Immature NK Cells in Donor Cord Blood Can Sabotage CAR NK Cell Therapy, MD Anderson Study Reveals

A previously unrecognized mechanism of dysfunction in chimeric antigen receptor (CAR) natural killer (NK) cell therapies has been uncovered by researchers at The University of Texas MD Anderson Cancer Center, revealing that a small population of immature NK cells in donor cord blood can actively sabotage the therapeutic product. The findings, published in Cancer Cell, identify how these immature cells can redirect potent immune cells away from tumors and cause them to attack one another, while also offering a straightforward manufacturing fix.

"Our findings show that a relatively small population of immature NK cells can have a disproportionately harmful effect on the entire therapeutic product," said principal investigator Katy Rezvani, M.D., Ph.D., vice president and head of the Institute for Cell Therapy Discovery & Innovation, and professor of Stem Cell Transplantation and Cellular Therapy at UT MD Anderson. "Importantly, this is a problem we can potentially address with a straightforward manufacturing strategy by removing these cells before therapy production."

The study was led by first and co-corresponding author Ye Ethan Li, M.D., Ph.D., an assistant professor at UT MD Anderson, whose work helped define the biological differences between these NK cell populations and uncover the mechanism responsible for impaired CAR NK cell function.

Trogocytosis: How Immature NK Cells Become False Targets

CAR NK cells are an investigational off-the-shelf immunotherapy in which natural killer cells are engineered to better recognize and eliminate cancer cells. At UT MD Anderson, researchers have pioneered the development of these therapies manufactured from donated umbilical cord blood. Unlike patient-specific cell therapies, cord blood-derived CAR NK cells can be manufactured in advance, cryopreserved, and made readily available to patients when needed.

However, donor cord blood units contain biologically diverse populations of NK cells, and the researchers sought to understand whether this cellular composition could influence the quality and effectiveness of the final CAR NK cell product. Their investigation revealed that immature NK cells can pick up proteins from cancer cells after coming into contact with them — a process known as trogocytosis.

As a result, the immature NK cells begin to display cancer proteins on their own surface. The engineered CAR NK cells can then mistake these immature immune cells for cancer cells and attack them. In effect, the immature NK cells create false targets that distract the therapeutic cells from the cancer. These interactions reduced the fitness and persistence of the stronger NK cells and weakened their ability to control the tumor.

A Practical Path to More Potent Therapies

The researchers found that cord blood units enriched for mature NK cells were linked to stronger treatment responses and better patient outcomes, while higher levels of immature NK cells were associated with reduced effectiveness. When the immature NK cells were removed before manufacturing, the remaining cells were more effective, persisted longer, and showed stronger antitumor activity.

This strategy enhanced tumor control and survival in preclinical models of lymphoma (搜索)搜索该疾病 and ovarian cancer (搜索)搜索该疾病, providing a new framework for selecting donor cord blood and manufacturing CAR NK cell therapies. The team is now working to incorporate these findings into next-generation CAR NK cell platforms with the goal of producing more consistent, potent, and durable therapies for patients.