Author:
Shrestha Niraj,Dee Michael J.,Chaturvedi Pallavi,Leclerc Gilles M.,Mathyer Mary,Dufour Celeste,Arthur Laura,Becker-Hapak Michelle,Foster Mark,McClain Ethan,Pena Natalia Valderrama,Kage Karen,Zhu Xiaoyun,George Varghese,Liu Bai,Egan Jack,Echeverri Christian,Wang Meng,You Lijing,Kong Lin,Li Liying,Berrien-Elliott Melissa M.,Cooper Matthew L.,Fehniger Todd A.,Rhode Peter R.,Wong Hing C.
Abstract
AbstractAdoptive cellular therapy (ACT) using memory-like (ML) natural killer (NK) cells, generated through overnight ex vivo activation with IL-12, IL-15, and IL-18, has shown promise for treating hematologic malignancies. We recently reported that a multifunctional fusion molecule, HCW9201, comprising IL-12, IL-15, and IL-18 domains could replace individual cytokines for priming human ML NK cell programming (“Prime” step). However, this approach does not include ex vivo expansion, thereby limiting the ability to test different doses and schedules. Here, we report the design and generation of a multifunctional fusion molecule, HCW9206, consisting of human IL-7, IL-15, and IL-21 cytokines. We observed > 300-fold expansion for HCW9201-primed human NK cells cultured for 14 days with HCW9206 and HCW9101, an IgG1 antibody, recognizing the scaffold domain of HCW9206 (“Expand” step). This expansion was dependent on both HCW9206 cytokines and interactions of the IgG1 mAb with CD16 receptors on NK cells. The resulting “Prime and Expand” ML NK cells exhibited elevated metabolic capacity, stable epigenetic IFNG promoter demethylation, enhanced antitumor activity in vitro and in vivo, and superior persistence in NSG mice. Thus, the “Prime and Expand” strategy represents a simple feeder cell-free approach to streamline manufacturing of clinical-grade ML NK cells to support multidose and off-the-shelf ACT.
Funder
HCW Biologics
Wugen
NIH
Paula C and Rodger O. Riney Blood Cancer Initiative
Publisher
Springer Science and Business Media LLC