Scientists reprogram stem cells to create renewable cancer-fighting T cells

For the first time in a clinical trial, UCLA scientists have demonstrated that they can reprogram a patient’s blood-forming stem cells to continuously produce functional T cells, the immune system’s most powerful cancer-killing agents. This approach offers a new way to deliver immunotherapy by acting as an internal factory for producing tumor-targeting immune cells with the potential for long-lasting protection.

The early-stage study, published in Nature Communications, was led by physician-scientist Dr. Theodore Scott Nowicki in collaboration with Drs. Antoni Ribas, Owen Witte, Donald Cohn, Lily Yang of UCLA, and David Baltimore of Caltech. The study represents a new strategy for treating difficult-to-treat cancers, particularly solid tumors that have proven more resistant to traditional T-cell therapies.

Nowicki, an assistant professor of pediatric hematology/oncology, microbiology, immunology, and molecular genetics at the David Geffen School of Medicine at UCLA, and Ribas, a professor of medicine and director of the tumor immuno-oncology program at UCLA Health Jonsson Comprehensive Cancer Center, discuss the promise of this approach and its potential to transform cancer care and other areas.

— What problem in cancer treatment were you trying to solve by combining engineered T cells with genetically modified stem cells, and how does this approach work?

Novitzky: We’re trying to solve a problem that limits many current immunotherapies for solid tumor cancers: They often work at first, but the effect doesn’t last because the infused T cells eventually die or are exhausted. The idea was to create a system in which the patient’s own body would continually generate new cancer-fighting immune cells — a kind of constant immune refresh. That’s where stem cells come in. If we can reprogram a patient’s stem cells to continually produce fresh cancer-fighting T cells, we can provide much longer-term protection against the disease.

— Why did you choose the specific cancer marker NY-ESO-1 as a target?

Novitzky: NY-ESO-1 is what’s called a “cancer testis antigen.” It’s found in a number of cancers, including melanoma and sarcoma, but it’s rarely found in healthy adult tissue, making it a relatively safe target. That means our engineered T cells can recognize and attack tumors without harming other tissues.

— You tested this approach on people with aggressive sarcomas. Why them?

Novitzky: Sarcomas are rare, aggressive tumors that often express NY-ESO-1. About 80% of synovial sarcomas have this tumor marker. Even after standard treatments — chemotherapy or surgery — the disease often recurs. And when it does, patients usually have very few options.

— What are the results of this first study?

Novitzky: We saw that the engineered stem cells successfully engrafted in patients and began producing cancer-targeting T cells. In one patient, the tumor regressed and these new immune cells were detectable within a few months. Importantly, we were able to visualize the stem cells in the body, proving that they were engrafting. We essentially trained the body to produce its own supply of cancer-fighting T cells.

— Could such therapy be too complex or risky for most patients?

Novitzky: Early results are encouraging, but it’s still an experimental technique with risks. It’s really difficult now, but so was bone marrow transplantation in the early days. The therapy requires harvesting stem cells, genetically modifying them, and high-dose chemotherapy to prepare the body, which takes time, expertise, and patient resilience.

— Could this strategy work for diseases other than cancer?

Novitzky: This strategy of using engineered stem cells to create long-lasting immune responses isn’t limited to cancer. In the future, it could be used to fight infections like HIV or to rewire the immune system in autoimmune diseases. Our study is a first step, but the potential is much broader.

— What is the most important thing people should understand from this research?

Novitzky: We’ve shown that it’s possible to reprogram a patient’s own stem cells to create a regenerative immune defense against cancer. This has never been done before in humans. It’s not a cure yet, and it’s not ready for widespread use, but it points to a future where we don’t just cure cancer — we prevent it from coming back.

Ribas: It took a team of more than 30 dedicated scientists and more than a decade of work to bring the concept of genetically programming the human immune system to fruition to produce a renewable source of cancer-targeting immune cells. The basic scientific principles were established in preclinical models, and this study showed that they could be tested in cancer patients.