Research usually advances by inches forward, not leaps. Epiphanies that open new avenues of investigation are relatively rare. Fred Hutchinson Cancer Research Center’s Dr. Matthias Stephan experienced just such a flash of insight in the dark early hours of a Sunday morning several years ago. As several threads of knowledge coalesced into a unified idea, Stephan realized how, with a single device, he could bring the power of the immune system to bear against solid tumors like breast cancer.
Stephan is a pioneer in the field of immunobioengineering, working where “materials science meets immunology” to create unconventional solutions to treating cancer. Drawing from gene therapy, bioengineering, and immunotherapy Stephan is pinpointing the best tools in each discipline, and finding new ways to combine them. In doing so, he is devising inventive strategies to circumvent the hurdles that prevent immunotherapy from being cost-effective, widely available and effective against many types of cancer.
Focusing on solid tumors
Stephan’s foggy early morning brainwave illuminated an unexpectedly simple approach to making cell-based immunotherapy, in which cancer-targeting immune cells are enlisted to fight tumor cells, as effective against solid tumors as it has been against blood cancers like leukemia. In current immunotherapies, engineered T cells are infused intravenously into patients and then must begin hunting for their targets. This works well for diffuse leukemias, but most T cells lose their way long before arriving at a single solid-tumor site. Stephan realized that he could load anti-tumor T cells — immune cells specially engineered to recognize and destroy cancers — into dissolving polymer scaffolds and place them directly at tumor sites. These T cells could mop up tumor cells that remain after surgery to prevent relapse. The technique could also be used to help shrink inoperable tumors.
His insight wove together several threads of background knowledge, Stephan explained. He knew of implants designed to help recruit cells to heal wounded tissue, such as injured spinal discs. Dissolving polymer wafers soaked with chemotherapy drugs were being implanted near tumors, but Stephan knew that T cells, which are capable of “squeezing throughout the entire tumor bed,” would be more effective than drugs, which can only penetrate a millimeter or so into tissue.
But if T cells are just injected after tumor-removal surgery, they will wash away, he explained. To prevent this, Stephan knew he needed to create a tool that mimics the specialized tissues where the T cells will feel at home. By combining the biodegradable scaffold, anti-cancer T cells and immune-stimulating factors into a single unit, Stephan realized that he could create a home base for T cells that could be situated exactly where needed.
His scaffold cleared two hurdles in a single bound: the long slog through tissues in which most cancer-hunting T cells are lost, and the toxicity that immune-stimulating factors can cause when administered systemically.
Just last December, Stephan and his team published promising results in Nature Biotechnology. Using a preclinical model of breast cancer, the researchers showed that anti-tumor cells placed via scaffold prevented relapse while intravenously administered T cells did not. They were able to follow scaffold-delivered T cells as they traveled along the lymphatic system, the same route metastatic cells take on their way to new homes in distant organs.
The work shows that “once you have slow release [of T cells] you can really saturate a large area and help purge healthy tissue from metastases,” Stephan said.
In an ovarian cancer model, the group saw that placing T cells near tumors caused them to shrink — but again, intravenously delivered T cells did not. Stephan is currently experimenting with the right mix of immune response-supporting factors, including those that can attract the patient’s own immune system for a sustained anti-cancer response.
He is also developing an injectable scaffold that can be inserted without surgery. Working with a polymer that is liquid at cold-storage temperatures but solidifies as it warms to body temperature, Stephan may be able to create a T-cell depot that is even less invasive and easier to administer.
A miniscule innovation boosts T-cell immunotherapy
Stephan’s search for the right tools to optimize immunotherapy began with an interest in gene therapy — and a frustration with its limitations. When he began his Ph.D. work in engineering anti-tumor T cells, gene therapy seemed like the key. Researchers were manipulating the expression of specific genes inside cells to treat “everything from baldness to cancer,” he recalled.
But Stephan quickly realized the strategy’s limitations: only about two new genes could be introduced into cells, and scientists were limited by the types of molecules that human cells can produce. No gene therapy could force a cancer cell to manufacture its own chemotherapy.
He decided to branch into other fields in his quest to better engineer cancer-destroying T cells and joined the lab of nanoparticle expert Dr. Darrell Irvine at the Massachusetts Institute of Technology. There, Stephan began developing nanoparticles able to convey anything from new genes to immune-stimulating factors to T cells inside patients.
Engineered T cells have the amazing ability to overpower cancer while sparing healthy tissue, but generating them is a costly process that’s only possible at a few specialized labs worldwide. It also takes weeks to produce enough programmed T cells to treat a patient, whose cancer may have turned deadly as they waited. Stephan is designing nanoparticles that could catapult immunotherapy over these challenges. His gene therapy–delivering nanoparticles could transform patients into their own T-cell engineering labs, allowing them to be treated with reprogrammed T cells almost from the moment of diagnosis, skipping the waiting period and high cost of current approaches.
“I’m excited about developing techniques to apply T-cell therapy and make it affordable so it can be developed and produced and distributed just like chemotherapy,” Stephan said.
Stephan’s nanoparticles also have the potential to help make current immunotherapies more effective by providing T cells with nanoparticle “backpacks” to carry the right mix of molecules that T cells need to survive and sustain a robust anti-cancer response. This would prevent the toxicity seen when patients are treated with systemic immune-boosting therapies and reduce the need for multiple rounds of T-cell treatment.
“I know that every field has a certain time when it’s hot,” Stephan said. Immunotherapy’s time is now, and he is excited to be working at the forefront of strategies that could make the approach a treatment option for any patient in need.
Dr. Sabrina Richards, a staff writer at Fred Hutchinson Cancer Research Center, has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a Ph.D. in immunology from the University of Washington, an M.A. in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University. Reach her at srichar2@fredhutch.org.
Solid tumors, such as those of the breast, are the focus of Solid Tumor Translational Research, a network comprised of Fred Hutchinson Cancer Research Center, UW Medicine and Seattle Cancer Care Alliance. STTR is bridging laboratory sciences and patient care to provide the most precise treatment options for patients with solid tumor cancers.
