Donor Cord Blood Composition May Influence CAR NK Cell Therapy Outcomes
A study in Cancer Cell reveals that immature NK cells in donor cord blood can sabotage CAR NK cell therapy through trogocytosis, causing fratricide. Removing these cells before manufacturing improves antitumor activity in preclinical models, offering a strategy for more consistent off-the-shelf therapies.
A small population of immature natural killer (NK) cells present in donor cord blood can undermine the activity of chimeric antigen receptor (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.
The 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, creating 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.
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.
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.
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.