Cancer Research News Exclusive: Taking the fight straight to the source
SEATTLE—Cell therapies, which feature immune cells such as T cells, chimeric antigen receptor (CAR) T cells or natural killer cells, have become something of a household name within the oncology field as a new way to target tumors in a variety of approaches. And a research team from Fred Hutchinson Cancer Research Center—led by Dr. Matthias Stephan, a faculty member in the Fred Hutch Clinical Research Division—has published their findings on one such new approach. In a proof-of-principle study, they found that a thin sheet of mesh loaded with T cells led to significant tumor clearance in animal models. Their work appeared in Nature Biomedical Engineering.
While cell therapies have seen promising results in liquid tumors, their track record against solid tumors is not as encouraging, which Stephan attributes to tumor location and environment. While T cells are easily delivered to liquid tumors via the bloodstream, finding solid tumors is just the first obstacle for cell therapies.
“In solid tumors it's more complicated, because you very often have single lesions that surround themselves with tumor stroma and connective tissue and immunosuppressive cells; they build a little castle to defend themselves from the immune system, and so they're well defended,” he explains. “So even if some T cells that you infuse intravenously end up finding solid tumor lesions, they're very often rendered dysfunctional by the tumor microenvironment. That's a big challenge to overcome, and that's where our technology comes into play.”
Another problem, Stephan tells DDNews, is the heterogeneity of solid tumors. Liquid tumors are clonal, he says, and nearly 100 percent of leukemia tumor cells present with the same surface markers, making it easy to engineer cell therapies against a single target. With solid tumors, however, “Even if the T cells are doing their job, wiping out all the antigen-positive tumor cells, there's still a large number of tumor cells that don't express the antigen—and then they just escape and grow out, so the patient then develops resistance against this cell therapy.”
The Fred Hutch technology targets tumors directly by surgically implanting a T cell-loaded mesh film directly on top of a tumor. Created by Monarch Biosciences, the mesh is only 10 micrometers thick—roughly seven times thinner than the width of the average human hair. The mesh is made of nickel titanium, which Stephan says is the most commonly used material for transplants and is non-toxic, posing no risk of triggering an immune response. Each “hole” in the mesh is filled with T cells or anti-cancer drugs, and it can be customized into different patterns for different payloads. The contents then spread around the tumor and surrounding microenvironment to target and destroy tumor cells.
“We provide all the factors that T cells need for full-fledged activation,” Stephan reports. “In a way, we want them to feel like they're in a lymph node when you have an acute inflammation and they're on fire. They're sitting on top of a tumor, which is the exact opposite—the tumor is usually trying to suppress immune cells, calm them down and render them dysfunctional. So this implant, in a way, provides a three-dimensional space, kind of like an artificial lymph node, where they feel at home and they don't feel anything of the suppressive environment of the tumor.”
In testing this approach, Stephan and his team worked with preclinical mouse models of ovarian cancer. The mesh was loaded with CAR T cells targeted toward ROR1, a marker found on ovarian cancer cells, and then implanted on the mice's tumors. Within 10 days of implantation, the tumors had disappeared, and by 20 days, 70 percent of the mice were still tumor-free.
This technology has promise in a number of cancers, according to Stephan, particularly ones that are unresectable, such as glioblastoma, or that occur in tube-like sections of the body, such as lung, esophageal or pancreatic cancer. In fact, when the research team tested the mesh film in a tube version, they found that the loaded mesh prevented tumors from growing into the tube.
Stents are already commonly used in such cancer types “as a palliative measure,” Stephan explains, to keep a tumor from blocking off passages or lumens (the interior of tubular structures such as arteries or airways).
“What we're saying is that we can now use these thin films, wrap them around a stent, put them inside of these lesions, and then not just keep the lumen open, but also send out tumor-specific T cells that can then destroy tumor tissue,” he details. “So it's not just a palliative therapy, but it's actually a potentially curative therapy.”
He adds that he envisions this eventually being an off-the-shelf product, in which T cells provided by healthy donors or generated with an approach such as CRISPR are manufactured, frozen, and then thawed and added to the mesh before being implanted. The film can be customized with supportive factors for any kind of cell type, Stephan notes, and only “around four million cells per patient” are needed, “because the cells are expanding at the tumor site inside of these devices vs. expanding them in the laboratory by adding stimulatory cytokines.” This makes the process both faster and less expensive, he points out.
“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,” Stephan said in a press release.