CAR T cells have made a name for themselves as powerful cancer fighters. Engineered to recognize and destroy specific targets, these specialized immune cells have transformed treatment for various blood cancers. But what if the same technology could be just as valuable for understanding disease as it is for treating it?
Researchers from the Peterson Lab in the Translational Science and Therapeutics Division at Fred Hutch explore that idea in a recent study published in the journal Human Gene Therapy. The team tested whether CAR T cells could selectively eliminate natural killer (NK) cells, potentially providing a new way to investigate their roles in the immune system.
NK cells are an important part of the body's early defense against viruses like HIV. But their activity may also contribute to harmful inflammation. NK cells have a complicated role in viral infection but understanding their precise contributions has been difficult, in part because scientists have lacked reliable ways to selectively remove them.
“Sometimes the best way to study something is to take it out and see what happens,” explained Dr. Taylor Oeschger, a postdoctoral researcher in the Peterson Lab and lead author of the study.
Previous efforts to deplete NK cells using drugs or antibodies have had limited success, often affecting other immune cells in the process. CAR T cells offer a more targeted and potentially longer-lasting alternative. Unlike conventional drugs, these engineered cells can recognize and eliminate cells displaying a particular surface protein. They can also multiply and persist in the body, allowing for continued elimination of their targets over time.
"We're trying to use those advantages in a new way," explained Oeschger.
To test the approach, the researchers engineered CAR T cells to recognize two different targets found on NK cells: CD16 and NKG2A/C. Both designs successfully eliminated cells carrying their respective targets in laboratory experiments. The team then tested their most promising candidates in healthy rhesus macaques, whose immune systems share important similarities with those of humans.
The results were promising, but not entirely as expected.
CAR T cells targeting NKG2A/C were associated with substantial reductions in NK-cell numbers in both blood and tissues, particularly after a second infusion. In contrast, CAR T cells targeting CD16, which is expressed on several cell types in addition to NK cells, did not consistently reduce NK-cell numbers. However, differences in dosing due to variability in initial cell isolation and expansion made direct comparisons between the two targets difficult.
Perhaps more surprising was what the researchers didn't observe. Despite the reduction in NK cells, the researchers found little evidence that the CAR T cells had multiplied substantially or persisted at high levels, two properties that would make them especially useful as research tools.
One possible explanation lies in the medications administered alongside the CAR T cells. To protect the animals from risk of excessive inflammation, the researchers used drugs that suppress immune activity. But these medications may also have inadvertently dampened the CAR T cells themselves. "It's a really tough balance," explained senior author Dr. Christopher Peterson, “developing these new research tools requires balancing CAR T-cell activity with safety.”
The study also introduced an unusual biological challenge. Unlike the B cells targeted by many cancer-directed CAR T cell therapies, NK cells are themselves capable of killing other cells.
"We were putting two attacking cells against each other," Oeschger explained.
This raises the intriguing possibility that the NK cells could have fought back against their engineered attackers. Although the researchers found no direct evidence of this, the possibility raises new questions about what happens when CAR T cells are directed against other immune cells.
This work demonstrates the potential of CAR T cells as tools for investigating the immune system, while highlighting challenges that will need to be addressed before the approach can be used more broadly. The study also opens the possibility of using CAR T cells to investigate other immune cell populations whose functions remain poorly understood, such as monocytes, another CD16-expressing subset which may influence the effectiveness and safety of CAR T-cell therapies.
Ultimately, Oeschger hopes the work will inspire scientists to "expand their idea of what a CAR T cell can do."
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Members Drs. James M. Olson and Christopher W. Peterson contributed to this research.
The spotlighted research was funded by the National Institutes of Health.
Oeschger TM, Varco-Merth B, Starke CE, Poole NH, Reddy SS, Cruz A, Medina M, Dannay R, Singh SP, Nekorchuk M, Swanson T, McAllister R, Bochart R, Labriola C, Magnani DM, Olson JM, Price JP, Estes JD, Peterson CW, and Okoye AA. 2026. Chimeric Antigen Receptor T Cell Targeting of Natural Killer Cells in Peripheral Blood and Tissues of Rhesus Macaques. Human Gene Therapy. DOI: 10.1177/10430342261486115.