TY - JOUR
T1 - Combining AFM13, a bispecific CD30/CD16 antibody, with cytokine-activated blood and cord blood–derived NK cells facilitates CAR-like responses against CD30+ malignancies
AU - Kerbauy, Lucila N.
AU - Marin, Nancy D.
AU - Kaplan, Mecit
AU - Banerjee, Pinaki P.
AU - Berrien-Elliott, Melissa M.
AU - Becker-Hapak, Michelle
AU - Basar, Rafet
AU - Foster, Mark
AU - Melo, Luciana Garcia
AU - Neal, Carly C.
AU - McClain, Ethan
AU - Daher, May
AU - Nunez Cortes, Ana Karen
AU - Desai, Sweta
AU - Lim, Francesca Wei Inng
AU - Mendt, Mayela Carolina
AU - Schappe, Timothy
AU - Li, Li
AU - Shaim, Hila
AU - Shanley, Mayra
AU - Ensley, Emily L.
AU - Uprety, Nadima
AU - Wong, Pamela
AU - Liu, Enli
AU - Ang, Sonny O.
AU - Cai, Rong
AU - Nandivada, Vandana
AU - Mohanty, Vakul
AU - Miao, Qi
AU - Shen, Yifei
AU - Baran, Natalia
AU - Fowlkes, Natalie W.
AU - Chen, Ken
AU - Muniz-Feliciano, Luis
AU - Champlin, Richard E.
AU - Nieto, Yago L.
AU - Koch, Joachim
AU - Treder, Martin
AU - Fischer, Wolfgang
AU - Okamoto, Oswaldo Keith
AU - Shpall, Elizabeth J.
AU - Fehniger, Todd A.
AU - Rezvani, Katayoun
N1 - Funding Information:
This work is supported by grants from the NIH (1 R01 CA211044-01, 5 P01CA148600-03, and P50CA100632-16). The MD Anderson Cancer Center Flow Cytometry and Cellular Imaging Facility and the RNA sequencing core facility is supported in part by a grant from the NIH, NCI (CA016672). The Siteman Flow Cytometry Core and the Immune Monitoring Laboratory of the Siteman Cancer Center in Washington University, School of Medicine, St. Louis, MO are supported by the NCI CCC support (P30CA091842). Additional support for the study includes NIH: K12CA167540 (M.M. Berrien-Elliott), SPORE in Leukemia P50CA171963 (T.A. Fehniger, M.M. Berrien-Elliott), and R01CA205239 (T.A. Fehniger). This study was partially supported by Affimed.
Funding Information:
support from Takeda and Affimed during the conduct of the study. S.O. Ang reports other support from Takeda and Affimed during the conduct of the study. R.E. Champlinreports grants fromAffimedduring the conduct ofthe study. Y.L. Nieto reports grants from AstraZeneca, BioSecura, and Affimed outside the submitted work. J. Koch is an employee of Affimed. W. Fischer is an employee of Affimed. O.K. Okamoto reports grants from FAPESP 2013/08028-1 and CNPq 307611/ 2018-3 during the conduct of the study; O.K. Okamoto is a visiting scholar at HIAE. E.J. Shpall reports personal fees and other support from Bayer HealthCare Pharmaceuticals, Novartis, and Magenta, as well as other support from Adaptimmune, Mesoblast, and Axio outside the submitted work; in addition, E.J. Shpall has a patent for Takeda licensed and a patent for Affimed licensed. T.A. Fehniger reports grants from Affimed during the conduct of the study. T.A. Fehniger also reports personal fees from Nektar; grants, personal fees, and other support from Wugen; other support from Indpata and Orca Bio; personal fees and other support from Kiadis; grants from Affimed; and grants and other support from Compass Therapeutics outside the submitted work. In addition, T.A. Fehniger has a patent for 15/983,275 pending and licensed to Wugen, a patent for PCT/US2019/060005 pending and licensed to Wugen, and a patent for 62/963,971 pending and licensed to Wugen. K. Rezvani reports other support from Affimed during the conduct of the study, as well as other support from Takeda Pharmaceutical Company outside the submitted work; K. Rezvani participates on the scientific advisory board for GemoAb, AvengeBio, Virogin, GSK, and Bayer. No disclosures were reported by the other authors.
Funding Information:
We thank the RNA sequencing core facility, which is supported by the Cancer Center Support (CORE), and the Research Animal Support Facility at MD Anderson Cancer Center. Figures created with biorender.com.
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/7/1
Y1 - 2021/7/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85108870600&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-21-0164
DO - 10.1158/1078-0432.CCR-21-0164
M3 - Article
C2 - 33986022
AN - SCOPUS:85108870600
SN - 1078-0432
VL - 27
SP - 3744
EP - 3756
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 13
ER -