Lucila N Kerbauy 1,2,3 , Nancy D Marin 4 , Mecit Kaplan 1 , Pinaki P Banerjee 1 , Melissa M Berrien-Elliott 4 , Michelle Becker-Hapak 4 , Rafet Basar 1 , Mark Foster 4 , Luciana Garcia Melo 1 , Carly C Neal 4 , Ethan McClain 4 , May Daher 1 , Ana Karen Nunez Cortes 1 , Sweta Desai 4 , Francesca Wei Inng Lim 1 , Mayela Carolina Mendt 1 , Timothy Schappe 4 , Li Li 1 , Hila Shaim 1 , Mayra Shanley 1 , Emily L Ensley 1 , Nadima Uprety 1 , Pamela Wong 4 , Enli Liu 1 , Sonny O Ang 1 , Rong Cai 1 , Vandana Nandivada 1 , Vakul Mohanty 5 , Qi Miao 5 , Yifei Shen 5 , Natalia Baran 6 , Natalie W Fowlkes 7 , Ken Chen 5 , Luis Muniz-Feliciano 1 , Richard E Champlin 1 , Yago L Nieto 1 , Joachim Koch 8 , Martin Treder 9 , Wolfgang Fischer 8 , Oswaldo Keith Okamoto 2,3 , Elizabeth J Shpall 1 , Todd A Fehniger 10 , Katayoun Rezvani 11 Show Affiliations »
Abstract
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. ©2021 American Association for Cancer Research.
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. ©2021 American Association for Cancer Research.
Entities: Chemical
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Year: 2021
PMID： 33986022 PMCID： PMC8254785 DOI： 10.1158/1078-0432.CCR-21-0164
Source DB: PubMed Journal: Clin Cancer Res ISSN： 1078-0432 Impact factor: 13.801