Retargeting of NK-92 cells against high-risk rhabdomyosarcomas by means of an ERBB2 (HER2/Neu)-specific chimeric antigen receptor

  • 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.

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Author:Leonie D. H. Gossel, Catrin Heim, Lisa-Marie PfeffermannGND, Laura M. Moser, Halvard-Björn BönigORCiDGND, Thomas KlingebielORCiDGND, Peter BaderORCiDGND, Winfried WelsORCiDGND, Michael MerkerORCiD, Eva RettingerORCiDGND
Parent Title (English):Cancers
Place of publication:Basel
Document Type:Article
Date of Publication (online):2021/03/22
Date of first Publication:2021/03/22
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2021/09/06
Tag:CAR; ERBB2; HER2/neu; NK-92; RMS; cancer immunotherapy
Issue:6, art. 1443
Page Number:18
First Page:1
Last Page:18
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.
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0