| Autor: |
Katayoun Rezvani, Todd A. Fehniger, Elizabeth J. Shpall, Oswaldo Keith Okamoto, Wolfgang Fischer, Martin Treder, Joachim Koch, Yago L. Nieto, Richard E. Champlin, Luis Muniz-Feliciano, Ken Chen, Natalie W. Fowlkes, Natalia Baran, Yifei Shen, Qi Miao, Vakul Mohanty, Vandana Nandivada, Rong Cai, Sonny O. Ang, Enli Liu, Pamela Wong, Nadima Uprety, Emily L. Ensley, Mayra Shanley, Hila Shaim, Li Li, Timothy Schappe, Mayela Carolina Mendt, Francesca Wei Inng Lim, Sweta Desai, Ana Karen Nunez Cortes, May Daher, Ethan McClain, Carly C. Neal, Luciana Garcia Melo, Mark Foster, Rafet Basar, Michelle Becker-Hapak, Melissa M. Berrien-Elliott, Pinaki P. Banerjee, Mecit Kaplan, Nancy D. Marin, Lucila N. Kerbauy |
| Rok vydání: |
2023 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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