Researchers from the University of Texas MD Anderson Cancer Center have discovered a mechanism of donor subset–driven chimeric antigen receptor (CAR) natural killer (NK) dysfunction and have developed a manufacturing strategy for improving the antitumor potency of CAR NK cell therapies for patients with cancer, according to research published in Cancer Cell.
“Our findings show that a relatively small population of immature NK cells can have a disproportionately harmful effect on the entire therapeutic product,” said senior author and principal investigator Katy Rezvani, MD, PhD, Vice President and Head of the Institute for Cell Therapy Discovery & Innovation, and Professor of Stem Cell Transplantation and Cellular Therapy. “Importantly, this is a problem we can potentially address with a straightforward manufacturing strategy by removing these cells before therapy production.”
Background
Donor heterogeneity has been a considerable barrier to using allogeneic CAR-engineering NK cells for off-the-shelf therapies.
Researchers developed a potential solution to improve the potency and consistency of NK cell therapies.
Study Findings
Researchers identified an immature CD16, CD161 double-negative NK subset that was associated with poor patient outcomes. The double negative–derived NK cells were hypofunctional and showed exaggerated trogocytosis, amassing high levels of cognate antigen to form an intra-product trogocytic-antigen sink, which diverted CAR engagement from the tumor targets and instead promoted on-target, off-tumor interactions within the product.
They then analyzed a CD16, CD161 double-positive NK subset and found that its effectors, when exposed to the trogocytic-antigen sink, underwent sustained activation, metabolic stress, fratricide, reduced viability, programmed cell death, and progressive exhaustion, leading to impaired persistence and tumor control.
In both hematologic and solid tumor models, pre-manufacturing double negative depletion eliminated the trogocytic-antigen sink and restored double positive antitumor activity. In preclinical models of lymphoma and ovarian cancer, specifically, the manufacturing strategy demonstrated enhanced tumor control and survival.
DISCLOSURES: This research was supported by philanthropic contributions to the Institute for Cell Therapy Discovery & Innovation at UT MD Anderson. For full disclosures of the study authors, visit sciencedirect.com.
