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CAR T Cells Target Two Proteins, Shrink Brain Tumors in Phase I Trial
Mar. 18 2024

Human brain with tumor, 3D illustration. [Peterschreiber.media/Getty Images]

Early results from an ongoing Phase I clinical trial suggest that using CAR T cell therapy to target two brain tumor-associated proteins—epidermal growth factor receptor (EGFR) and interleukin-13 receptor alpha 2 (IL13Rα2)—could hold promise as a strategy for reducing solid tumor growth in patients with recurrent glioblastoma (rGBM), an aggressive form of brain cancer.


Trial investigators from the Perelman School of Medicine at the University of Pennsylvania and Penn Medicine’s Abramson Cancer Center, reported data from the first six patients using this dual-target approach, which they say demonstrated preliminary safety and bioactivity of the bivalent CART-EGFR-IL3Rα2 cells in recurrent GBM.


“This is the first time CAR T cell therapy with two targets, rather than just one, has been administered to patients with glioblastoma,” said the trial’s principal investigator, Stephen Bagley, MD, an assistant professor of hematology-oncology, and neurosurgery. “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 GBM.”

Bagley and colleagues published the interim results from the dose-ranging study in a paper in Nature Medicine, titled “Intrathecal bivalent CAR T cells targeting EGFR and IL13Rα2 in recurrent glioblastoma: phase 1 trial interim results.” In their report the investigators noted that the trial data also provided an early indication of efficacy. “An encouraging early efficacy signal was also detected and requires confirmation with additional patients and longer follow-up time,” they noted.

GBM is the most common and most aggressive type of malignant brain tumor in adults. Individuals with GBM usually expect to live 12–18 months following their diagnosis. Despite decades of research there is no known cure for GBM, and approved treatments such as surgery, radiation, and chemotherapy have limited effect in prolonging an individual’s life expectancy. Even after aggressive treatment, GBM returns in most patients, and the median survival rate for recurrent GBM is less than one year. “Clinically meaningful treatment options for relapsed disease after first-line radiotherapy are extremely limited, and no specific therapeutic intervention has ever been shown to prolong survival of patients with rGBM,” the investigators stated. “Effective therapy for rGBM remains one of the greatest unmet medical needs in oncology.”


Chimeric antigen receptor (CAR) T cell therapy uses a patient’s own immune system to fight cancer. To create CAR T cells, a patient’s own T cells—the white blood cells that find and fight illness and infection in the body—are removed, reprogrammed to recognize specific cancer-associated antigens, and then returned to the body, where they seek out and destroy the cancer cells. CAR T cell therapy is FDA approved to fight a number of blood cancers, such as leukemia, but researchers have struggled to engineer cells to successfully seek out and kill solid tumors, which make up the vast majority of cancer types, including GBM. Previous Phase I trials with CAR T cell therapy targeting GBM-specific and associated antigens have shown “limited evidence of efficacy in adults with GBM aside from isolated case reports,” the authors continued. “Resistance mechanisms identified through translational studies include a highly immunosuppressive tumor microenvironment, intrinsic T cell dysfunction and tumor antigen heterogeneity leading to antigen escape.”

Bagley further explained, “The challenge with GBM and other solid tumors is tumor heterogeneity, meaning not all cells within a GBM tumor are the same or have the same antigen that a CAR T cell is engineered to attack, and every person’s GBM is unique to them, so a treatment that works for one patient might not be as effective for another. What’s more, GBM 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.”

For their reported trial, researchers used a technology developed in the lab of 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, and scientific advisor to the trial. This technique delivers CAR T cells targeting two proteins commonly found in brain tumors. The EGFR epitope is estimated to be present on the tumor surface in 50–60% of all GBMs, the team noted, while “IL13Rα2 is expressed in 50–75% of patients with GBM  and has previously demonstrated promise as a target for cellular therapy in this disease.”

While CAR T cell therapy for blood cancers is typically delivered through an intravenous route, researchers administered these dual-target CAR T cells intrathecally, through an injection into the cerebrospinal fluid, so that the engineered cells could more directly reach the tumors in the brain.

The ongoing trial is a single-center, Phase I open-label study in adult patients with rGBM. The aim is primarily to evaluate safety—including adverse events and serious adverse events—and determine the maximum tolerated dose of the the CART-EGFR-IL3Rα2 therapy. As a secondary endpoint the trial is also evaluating objective radiographic response (ORR), duration of response and overall survival. The published report outlines an interim analysis of the first six patients treated at the first two dose levels. The first patient was treated on in June 2023, and the sixth in January 2024. Median follow-up time was 2.5 months (1–7.5 months).


MRI scans taken 24 to 48 hours after administration of the dual-target CAR T revealed reduced tumor sizes in all six patients, and these reductions have been sustained out to several months later in a subset of patients. “Although the sample size treated thus far is small, and the follow-up duration is relatively brief, CART-EGFR-IL13Rα2 cells mediated reductions in enhancement and tumor size at early post-treatment timepoints in all six patients with multifocal, treatment-refractory rGBM,” the team noted. Although none of the patients met criteria for an objective response, the team observed tumor shrinkage of at least 30% in three of six patients, while stable disease was maintained on scans performed at least two months after CAR T cell therapy in three of the four patients who had at least two-months follow up time, “… arguing against a ‘pseudo-response’ phenomenon” the team continued.

“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 individuals with recurrent GBM,” said O’Rourke. “This cancer 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.”

A major concern with CAR T cell therapy, especially when delivered to the brain, is neurotoxicity, which occurs when a toxic substance alters the activity of the nervous system, and can disrupt or kill brain cells, called neurons. The researchers reported that in all six patients treated with CAR T cell therapy in this trial, neurotoxicity was substantial but manageable. “We observed early-onset acute neurotoxicity associated with administration of CART-EGFR-IL13Rα2 cells that was manageable at both dose levels …” they wrote, acknowledging that “Larger numbers of treated patients and additional correlative work are needed to better characterize the neurotoxicity associated with CART-EGFR-IL13Rα2 cells and to develop optimal grading and management guidelines.”

The team acknowledged that initial results from the study have limitations, given that only six patients had been treated, and there was limited follow-up time. “Nonetheless, our promising early experience with CART-EGFR-IL13Rα2 cells in patients with multifocal disease sets the stage for further optimization of this approach for rGBM, an exceptionally challenging cancer with a survival of only 4–11 month,” they stated. The researchers confirmed that additional correlative studies are planned.

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