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  • Review Article
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Adoptive cell therapy using engineered natural killer cells

Abstract

The generation of autologous T cells expressing a chimeric antigen receptor (CAR) have revolutionized the field of adoptive cellular therapy. CAR-T cells directed against CD19 have resulted in remarkable clinical responses in patients affected by B-lymphoid malignancies. However, the production of allogeneic CAR-T cells products remains expensive and clinically challenging. Moreover, the toxicity profile of CAR T-cells means that currently these life-saving treatments are only delivered in specialized centers. Therefore, efforts are underway to develop reliable off-the-shelf cellular products with acceptable safety profiles for the treatment of patients with cancer. Natural killer (NK) cells are innate effector lymphocytes with potent antitumor activity. The availability of NK cells from multiple sources and their proven safety profile in the allogeneic setting positions them as attractive contenders for cancer immunotherapy. In this review, we discuss advantages and potential drawbacks of using NK cells as a novel cellular therapy against hematologic malignancies, as well as strategies to further enhance their effector function.

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References

  1. June CH, Blazar BR, Riley JL. Engineering lymphocyte subsets: tools, trials and tribulations. Nat Rev Immunol. 2009;9:704–16.

    Article  CAS  Google Scholar 

  2. Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME. Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer. 2008;8:299–308.

    Article  CAS  Google Scholar 

  3. Sadelain M, Riviere I, Brentjens R. Targeting tumours with genetically enhanced T lymphocytes. Nat Rev Cancer. 2003;3:35–45.

    Article  CAS  Google Scholar 

  4. Brentjens RJ, Davila ML, Riviere I, Park J, Wang X, Cowell LG, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med. 2013;5:177ra38.

    Article  Google Scholar 

  5. Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013;368:1509–18.

    Article  CAS  Google Scholar 

  6. Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365:725–33.

    Article  CAS  Google Scholar 

  7. Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377:2531–44.

    Article  CAS  Google Scholar 

  8. Panel OKs CAR T therapy for leukemia. Cancer Discov. 2017;7:924.

  9. Goulmy E. Human minor histocompatibility antigens: new concepts for marrow transplantation and adoptive immunotherapy. Immunol Rev. 1997;157:125–40.

    Article  CAS  Google Scholar 

  10. Lanier LL. Up on the tightrope: natural killer cell activation and inhibition. Nat Immunol. 2008;9:495–502.

    Article  CAS  Google Scholar 

  11. Yawata M, Yawata N, Draghi M, Partheniou F, Little AM, Parham P. MHC class I-specific inhibitory receptors and their ligands structure diverse human NK-cell repertoires toward a balance of missing self-response. Blood. 2008;112:2369–80.

    Article  CAS  Google Scholar 

  12. Caligiuri MA. Human natural killer cells. Blood. 2008;112:461–9.

    Article  CAS  Google Scholar 

  13. Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science. 2002;295:2097–2100.

    Article  CAS  Google Scholar 

  14. Ljunggren HG, Karre K. In search of the ‘missing self’: MHC molecules and NK cell recognition. Immunol Today. 1990;11:237–44.

    Article  CAS  Google Scholar 

  15. Olson JA, Leveson-Gower DB, Gill S, Baker J, Beilhack A, Negrin RS. NK cells mediate reduction of GVHD by inhibiting activated, alloreactive T cells while retaining GVT effects. Blood. 2010;115:4293–301.

    Article  CAS  Google Scholar 

  16. Miller JS, Soignier Y, Panoskaltsis-Mortari A, McNearney SA, Yun GH, Fautsch SK, et al. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood. 2005;105:3051–7.

    Article  CAS  Google Scholar 

  17. Curti A, Ruggeri L, D’Addio A, Bontadini A, Dan E, Motta MR, et al. Successful transfer of alloreactive haploidentical KIR ligand-mismatched natural killer cells after infusion in elderly high risk acute myeloid leukemia patients. Blood. 2011;118:3273–9.

