wider range of patients will help us determine the optimal dose, better understand effects like neurotoxicity, and more firmly establish efficacy,” he concluded.

Disclosure: The research in this trial was supported by the Gilead Company Kite and grants from the National Institutes of Health. For full disclosures of the study authors, visit

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