Q1 · MEDICINE
Article
Author: Shaim, Hila ; Cai, Rong ; Inng Lim, Francesca Wei ; McClain, Ethan ; Neal, Carly C. ; Fischer, Wolfgang ; Koch, Joachim ; Uprety, Nadima ; Banerjee, Pinaki P. ; Kerbauy, Lucila N. ; Rezvani, Katayoun ; Miao, Qi ; Daher, May ; Nandivada, Vandana ; Li, Li ; Ang, Sonny O. ; Wong, Pamela ; Okamoto, Oswaldo Keith ; Foster, Mark ; Kaplan, Mecit ; Chen, Ken ; Mohanty, Vakul ; Schappe, Timothy ; Ensley, Emily L. ; Nunez Cortes, Ana Karen ; Fehniger, Todd A. ; Muniz-Feliciano, Luis ; Garcia Melo, Luciana ; Baran, Natalia ; Desai, Sweta ; Liu, Enli ; Treder, Martin ; Fowlkes, Natalie W. ; Shanley, Mayra ; Shen, Yifei ; Basar, Rafet ; Marin, Nancy D. ; Champlin, Richard E. ; Nieto, Yago L. ; Berrien-Elliott, Melissa M. ; Shpall, Elizabeth J. ; Mendt, Mayela Carolina ; Becker-Hapak, Michelle
Purpose::Natural killer (NK)-cell recognition and function against NK-resistant cancers remain substantial barriers to the broad application of NK-cell immunotherapy. Potential solutions include bispecific engagers that target NK-cell activity via an NK-activating receptor when simultaneously targeting a tumor-specific antigen, as well as enhancing functionality using IL12/15/18 cytokine pre-activation.
Experimental Design::We assessed single-cell NK-cell responses stimulated by the tetravalent bispecific antibody AFM13 that binds CD30 on leukemia/lymphoma targets and CD16A on various types of NK cells using mass cytometry and cytotoxicity assays. The combination of AFM13 and IL12/15/18 pre-activation of blood and cord blood–derived NK cells was investigated in vitro and in vivo.
Results::We found heterogeneity within AFM13-directed conventional blood NK cell (cNK) responses, as well as consistent AFM13-directed polyfunctional activation of mature NK cells across donors. NK-cell source also impacted the AFM13 response, with cNK cells from healthy donors exhibiting superior responses to those from patients with Hodgkin lymphoma. IL12/15/18-induced memory-like NK cells from peripheral blood exhibited enhanced killing of CD30+ lymphoma targets directed by AFM13, compared with cNK cells. Cord-blood NK cells preactivated with IL12/15/18 and ex vivo expanded with K562-based feeders also exhibited enhanced killing with AFM13 stimulation via upregulation of signaling pathways related to NK-cell effector function. AFM13–NK complex cells exhibited enhanced responses to CD30+ lymphomas in vitro and in vivo.
Conclusions::We identify AFM13 as a promising combination with cytokine-activated adult blood or cord-blood NK cells to treat CD30+ hematologic malignancies, warranting clinical trials with these novel combinations.