UCLA scientists have achieved a medical first by successfully reprogramming patients' blood-forming stem cells to generate a continuous supply of cancer-fighting T cells, marking a potential breakthrough in immunotherapy delivery. The first-of-its-kind clinical trial, published in Nature Communications, demonstrates that engineered stem cells can act as an internal factory producing tumor-targeting immune cells over time.
The early-stage study was led by physician-scientist Dr. Theodore Scott Nowicki in collaboration with Dr. Antoni Ribas, Dr. Owen Witte, Dr. Donald Kohn, Dr. Lili Yang of UCLA, and Dr. David Baltimore from the California Institute of Technology. The research represents over a decade of work by more than 30 dedicated academic investigators.
Addressing Immunotherapy Limitations
The approach targets a fundamental challenge in cancer immunotherapy for solid tumors. "We're trying to address a problem that limits many current cancer immunotherapies for solid tumors, which is that they often work at first, but the benefit doesn't last because the T cells we infuse eventually die off or become exhausted," explained Dr. Nowicki, assistant professor-in-residence of pediatric hematology/oncology and microbiology, immunology, and molecular genetics at the David Geffen School of Medicine at UCLA.
The strategy involves inserting cancer-specific receptors into stem cells using gene therapy techniques, followed by bone marrow transplant to engraft the genetically modified stem cells. These engineered stem cells then produce genetically-redirected cancer-fighting immune cells within the patient's body.
Targeting NY-ESO-1 in Aggressive Sarcomas
The researchers chose to target NY-ESO-1, a cancer-testis antigen found in various cancers including melanoma and sarcoma. "NY-ESO-1 is found in a range of cancers, including melanoma and sarcoma, but it's rarely seen in healthy adult tissues, which makes it a relatively safe target," noted Dr. Nowicki.
The trial focused on patients with aggressive sarcomas, particularly relevant since approximately 80% of synovial sarcomas express the NY-ESO-1 tumor marker. These rare, aggressive cancers frequently recur even after standard treatments like chemotherapy or surgery, leaving patients with limited therapeutic options.
Clinical Trial Results
The pilot study provided encouraging evidence of feasibility and early efficacy. The engineered stem cells successfully engrafted in patients and began producing cancer-targeting T cells. Notably, one patient demonstrated signs of tumor regression and maintained detectable levels of the engineered immune cells for months following treatment.
"We saw that the engineered stem cells could successfully engraft in the patients and begin producing cancer-targeting T cells," reported Dr. Nowicki. "Importantly, we were able to visualize the stem cells in the body, showing they took hold. We essentially taught the body to grow its own supply of cancer-fighting T cells."
Broader Therapeutic Potential
The implications extend beyond cancer treatment. Dr. Nowicki suggested the strategy could potentially address other medical conditions: "This strategy of using engineered stem cells to generate long-lasting immune responses isn't just for cancer. In the future, we could use it to fight infections like HIV or even retrain the immune system in autoimmune diseases."
Current Limitations and Future Outlook
While promising, the therapy remains experimental and complex. The treatment protocol involves stem cell collection, gene modification, and high-dose chemotherapy to prepare the body, requiring significant expertise and patient strength. "The early results are promising, but this is still experimental and not without risk," cautioned Dr. Nowicki.
Dr. Antoni Ribas, professor of medicine and director of the tumor immunology program at the UCLA Health Jonsson Comprehensive Cancer Center, emphasized the significance of translating preclinical research to human application: "This pilot study provided exciting evidence that the human immune system can be programmed to become cancer-focused by genetically engineering blood stem cells."
The research represents a foundational step toward a future where cancer treatment focuses not just on eliminating existing tumors but preventing recurrence through sustained immune surveillance. As Dr. Nowicki concluded, "We've shown that it's possible to reprogram a patient's own stem cells to create a renewable immune defense against cancer. That's never been done in humans before."
