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Immunotherapy in Multiple Myeloma

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Front. Immunol. | doi: 10.3389/fimmu.2018.02743

Enhancing the activation and releasing the brakes: a double hit strategy to improve NK cell cytotoxicity against multiple myeloma.

 Sara Tognarelli1, 2, 3, 4*,  Sebastian Wirsching4, 5, 6, Ivana Metzler1, 2, Bushra Rais4, 5, 6,  Benedikt Jacobs7, Hubert Serve2,  Peter Bader5 and  Evelyn Ullrich4, 5, 6*
  • 1Childrens Hospital, Experimental Immunology, Goethe-Universität Frankfurt am Main, Germany
  • 2Goethe-Universität Frankfurt am Main, Germany
  • 3Childrens Hospital, Department of Pediatric Stem Cell Transplantation and Immunology, Universitätsklinikum Frankfurt, Germany
  • 4Center for Cell and Gene Therapy Frankfurt, Faculty of Medicine, Goethe University Frankfurt am Main, Germany
  • 5Abteilung für Experimentelle Immunologie, Goethe-Universität Frankfurt am Main, Germany
  • 6Abteilung für Stammzelltransplantation und Immunologie, Universitätsklinikum Frankfurt, Germany
  • 7Department of Hematology and Oncology, Universitätsklinikum Erlangen, Germany

Natural killer (NK) cells are innate lymphocytes with a strong antitumor ability. In tumor patients, such as multiple myeloma (MM) patients, an elevated number of NK cells after stem cell transplantation (SCT) has been reported to be correlated with a higher overall survival rate. With the aim of improving NK cell use for adoptive cell therapy, we also addressed the cytotoxicity of patient-derived, cytokine-stimulated NK cells against MM cells at specific time points: at diagnosis and before and after autologous stem cell transplantation. Remarkably, after cytokine stimulation, the patients’ NK cells did not significantly differ from those of healthy donors. In a small cohort of MM patients, we were able to isolate autologous tumor cells, and we could demonstrate that an IL-2/15 stimulated autologous NK cells were able to significantly improve their killing capacity of autologous tumor cells. With the aim to further improve the NK cell killing capacity against MM cells, we investigated the potential use of NK specific check point inhibitors with focus on NKG2A because this inhibitory NK cell receptor was upregulated following ex vivo cytokine stimulation and MM cells showed HLA-E expression that could further be increased by exposure to IFN-γ. Importantly, blocking of NKG2A resulted in a significant increase in the NK cell-mediated lysis of different MM target cells. Finally, these results let suggest that combining cytokine induced NK cell activation and the specific check point inhibition of the NKG2A-mediated pathways can be an effective strategy to optimize NK cell therapeutic approaches for treatment of multiple myeloma.

Keywords: Multiple myeloma (MM), NK cells, Autologous stem cell transplantation (SCT), adoptive cell therapy, NKG2A blocking, checkpoint inhibition/blockade

Received: 16 Jul 2018; Accepted: 07 Nov 2018.

Edited by:

Nicola Giuliani, Università degli Studi di Parma, Italy

Reviewed by:

Kerry S. Campbell, Fox Chase Cancer Center, United States
Alessandro Gozzetti, Università degli Studi di Siena, Italy
Akiyoshi Takami, Aichi Medical University, Japan  

Copyright: © 2018 Tognarelli, Wirsching, Metzler, Rais, Jacobs, Serve, Bader and Ullrich. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Dr. Sara Tognarelli, Goethe-Universität Frankfurt am Main, Childrens Hospital, Experimental Immunology, Frankfurt, 60325, Hesse, Germany,
Prof. Evelyn Ullrich, Abteilung für Experimentelle Immunologie, Goethe-Universität Frankfurt am Main, Frankfurt, Germany,