TY - JOUR A1 - Gossel, Leonie D. H. A1 - Heim, Catrin Birgit A1 - Pfeffermann, Lisa-Marie A1 - Moser, Laura M. A1 - Bönig, Halvard-Björn A1 - Klingebiel, Thomas A1 - Bader, Peter A1 - Wels, Winfried A1 - Merker, Michael A1 - Rettinger, Eva T1 - Retargeting of NK-92 cells against high-risk rhabdomyosarcomas by means of an ERBB2 (HER2/Neu)-specific chimeric antigen receptor T2 - Cancers N2 - The dismal prognosis of pediatric and young adult patients with high-risk rhabdomyosarcoma (RMS) underscores the need for novel treatment options for this patient group. In previous studies, the tumor-associated surface antigen ERBB2 (HER2/neu) was identified as targetable in high-risk RMS. As a proof of concept, in this study, a novel treatment approach against RMS tumors using a genetically modified natural killer (NK)-92 cell line (NK-92/5.28.z) as an off-the-shelf ERBB2-chimeric antigen receptor (CAR)-engineered cell product was preclinically explored. In cytotoxicity assays, NK-92/5.28.z cells specifically recognized and efficiently eliminated RMS cell suspensions, tumor cell monolayers, and 3D tumor spheroids via the ERBB2-CAR even at effector-to-target ratios as low as 1:1. In contrast to unmodified parental NK-92 cells, which failed to lyse RMS cells, NK-92/5.28.z cells proliferated and became further activated through contact with ERBB2-positive tumor cells. Furthermore, high amounts of effector molecules, such as proinflammatory and antitumoral cytokines, were found in cocultures of NK-92/5.28.z cells with tumor cells. Taken together, our data suggest the enormous potential of this approach for improving the immunotherapy of treatment-resistant tumors, revealing the dual role of NK-92/5.28.z cells as CAR-targeted killers and modulators of endogenous adaptive immunity even in the inhibitory tumor microenvironment of high-risk RMS. KW - RMS KW - ERBB2 KW - HER2/neu KW - NK-92 KW - CAR KW - cancer immunotherapy Y1 - 2021 UR - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/62465 UR - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-624650 SN - 2072-6694 N1 - This research was funded by the LOEWE-FCI, Frankfurt Cancer Institute, Frankfurt am Main, Germany, funded by the Hessian Ministry of Higher Education, Research and the Arts(2019). This work was also supported by grants from the Else Kröner-Fresenius-Stiftung (to L.M.M.),grants from the Mildred-Scheel-Nachwuchszentrum (MNSZ), Frankfurt am Main, Germany (to E.R.,70113301), grants from the Parents Association “Hilfe für krebskranke-Kinder e.V.”, Frankfurt amMain, Germany, and unrestricted grants from Baker & McKenzie Partnerschaft von Rechtsanwältenund Steuerberatern mbB, Frankfurt am Main, Germany. VL - 13 IS - 6, art. 1443 SP - 1 EP - 18 PB - MDPI CY - Basel ER -