Combining AFM13, a Bispecific CD30/CD16 Antibody, with Cytokine-Activated Blood and Cord Blood-Derived NK Cells Facilitates CAR-like Responses Against CD30+ Malignancies.
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Kerbauy Lucila N, Marin Nancy D, Kaplan Mecit, Banerjee Pinaki P, Berrien-Elliott Melissa M, Becker-Hapak Michelle, Basar Rafet, Foster Mark, Garcia Melo Luciana, Neal Carly C, McClain Ethan, Daher May, Nunez Cortes Ana Karen, Desai Sweta, Inng Lim Francesca Wei, Mendt Mayela Carolina, Schappe Timothy, Li Li, Shaim Hila, Shanley Mayra, Ensley Emily L, Uprety Nadima, Wong Pamela, Liu Enli, Ang Sonny O, Cai Rong, Nandivada Vandana, Mohanty Vakul, Miao Qi, Shen Yifei, Baran Natalia, Fowlkes Natalie W, Chen Ken, Muniz-Feliciano Luis, Champlin Richard E, Nieto Yago L, Koch Joachim, Treder Martin, Fischer Wolfgang, Okamoto Oswaldo Keith, Shpall Elizabeth J, Fehniger Todd A, Rezvani Katayoun
Аннотация
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.