A bold strategy to enhance CAR T-cell therapies, capable of targeting DIPG and other tough-to-treat cancers

CAR T-cell therapy uses a patient's own genetically modified T cells to attack cancer, as pictured here, where T cells surround a cancer cell.
T cells surround a cancer cell. Credit: National Institutes of Health

A Boston-based team of researchers, made up of scientists and pediatric oncologists, believe a better CAR T-cell therapy is on the horizon.

They say it could treat a range of cancers — including the notorious, universally-fatal childhood brain cancer known as diffuse intrinsic pontine glioma or DIPG — by targeting tumor cells in an exclusive manner that reduces life-threatening side effects (such as off-target toxicities and cytokine release syndrome). The team, led by Carl Novina, MD, PhD, and Mark Kieran, MD, PhD, of the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, calls their approach “small molecule CAR T-cell therapy.”

Their plan is to optimize the ability for CAR T-cell therapies, which use a patient’s genetically modified T cells to combat cancer, to more specifically kill tumor cells without setting off an immune response “storm” known as cytokine release syndrome. The key ingredient is a unique small molecule that greatly enhances the specificity of the tumor targeting component of the therapy.

“Cytokine storms occur when large numbers of immune cells are activated and begin releasing inflammatory signals to further sound the alarm across the immune system,” says Kieran. “In the case of traditional CAR T-cell therapies, these effects can be even more exacerbated by the genetically-enhanced ability of the T cells to kill their tumor cell targets.”

A bevy of such therapies have been in the limelight since the Food and Drug Administration’s historic decision in August 2017 to approve a CAR T-cell therapy, KYMRIAH, for acute lymphoblastic leukemia (ALL), the most common childhood cancer. It was the first-ever gene therapy to enter the U.S. market.

A safer CAR T-cell therapy for DIPG?

Made by Novartis and available through the Dana-Farber/Boston Children’s gene therapy program, KYMRIAH works by modifying a patient’s immune cells to target and destroy a protein called CD19 found on ALL cells. But finding similar “pay dirt” on other types of cancer cell surfaces has so far remained elusive.

“It’s rare that tumor cell-surface markers — such as the CD19 protein on ALL cells — are found only on cancerous cells,” says Novina. “Often, normal cells carry similar surface markers as tumor cells, making it difficult to attack the cancer cells without killing healthy cells and setting off a life-threatening immune response.”

For a cancer like DIPG, found in a child’s brainstem, an immune super-reaction could be fatal on its own. In California, for example, a recent CAR T-cell approach for DIPG tested in mice was able to clear most of DIPG’s cells, but at the cost of “dangerous levels of brain swelling” in some animals. Although the therapy is now heading to human clinical trials, it remains unknown whether it will be safe in humans.

“When it comes to brain tumors, the effects of such an inflammatory response become even more dangerous when trapped inside the skull,” Kieran says.

A systematic roadmap to the future of CAR T-cell therapy

So Novina and Kieran have dreamed up a workaround to this problem, and are beginning to use mouse models to bring their vision to reality. For treating DIPG and other cancers, they plan to leverage the presence of certain cell surface markers that appear more often on cancerous cells than healthy cells.

First, they will dispatch a tumor targeting system, built of a small, man-made molecule attached to an antibody, that is capable of entering the body and latching onto their intended cell surface markers. Through normal processes, the body’s non-cancerous cells will ingest these molecules. As a result, tumor cells will be more likely than normal cells to leave these decorations exposed on their cell surfaces.

Meanwhile, specially-prepared CAR T-cells will have been readied in the lab, designed to latch onto the man-made small molecules. Once released into the body, the CAR T-cells find the small molecules and begin to attack the cells they are decorating. The tumor cells, their surfaces covered in the small molecules, become sitting ducks.

“Last but not least, the body’s own immune system will also learn to attack the cells covered in these small molecules, doubling down on the cancer cells,” Novina says.

Novina’s first prerogative is to fine-tune the small molecule targeting system. He’s planning to do this with the help of Allison O’Neill, MD, whose Dana-Farber/Boston Children’s laboratory specializes in sarcoma mouse models. Then, the team will move onward to applying the approach to cancer tumor targets in the brain, using mouse models of DIPG.

“There’s no opportunity lost here – this effort isn’t just about creating CAR T-cell therapies for DIPG but, by tackling the most challenging childhood cancer out there, we’ll also map out the strategy for adapting small molecule CAR T-cell therapy to treat countless other kinds of pediatric and adult cancers,” Novina says.

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