ErbB2 (HER2)-CAR-NK-92 cells for enhanced immunotherapy of metastatic fusion-driven alveolar rhabdomyosarcoma

Catrin Heim; Laura M Moser; Herman Kreyenberg; Halvard B Bonig; Torsten Tonn; Winfried S Wels; Elise Gradhand; Evelyn Ullrich; Michael T Meister; Marian Groot Koerkamp; Frank C P Holstege; Jarno Drost; Jan-Henning Klusmann; Peter Bader; Michael Merker; Eva Rettinger

doi:10.3389/fimmu.2023.1228894

ErbB2 (HER2)-CAR-NK-92 cells for enhanced immunotherapy of metastatic fusion-driven alveolar rhabdomyosarcoma

Front Immunol. 2023 Aug 18:14:1228894. doi: 10.3389/fimmu.2023.1228894. eCollection 2023.

Authors

Catrin Heim¹, Laura M Moser^{1

2

3

4}, Herman Kreyenberg¹, Halvard B Bonig^{5

6}, Torsten Tonn^{7

8}, Winfried S Wels^{2

3

9}, Elise Gradhand^{4

10}, Evelyn Ullrich^{2

3

4

11}, Michael T Meister^{12

13}, Marian Groot Koerkamp^{12

13}, Frank C P Holstege^{12

14}, Jarno Drost^{12

13}, Jan-Henning Klusmann^{2

3

4

15}, Peter Bader^{1

4}, Michael Merker^{1

4}, Eva Rettinger^{1

2

3

4}

Affiliations

¹ Goethe University Frankfurt, Department of Pediatrics, Division for Stem Cell Transplantation, Immunology and Intensive Care Medicine, Frankfurt am Main, Germany.
² German Cancer Consortium (DKTK), Partner Site Frankfurt am Main, a Partnership Between DKFZ, University Hospital and Georg-Speyer-Haus, Frankfurt am Main, Germany.
³ Frankfurt Cancer Institute (FCI), Goethe University, Frankfurt am Main, Germany.
⁴ Universitäres Centrum für Tumorerkrankungen (UCT), Frankfurt am Main, Germany.
⁵ Department of Cellular Therapeutics/Cell Processing, Institute for Transfusion Medicine and Immunotherapy, Goethe University, Frankfurt am Main, Germany.
⁶ Division of Hematology, Department of Medicine, University of Washington, Seattle, WA, United States.
⁷ Experimental Transfusion Medicine, Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany.
⁸ German Cancer Consortium (DKTK), Partner Site Dresden, Dresden, Germany.
⁹ Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany.
¹⁰ Dr. Senckenberg Institute of Pathology, University Hospital Frankfurt, Frankfurt, Germany.
¹¹ Experimental Immunology, Department for Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt, Germany.
¹² Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands.
¹³ Oncode Institute, Utrecht, Netherlands.
¹⁴ Center for Molecular Medicine, UMC Utrecht and Utrecht University, Utrecht, Netherlands.
¹⁵ Goethe University Frankfurt, Department of Pediatrics, Frankfurt am Main, Germany.

Abstract

Introduction: Metastatic rhabdomyosarcoma (RMS) is a challenging tumor entity that evades conventional treatments and endogenous antitumor immune responses, highlighting the need for novel therapeutic strategies. Applying chimeric antigen receptor (CAR) technology to natural killer (NK) cells may offer safe, effective, and affordable therapies that enhance cancer immune surveillance.

Methods: Here, we assess the efficacy of clinically usable CAR-engineered NK cell line NK-92/5.28.z against ErbB2-positive RMS in vitro and in a metastatic xenograft mouse model.

Results: Our results show that NK-92/5.28.z cells effectively kill RMS cells in vitro and significantly prolong survival and inhibit tumor progression in mice. The persistence of NK-92/5.28.z cells at tumor sites demonstrates efficient antitumor response, which could help overcome current obstacles in the treatment of solid tumors.

Discussion: These findings encourage further development of NK-92/5.28.z cells as off-the-shelf immunotherapy for the treatment of metastatic RMS.

Keywords: ERBB2 (HER2/neu); cancer immunotherapy; chimeric antigen receptor; rhabdomyosarcoma; xenograft.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Disease Models, Animal
Humans
Immunotherapy
Killer Cells, Natural
Mice
Neoplasms, Second Primary*
Receptors, Chimeric Antigen* / genetics
Rhabdomyosarcoma* / therapy
Rhabdomyosarcoma, Alveolar* / therapy

Substances

Receptors, Chimeric Antigen

Grants and funding

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 LMM), by grants from the Mildred-Scheel-Nachwuchszentrum (MNSZ), Frankfurt am Main, Germany (to ER, 70113301), by grants of the Schwiete Stiftung (Projekt Nr. 2021-012) and by grants from the Parents Association “Hilfe für krebskranke-Kinder e.V.”, Frankfurt am Main, Germany. J-HK receives funding from the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme (grant agreement No. 714226). Establishment of tumor organoid RMS cells was funded by Deutsche Forschungsgemeinschaft (DFG). Grant Number: 408083583; EC ¦ H2020 ¦ H2020 Priority Excellent Science ¦ H2020 European Research Council (ERC). Grant Number: 850571; KWF Kankerbestrijding (DCS). Grant Number: 10218; Stichting Kinderen Kankervrij (KiKa). Grant Number: 292.