Simultaneous ADAM17 inhibition and CD16A stimulation augments memory-like NK cell activation and proliferation 3748

Abstract Description Cytokine-induced memory-like (CIML) NK cells are a cellular therapy currently in clinical trials for multiple cancers. CIML NK cells are generated by stimulating NK cells ex vivo with the cytokines IL-12, IL-15, and IL-18 (IL-12/15/18) for 16 to 18 hours, conveying enhanced anti-tumor function and persistence in vivo. However, IL-12/15/18 stimulation activates the membrane-bound metalloprotease ADAM17, inducing cleavage of multiple substrates, such as the IgG Fc receptor CD16A, which restrains NK cell function in a polyfunctional manner. We show that Medi-1, a fully human IgG1 mAb that blocks ADAM17, when bound to NK cells, is engaged by CD16A and prevents its shedding, inducing and prolonging its signaling, which enhances IL-12/15/18 stimulation. CIML NK cells treated with Medi-1 displayed increased expression of CD25 (IL-2Rα) and the co-activation receptor CD137 (4-1BB), and when reintroduced with PBMCs, as would occur upon administration to patients, underwent a significant increase in proliferation in the presence of low-dose IL-15 (1 ng/ml) or IL-2 (5 IU/ml). Reintroduced NK cells also experienced an enrichment of effector memory-like cells (CD57-/CD117-/NKG2A+/CD39+). Ongoing studies are examining the anti-tumor function of IL-12/15/18/Medi-1 generated CIML NK cells. Medi-1 treatment represents a novel strategy to enhance CIML NK cell expansion and anti-tumor activity that may be of therapeutic importance for treating various malignancies. Funding Sources This work was supported by NIH R01CA203348 Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)