Immature NK cells in donor cord blood can undermine CAR NK cell therapy activity

The composition of donor cord blood may play a critical role in the success of chimeric antigen receptor (CAR) natural killer (NK) cell therapies. A small population of immature NK cells present in donor cord blood can undermine the activity of CAR NK cell therapy by redirecting potent immune cells away from tumors and causing them to attack one another, according to researchers from The University of Texas MD Anderson Cancer Center. 

The study, published in Cancer Cell, identifies a previously unrecognized mechanism of CAR NK cell dysfunction and offers a practical strategy to improve the potency and consistency of future off-the-shelf NK cell therapies. 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. The team discovered that these immature cells actively disrupted the function of more potent CAR NK cells. 

Our findings show that a relatively small population of immature NK cells can have a disproportionately harmful effect on the entire therapeutic product. Importantly, this is a problem we can potentially address with a straightforward manufacturing strategy by removing these cells before therapy production.” 

Katy Rezvani, M.D., Ph.D., principal investigator, vice president and head of the Institute for Cell Therapy Discovery & Innovation, and professor of Stem Cell Transplantation and Cellular Therapy

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. 

What are CAR NK cell therapies? 

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 off-the-shelf CAR NK cell 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 potentially made readily available to patients when needed. 

However, donor cord blood units contain biologically diverse populations of NK cells. The researchers sought to understand whether this cellular composition could influence the quality and effectiveness of the final CAR NK cell product. 

What are the key findings of the study? 

Researchers discovered that immature NK cells can pick up proteins from cancer cells after coming into contact with them. This process is 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. 

Can removing immature NK cells improve CAR NK cell therapy? 

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 and ovarian cancer. 

The study provides a new framework for selecting donor cord blood and manufacturing CAR NK cell therapies. Researchers now are 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.