Dr. Matthias Stephan has a bold vision. He imagines a future where patients with leukemia could be treated as early as the day they are diagnosed with cellular immunotherapy that’s available in their neighborhood clinic and is as simple to administer as today’s chemotherapy, but without the harsh side effects.
The key to that scientific leap? Nanoparticles, tiny technology that’s able to carry tumor-targeting genes directly to immune cells still within the body and program them to destroy cancer.
In a proof-of-principle study published Monday in Nature Nanotechnology, Stephan and other researchers at Fred Hutchinson Cancer Research Center showed that nanoparticle-programmed immune cells, known as T cells, can clear or slow the progression of leukemia in a preclinical model.
“Our technology is the first that we know of to quickly program tumor-recognizing capabilities into T cells without extracting them for laboratory manipulation,” said Stephan, the study’s senior author. Although his method for programming T cells is still several steps away from the clinic, Stephan envisions a future in which biodegradable nanoparticles could transform cell-based immunotherapies — whether for cancer or infectious disease — into an easily administered, off-the-shelf treatment that’s available anywhere.
Stephan imagines that in the future, nanoparticle-based immunotherapy could be “something that is available right away and can hopefully out-compete chemotherapies. That’s my excitement.”
The body as genetic engineering lab
Stephan created his T cell–homing nanoparticles as a way to bring the power of cellular cancer immunotherapy to more people. Cell-based cancer-killing immunotherapies are currently only available through clinical trials, but are showing great promise for patients with certain leukemias whose tumors resist conventional treatment options.
T cells are specialized to already trek through the body, on the lookout for diseased cells, making them an ideal starting point for scientists working to generate a living anti-cancer therapy. Researchers have developed strategies to rewire T cells’ genetics so that certain cancer cells pop up on their radar as dangerous. One class of engineered T cells is known as CAR T cells, for the researcher-designed chimeric antigen receptors encoded in their new genes.
Stephan would like to spare patients receiving CAR T cells the long, expensive process that is only available at a few specialized research centers (including Fred Hutch and its clinical care partner, Seattle Cancer Care Alliance). The procedure requires removing T cells from patients’ blood, growing and genetically engineering the cells in a lab — a several weekslong process — before transfusing them back into patients.
Additionally, patients must undergo chemotherapy regimens that tackle their cancer and also decimate their other immune cells — making room for the new army of CAR T cells they’ll soon receive. Successful CAR T cells act as living drugs, able to respond to tumor cells, expand their numbers, and subsist long enough to potentially mount a defense against cancer relapse.
But “you already have living drugs inside of your own body, it’s just that you need to retarget them,” noted Stephan. In his method, the laborious, time-consuming T-cell programming steps all take place within the body, creating a potential fleet of “serial killers” within days.
In the current study, Stephan and his team developed biodegradable nanoparticles that carry CAR-encoding genes and are tagged with molecules that make them stick like burrs to T cells. Once a T cell engulfs the particles, they hitch a ride along the cell’s internal traffic system to the nucleus. In this preliminary study, Stephan and his team designed the new CAR genes to integrate into chromosomes housed in the nucleus, making it possible for T cells to begin decoding the new genes and producing CARs within 24 to 48 hours.
Once the team determined that their CAR-carrying nanoparticles reprogrammed a noticeable percent of T cells, they tested their efficacy. Using a preclinical model of leukemia, Stephan and his colleagues compared their nanoparticle-programming strategy against chemotherapy followed by an infusion of T cells programmed in the lab to express CARs, which mimics current CAR T-cell therapy.
The nanoparticle-programmed CAR T cells held their own against the infused CAR T cells. Treatment with nanoparticles or infused CAR T cells improved survival 58 days on average, up from a median survival of about two weeks.
Fred Hutch file
Making immunotherapy easier
That the nanoparticles can produce T cells with a similar cancer-fighting potency as current methods gives Stephan hope that he can contribute to a gentler, cheaper and easier way to deliver immunotherapy to patients. Unlike infused CAR T cells, nanoparticle-programmed T cells don’t rely on chemotherapy to clear their way; in fact, the more T cells available for nanoparticle targeting, the better.
“We’re using the T cells already in the patient,” Stephan pointed out. “The novelty is that … in theory, this could be frontline therapy [for leukemia] that would not require chemotherapy at all.”
Because nanoparticles are cheap and easy to produce, he envisions a therapy that is as easy to store and administer as chemotherapy or antibody-based immunotherapies like Keytruda, but which trains the immune system in the same way as genetically engineered T cells.
“We’re combining the pros from all technologies,” he said. Someday, nanoparticles could make cellular immunotherapy an option “the day you get diagnosed … and it could be done in your neighborhood.”
Stephan’s nanoparticles still have to clear several hurdles before they get close to human trials. He’s pursuing new strategies to make the gene-delivery and -expression system safe in people and working with companies that have the capacity to produce nanoparticles at clinical grade. Additionally, Stephan has turned his sights to solid tumors and is collaborating with several research groups at Fred Hutch.
And, he said, immunotherapy may be just the beginning. In theory, nanoparticles could be modified to serve the needs of patients whose immune systems need a boost to protect against a virus, but who cannot wait for several months for a conventional vaccine to kick in.
“We hope that this can be used for infectious diseases like hepatitis” said Stephan. This method may be a way to “provide patients with receptors they don’t have in their own body, and you just need a tiny number of programmed T cells to actually protect against a virus.”
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Sabrina Richards is a staff writer at Fred Hutchinson Cancer Research Center. She 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 firstname.lastname@example.org.
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