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After Setbacks, Cell Therapy for Glioblastoma Moves onto New Chapter

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Donald M. O’Rourke, MD, director of the Glioblastoma Translational Center of Excellence at Penn Medicine, feels energized.

After a lot of frustration and too few successes, the cell therapy field has reached a new phase in its pursuit for better treatments for the deadly brain cancer glioblastoma multiforme (GBM). For decades, treatment approaches using surgery, chemotherapy, and radiation have sometimes helped to slow tumors’ growth, but the disease has almost always recurred and proved lethal. For that reason, over the last decade, O’Rourke and others began to explore cellular immunotherapies — similar to those developed at Penn Medicine and approved for certain blood cancers — as a potential better option for these brain tumors.

This decade-long focus in the lab and clinic, heightened by President Biden’s Moonshot initiative over the last five years, has helped answer questions about the tumor itself and previous therapies’ shortcomings. Now, researchers are on the cusp of delivering the next generation of chimeric antigen receptor cellular therapies (CARs) that could instill fresh hope for patients with GBM and other types of solid tumors.

“The amount and richness of GBM research is dramatically better than it was,” said O’Rourke, who also serves as the John Templeton, Jr., M.D. Professor in Neurosurgery in the Perelman School of Medicine at the University of Pennsylvania. “And when there is increased work and scholarship being done in the field, it will get clinically translated and there will be an improvement.”

At Penn, a leader in GBM cellular therapies since the early days of this technology, a new CAR cell therapy could find its way into clinical trials by next year in collaboration with Tmunity Therapeutics, a Philadelphia-based biotherapeutics developer. O’Rourke and his team believe this “dual target” CAR could accomplish what its predecessors couldn’t: withstand a hostile tumor microenvironment and more precisely target and fight the tumor unhindered.

The timing is a tough reminder just how hard that has been for any treatment. Fifty years after the architects of the National Cancer Act signed it into law and more than 200 years since GBM was first reported, the median survival time is only 15 months, even after today’s aggressive treatments with chemotherapy and radiation. The five-year survival rate remains at just 10 percent, and nearly everyone who battles the disease loses.

“This is important for two reasons: for the field, which is really filled with desperation right now and continued setbacks,” O’Rourke said. “And for desperate patients who have a disease that still has no standard of care, which is an illustration of how bad things have been.”

orourke
Donald M. O’Rourke, MD

Stubborn but not impossible

GBM patients, many treated at Penn Medicine, have had responses to experimental CAR therapies, such as reduction in levels of the CAR T tumor target and proliferation and expansion of CAR T cells in tumor cells. But the majority of these treatment responses have not been maintained over time.

Brain tumors are notoriously stubborn against nearly everything in the armament, including CAR T cell therapies.

The problem 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. On top of that, GBM tumors grow in a microenvironment that blocks the activity of immune cells that might otherwise fight the tumor. This includes both engineered CAR T cells and a patients’ innate T cells.

A cellular therapy for GBM, as well as most solid tumors, needs to overcome those challenges.

Two previous clinical trials at Penn that included 17 patients, along with other trials at fellow institutions, helped tease out the biology to explain how and why some respond better than others.

The first round of CARs used for GBM were designed to target the antigen EGFRvIII, a known driver of the disease expressed in cancer cells. Studies had proven this was a feasible and safe approach, but when patients with recurrent GBM were infused with EGFRvIII CAR-T cells, researchers saw those infused cells diminish in most patients, leading to relapses. Analyses of their blood and tissue made it clear that expression of the antigen decreased over time and the tumor microenvironment was firing off too many anti-immune-cell soldiers to disable immune cells.

All was not lost, though. The studies showed CARs can pass the blood brain barrier and reduce the tumor if they stick around; one patient even had an exceptional response, surviving 36 months post infusion.

That invaluable data joined other research from Penn, including studies led by O’Rourke, Zev Binder, MD, PhD, an instructor of Neurosurgery, and others in Neuro-oncology, that has informed cell therapy approaches up to this point and in the future. Having the infrastructure and expertise from Penn’s Center for Cellular Immunotherapies, led by Carl June, MD, the Richard W. Vague Professor in Immunotherapy in the department of Pathology and Laboratory Medicine, only supports this science further. Bold swings that pay off, after all, are what this group excels at. The CAR T therapy known as CTL019 when it was developed by June and his lab and is now known as Kymriah, is the first FDA approved CAR therapy, giving patients with advanced leukemias who had little to no options left, another chance.

To move ahead in the GBM space, it was clear that CAR T cells had to be engineered to go after more targets than just one. Past studies have shown that targeting interleukin-13 receptor alpha 2 (IL13Rα2), another antigen molecule expressed in GBM tumors, with CARs could elicit responses in animals and patients.

It was time to double up.

Combining forces

Unlike past designs that target one antigen, the newer CAR expands its abilities by doing just that, targeting two — EGFR and IL-13Rα2.

Because of the tumor heterogeneity in GBM, there are pockets that will express target A and pockets that will express target B,” O’Rourke said. “We’re hoping we will get more cell coverage by adding a molecule in CAR T cells that express both binding domains so we can hit more cells.”

A significant sponsored research agreement with Tmunity that began last September has fueled preclinical studies and design of a clinical trial to be conducted at Penn Medicine with a multivariant CAR. Anywhere from 15 to 20 patients with recurrent GBM are expected to be enrolled by this time next year or soon after.

It’s just the beginning, O’Rourke said, of a series of collaborative investigations with Tmunity and likely other industry partners that will allow them to expand the number of patients and try new approaches. One idea is to pair these types of CARs with other therapies to build up the immune system’s defense against the tumors.

The groundwork is there. Past studies from Penn Medicine showed that combining a type of immunotherapy called checkpoint inhibitors with CARs in animal models inhibited brain tumors. Another one from June 2021 showed how bispecific T-cell engagers (or BiTEs) redirected T cells to target antigen-expressing tumors, acting as a helping hand to fight the tumor.

Similar research has been in play across the field, with other institutions upping their research on brain tumors, pivoting as new information rolls in. Today, there are about 30 active clinical trials involving CAR T cells and gliomas.

And since the kickoff of Biden’s Moonshot initiative — which was driven by his son’s death of GBM — at Penn’s Abramson Cancer Center in 2016, additional dollars have gone toward brain tumor research, including pediatric GBM, and awareness around the lack of treatments has only increased.

It’s the kind of momentum O’Rourke and other neuro-oncology teams at Penn want to keep up.

“There is a lot of incredible science going on that has broad scientific impact beyond GBM,” O’Rourke said. “We want to work with many groups, both in industry and academia, to supercharge that into clinical translation. It will take time, but we hope to shorten that lag time by starting off with this new study, which I think is going to be a big advance over the previous work.”

Editor’s Note: O’Rourke is a scientific collaborator with Tmunity. He receives sponsored research funding from Tmunity and, as an inventor of licensed technology, he may receive additional future financial benefits under licenses granted by Penn to Tmunity. The University of Pennsylvania also holds equity and licensing interests in Tmunity.

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