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Updated: Jun 3, 2025
Natural Killer NK and CAR-NK Cell Expansion Method using Membrane Bound-IL-21-Modified B Cell Line
Published on: February 8, 2022
Soluble factors released by peripheral blood-derived CAR-NK cells cause bystander myeloid cell activation
Supreet Khanal1, Alan Baer1, Md Kamal Hossain1
1Tumor Vaccine and Biotechnology Branch, Office of Cellular Therapy and Human Tissues, Office of Therapeutic Products, Center for Biologics Evaluation and Research, United States Food and Drug Administration (U.S. FDA), Silver Spring, MD, United States.
Introduction:
CAR-T cell therapy is associated with life-threatening inflammatory toxicities, partly due to the activation and secretion of inflammatory cytokines by bystander myeloid cells (BMCs). However, due to limited clinical data, it is unclear whether CAR-NK cells cause similar toxicities.
Methods:
We characterized the soluble factors (SFs) released by activated human CAR-T and CAR-NK cells and assessed their role in BMC activation (BMCA).
Results:
We found that SFs from both activated, peripheral blood-derived CAR-T (PB-CAR-T) and CAR-NK (PB-CAR-NK) cells induced BMCA; however, PB-CAR-NK cells caused significantly lower BMCA compared to PB-CAR-T cells. Interestingly, SFs from cord-blood-derived (CB) NK cells caused little to no BMCA, consistent with previous clinical studies showing minimal inflammatory toxicity with CB-CAR-NK cells. Comparative analysis of SFs released by PB-NK and PB-CAR-NK cells following CAR-dependent and CAR-independent activation revealed several candidate factors with the potential to cause BMCA. Antibody-mediated neutralization studies identified a combination of four factors that contribute to PB-CAR-NK cell-mediated BMCA. siRNA-mediated knockdown studies confirmed that inactivating these four factors in PB-CAR-NK cells significantly reduces BMCA. Importantly, neutralization or knockdown of these four factors did not affect CAR-NK cell potency.
Discussion:
These data suggest that specific SFs released by PB-CAR-NK cells activate BMCs and have the potential to contribute to inflammatory toxicities. Furthermore, inactivation of these four factors in PB-CAR-NK cells could reduce inflammatory toxicities and improve safety of PB-CAR-NK cell therapy without compromising potency.
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