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Polyvalent immunoglobulins, platelet lysate and lenalidomide: cocktail for polyfunctional NK cells expansion for multiple myeloma

Bone Marrow Transplantation volume 52, pages 480–483 (2017)Cite this article

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Despite the rapid development of new agents, myeloma (MM) continues to be an incurable disease. Growing bodies of literature suggest a key role of natural killer (NK) cells, a unique subset of CD3−CD56+ innate lymphoid cells in the control of newly diagnosed MM.1 MM cells promote a state of progressive immune dysregulation and suppression of NK cell functions, which support a growing interest for NK cell-based immunotherapy.2 A major challenge to the broader application of adoptive NK cell therapy is to improve methods for in vitro expansion of low-frequency NK cells. Large-scale expansions have been obtained with various feeder cell-based systems but whereas these methods have merit, they also have major drawbacks including complicated procedures, safety issues for human administration and/or the expansion of exhausted NK cells.3 Developing innovative strategies to generate clinically efficient NK cells with minimal in vitro manipulation, in large numbers, would provide an important breakthrough in NK cell-based immunotherapy. In the present studies, we report a strategy designed specifically for MM through expansion with polyvalent immunoglobulins (polyIgs) and platelet lysate (PL) in the presence of lenalidomide.

NK cells were isolated from the non-mobilized apheresis product of 15 healthy donors who had given informed consent. The apheresis product started with 8.1±4.4% NK cells. After depletion of CD3+ T cells and enrichment of CD56+ NK cells using the MACS selection system with CD3 and CD56 microbeads (Miltenyi Biotec GmbH, Bergisch Gladbach, Germany), the mean frequency of CD3−CD56+ NK cells was 94.6±1.9%, yielding an NK cell recovery of 35% with a mean T-cell depletion of 2.99 log.

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References

  1. Ponzetta A, Benigni G, Antonangeli F, Sciumè G, Sanseviero E, Zingoni A et al. Multiple myeloma impairs bone marrow localization of effector natural killer cells by altering the chemokine microenvironment. Cancer Res 2015; 75: 4766–4777.

    Article  CAS  Google Scholar 

  2. Dosani T, Carlsten M, Maric I, Landgren O . The cellular immune system in myelomagenesis: NK cells and T cells in the development of MM and their uses in immunotherapies. Blood Cancer J 2015; 5: e321.

    Article  CAS  Google Scholar 

  3. Knorr DA, Bachanova V, Verneris MR, Miller JS . Clinical utility of natural killer cells in cancer therapy and transplantation. Semin Immunol 2014; 26: 161–172.

    Article  CAS  Google Scholar 

  4. Rodella L, Zamai L, Rezzani R, Artico M, Peri G, Falconi M et al. Interleukin 2 and interleukin 15 differentially predispose natural killer cells to apoptosis mediated by endothelial and tumour cells. Br J Haematol 2001; 115: 442–450.

    Article  CAS  Google Scholar 

  5. Lim O, Lee Y, Chung H, Her JH, Kang SM, Jung MY et al. GMP-compliant, large-scale expanded allogeneic natural killer cells have potent cytolytic activity against cancer cells in vitro and in vivo. PLoS One 2013; 8: e53611.

    Article  CAS  Google Scholar 

  6. Pierson BA, McGlave PB, Hu WS, Miller JS . Natural killer cell proliferation is dependent on human serum and markedly increased utilizing an enriched supplemented basal medium. J Hematother 1995; 4: 149–158.

    Article  CAS  Google Scholar 

  7. Berahovich RD, Lai NL, Wei Z, Lanier LL, Schall TJ . Evidence for NK cell subsets based on chemokine receptor expression. J Immunol 2006; 177: 7833–7840.

    Article  CAS  Google Scholar 

  8. Bjorkstrom NK, Riese P, Heuts F, Andersson S, Fauriat C, Ivarsson MA et al. Expression patterns of NKG2A, KIR, and CD57 define a process of CD56dim NK-cell differentiation uncoupled from NK-cell education. Blood 2010; 116: 3853–3864.

    Article  Google Scholar 

  9. Frenzel K, Lehmann J, Kruger DH, Martin-Parras L, Uharek L, Hofmann J et al. Combination of immunoglobulins and natural killer cells in the context of CMV and EBV infection. Med Microbiol Immunol 2014; 203: 115–123.

    Article  CAS  Google Scholar 

  10. Le Garff-Tavernier M, Decocq J, de Romeuf C, Parizot C, Dutertre CA, Chapiro E et al. Analysis of CD16+CD56dim NK cells from CLL patients: evidence supporting a therapeutic strategy with optimized anti-CD20 monoclonal antibodies. Leukemia 2011; 25: 101–109.

    Article  CAS  Google Scholar 

  11. Placke T, Kopp HG, Salih HR . Modulation of natural killer cell anti-tumor reactivity by platelets. J. Innate Immun 2011; 3: 374–382.

    Article  CAS  Google Scholar 

  12. Frohn C, Hoppner M, Schlenke P, Kirchner H, Koritke P, Luhm J . Anti-myeloma activity of natural killer lymphocytes. Br J Haematol 2002; 119: 660–664.

    Article  CAS  Google Scholar 

  13. Katodritou E, Terpos E, North J, Kottaridis P, Verrou E, Gastari V et al. Tumor-primed natural killer cells from patients with multiple myeloma lyse autologous, NK-resistant, bone marrow-derived malignant plasma cells. Am J Hematol 2011; 86: 967–973.

    Article  CAS  Google Scholar 

  14. Hayashi T, Hideshima T, Akiyama M, Podar K, Yasui H, Raje N et al. Molecular mechanisms whereby immunomodulatory drugs activate natural killer cells: clinical application. Br J Haematol 2005; 128: 192–203.

    Article  CAS  Google Scholar 

  15. Quach H, Ritchie D, Stewart AK, Neeson P, Harrison S, Smyth MJ et al. Mechanism of action of immunomodulatory drugs (IMiDS) in multiple myeloma. Leukemia 2010; 24: 22–32.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by grants from AP-HP, Direction de la Recherche Clinique. We thank Fanny Fava for myeloma cell selection; Mickael Bernard and Victoria Joannou for NK cell selection and culture; Virginie Leclercq for technical assistance in cell selection and culture, Holly Anderson and Pr Jerome Ritz for reading and improving the manuscript.

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Authors and Affiliations

  1. Department of Biotherapy, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France

    H Trébéden-Negre, M Rosenzwajg, M Cherai & F Norol

  2. Centre d'Immunologie et des Maladies Infectieuses (CIMI), UPMC CR7, INSERM U1135, CNRS ERL 8255, Groupe Hospitalier Pitié-Salpêtrière, Paris, France

    V Vieillard

  3. Department of Hematology, AP-HP, Hôpitaux Universitaires Saint Antoine, Paris, France

    L Garderet

  4. Department of Hematology, AP-HP, Hôpitaux Universitaires Pitié-Salpêtrière, Paris, France

    S Nguyen-Quoc

  5. Department of Statistics, AP-HP, Hôpitaux Universitaires Pitié-Salpêtrière, Paris, France

    M L Tanguy

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  1. H Trébéden-Negre
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Correspondence to H Trébéden-Negre.

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Trébéden-Negre, H., Vieillard, V., Rosenzwajg, M. et al. Polyvalent immunoglobulins, platelet lysate and lenalidomide: cocktail for polyfunctional NK cells expansion for multiple myeloma. Bone Marrow Transplant 52, 480–483 (2017). https://doi.org/10.1038/bmt.2016.311

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