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A diagram shows how a thin film of patterned nitinol can be used to hold CAR T cells, with fibrin protein used as a binding agent. (Fred Hutchinson Cancer Research Center Graphic)

Researchers at Seattle’s Fred Hutchinson Cancer Research Center have demonstrated the effectiveness of a new method for getting immune cells to fight solid tumors — by spreading them like jam onto ultra-thin sheets of metal mesh, and then laying the mesh onto the tumors.

So far, the technique for delivering genetically engineered T cells has been used only on mice — but the preclinical study published today in Nature Biomedical Engineering could help set the stage for the mesh to be used on humans as well.

“Cell therapies to fight cancer have had great success in blood cancers, but haven’t worked well with solid tumors,” senior study author Matthias Stephan, a faculty member in the Fred Hutch Clinical Research Division, explained in a news release.

“Our findings take a significant step toward making cell therapies effective against solid tumors by showing that a thin metal mesh loaded with T cells engineered to fight ovarian cancer cleared tumors in 70% of the treated mice,” he said.

The mesh is made of a micropatterned nickel-titanium alloy, commonly known as nitinol. It’s only 10 micrometers thick, which is thinner than the width of a human hair. Nitinol films are already used in a wide range of medical devices, including stents that are implanted in blood vessels to treat vascular disease.

Stephan and his colleagues have been working for years on a variety of delivery systems for chimeric antigen receptor T cells, better known as CAR T cells. Such cells are programmed to overcome the defenses of a patient’s cancer cells. Although injecting CAR T cells into the bloodstream is effective against leukemia and other types of blood cancer, that strategy appears to be too scattershot to work against solid tumors.

If CAR T delivery systems were more effective against solid tumors, they’d be attractive alternatives to chemotherapy and radiation. “In addition to minimizing side effects in patients, our ultimate goal is to make T-cell therapies faster and cheaper to make, and easier to deliver to patients,” Stephan said.

Matthias Stephan
Matthias Stephan is an expert in immunobioengineering and is an associate member in the Clinical Research Division at Fred Hutchinson Cancer Research Center. (Stephan Lab / Fred Hutch Photo)

Other researchers have looked into using scaffolds made of hydrogels or electrospun polymers as T-cell delivery platforms, but those materials may not have the optimal structure to hold high concentrations of T cells. Stephan and his colleagues turned instead to thin films of nitinol.

“We needed to find a pattern of the film that would work well for T cells,” Stephan explained. “The pattern needed to be small enough where the cells would not fall between the cracks, and not too small so that the T cells would feel too cramped and wouldn’t be able to move.”

A mesh that was patterned with maze-like straight lines seemed to work best. They coated the mesh with materials that would allow cells to grow and expand once they’re inside the body. Then they loaded the mesh with CAR T cells that were engineered to hunt down and destroy ovarian cancer cells.

“It’s like a piece of bread spread with marmalade on both sides,” Stephan said. “The metal film is the bread, and then we put CAR T cells on both sides of it, and then they soak into the middle, too.”

The technique was tested on mice that had been injected with human ovarian cancer cells, and developed tumors under their skin as a result. Ten mice had the T-cell mesh implanted onto their tumors. Ten other mice were given CAR T cells by injection, and 10 untreated mice served as a control group.

Within 10 days, the tumors disappeared in the mesh-treated mice, and seven of the 10 mice remained tumor-free weeks later. In contrast, all of the mice receiving the T-cell injections died within 60 days, and the untreated mice died within a month.

T-cell mesh
A photomicrograph shows the patterned surface of a thin metal film that’s been loaded with cancer-fighting CAR T cells. (Fred Hutchinson Cancer Research Center Photo)

In another experiment, the Fred Hutch team found that a tube-shaped version of the T-cell mesh kept tumors from growing into the tube. They said this approach could be used against cancers that cause obstruction of the respiratory or digestive system, as can be the case for lung cancer or pancreatic cancer. It could also be used against esophageal cancer, where stents are used to keep tumors from interfering with swallowing.

Stephan suggested that the structure of the metal mesh could come in handy for a wide variety of other medical applications. “We focused on CAR T cells in the current experiment, but I could see this approach working with T-cell receptor therapies, natural killer cells and other types of immune cells that target cancer,” he said.

In their research paper, the authors acknowledged that their experiments were done under unnatural conditions. Before the team moves on to human clinical trials, the T-cell mesh technique will have to be evaluated under more realistic conditions, with larger animals. In the meantime, the researchers are developing different mesh patterns, including hexagonal and spiral designs, in hopes of optimizing the therapeutic effect.

The principal authors of the paper in Nature Biomedical Engineering, “Nitinol Thin Films Functionalized With CAR-T Cells for the Treatment of Solid Tumours,” are Michael Coon and Sirkka Stephan of the Fred Hutch Clinical Research Division. Other authors include Vikas Gupta and Colin Kealey of Monarch Biosciences.

Monarch Biosciences manufactured the mesh used in the study, and provided funding for the research. Additional funding came from Fred Hutch and the Bezos Family Foundation. Fred Hutch and some of its scientists may benefit financially from this work in the future. Matthias Stephan and Colin Kealey have filed a patent application related to T-cell mesh technology, with Fred Hutch and Monarch Biosciences listed as assignees.

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