Miguel Bronchud, Co-Founder and Director of Clinical Research at BO REAL BioTech, shared on LinkedIn:
“Natural killer (NK) cells remain in many ways mysterious – according to Ye Li et al (MD Anderson, Houston ) they offer a promising allogeneic platform to adoptive cellular therapies (besides CAR T cells) because they can be given without HLA matching, enabling truly off-the-shelf therapy without the risk of graft-versus-host disease.
But a practical barrier to standardization is donor-to-donor variability, where a suboptimal source unit can translate into inconsistent expansion, persistence, and tumor control.
An immune Oncology research Group at MD Anderson Cancer Center reported a phase 1/2 clinical trial of cord blood (CB)-derived CAR19/IL-15 NK cells in heavily pretreated patients with CD19-positive B cell lymphoid malignancies (NCT03056339), demonstrating clinical activity with limited toxicity.
Because each patient received a product manufactured from a distinct banked CB unit, this study provided a direct opportunity to distinguish optimal versus suboptimal cords and to define the underlying biology driving these donor effects.
The same research group have now shown that CAR NK cell performance was strongly shaped by the balance between two CB-NK cell subsets defined by CD16 and CD161 expression, and they identified an actionable strategy to improve suboptimal CB donors.
In other words, US 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.
After expansion and CAR engineering, cells derived from the immature CD16-CD161- double-negative (DN) subset were hyporesponsive as direct tumor killers but exhibited exaggerated trogocytosis (TROG), accumulating high levels of cognate tumor antigen on their surface, a process further amplified by CAR signaling.
In mixed CB-NK cell products this trogocytic antigen pool redirected CAR engagement into on-target off-tumor interactions within the product, limiting effective tumor-directed killing and imposing sustained activation pressure on the CD16+CD161+ double-positive (DP) effector compartment.
As a result, otherwise cytotoxic DP-derived CAR NK cells underwent prolonged antigen exposure and activation-induced cell death (AICD), fratricide, and progressive dysfunction, culminating in reduced persistence and loss of tumor control.
By contrast, products enriched for DP cells showed superior cytotoxicity and persistence in multiple in vitro and in vivo tumor models.
Finally, they demonstrated that depleting DN cells before engineering was sufficient to prevent these interactions and to convert suboptimal donors.”
Title: Depletion of an immature cord blood NK subset reverses trogocytosis-driven CAR NK dysfunction
Authors: Ye Li, Huihui Fan, Guohui Wang, Xin Wang, Rafet Basar, Maliha Nuzhat Munir, Nadima Uprety, Rejeena Shrestha, Ludovica La Posta, Bin Liu, Jeffrey Wilson, Prashant Menon, Natalie Wall Fowlkes, Patrick Zhang, Enli Liu, Gary M. Deyter, Luis Muniz-Feliciano, Pinaki P. Banerjee, May Daher, David Marin, Eleonora Dondossola, Navin Varadarajan, Elizabeth J. Shpall, Katayoun Rezvani
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