    Article  CAS  Google Scholar 

  18. Shah N, Li L, McCarty J, Kaur I, Yvon E, Shaim H et al. Phase I study of cord blood-derived natural killer cells combined with autologous stem cell transplantation in multiple myeloma. Br. J. Haematol. 2017;177:457–466.

  19. Sotillo E, Barrett DM, Black KL, Bagashev A, Oldridge D, Wu G, et al. Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Discov. 2015;5:1282–95.

    Article  CAS  Google Scholar 

  20. Cooley S, Weisdorf DJ, Guethlein LA, Klein JP, Wang T, Le CT, et al. Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia. Blood. 2010;116:2411–9.

    Article  CAS  Google Scholar 

  21. Cooley S, Trachtenberg E, Bergemann TL, Saeteurn K, Klein J, Le CT, et al. Donors with group B KIR haplotypes improve relapse-free survival after unrelated hematopoietic cell transplantation for acute myelogenous leukemia. Blood. 2009;113:726–32.

    Article  CAS  Google Scholar 

  22. Venstrom JM, Pittari G, Gooley TA, Chewning JH, Spellman S, Haagenson M, et al. HLA-C-dependent prevention of leukemia relapse by donor activating KIR2DS1. N Engl J Med. 2012;367:805–16.

    Article  CAS  Google Scholar 

  23. Sekine T, Marin D, Cao K, Li L, Mehta P, Shaim H, et al. Specific combinations of donor and recipient KIR-HLA genotypes predict for large differences in outcome after cord blood transplantation. Blood. 2016;128:297–312.

    Article  CAS  Google Scholar 

  24. Fujisaki H, Kakuda H, Shimasaki N, Imai C, Ma J, Lockey T, et al. Expansion of highly cytotoxic human natural killer cells for cancer cell therapy. Cancer Res. 2009;69:4010–7.

    Article  CAS  Google Scholar 

  25. Bachanova V, Cooley S, DeFor TE, Verneris MR, Zhang B, McKenna DH, et al. Clearance of acute myeloid leukemia by haploidentical natural killer cells is improved using IL-2 diphtheria toxin fusion protein. Blood. 2014;123:3855–63.

    Article  CAS  Google Scholar 

  26. Imamura M, Shook D, Kamiya T, Shimasaki N, Chai SM, Coustan-Smith E, et al. Autonomous growth and increased cytotoxicity of natural killer cells expressing membrane-bound interleukin-15. Blood. 2014;124:1081–8.

    Article  CAS  Google Scholar 

  27. Nagashima S, Mailliard R, Kashii Y, Reichert TE, Herberman RB, Robbins P, et al. Stable transduction of the interleukin-2 gene into human natural killer cell lines and their phenotypic and functional characterization in vitro and in vivo. Blood. 1998;91:3850–61.

    Article  CAS  Google Scholar 

  28. Liu E, Tong Y, Dotti G, Shaim H, Savoldo B, Mukherjee M et al. Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. Leukemia. 2018;32:520–31. https://doi.org/10.1038/leu.2017.226.

  29. Liao NS, Bix M, Zijlstra M, Jaenisch R, Raulet D. MHC class I deficiency: susceptibility to natural killer (NK) cells and impaired NK activity. Science. 1991;253:199–202.

    Article  CAS  Google Scholar 

  30. Kim S, Poursine-Laurent J, Truscott SM, Lybarger L, Song YJ, Yang L, et al. Licensing of natural killer cells by host major histocompatibility complex class I molecules. Nature. 2005;436:709–13.

    Article  CAS  Google Scholar 

  31. Nijhof IS, Lammerts van Bueren JJ, van KB, Andre P, Morel Y, Lokhorst HM, et al. Daratumumab-mediated lysis of primary multiple myeloma cells is enhanced in combination with the human anti-KIR antibody IPH2102 and lenalidomide. Haematologica. 2015;100:263–8.

    Article  Google Scholar 

  32. Kohrt HE, Thielens A, Marabelle A, Sagiv-Barfi I, Sola C, Chanuc F, et al. Anti-KIR antibody enhancement of anti-lymphoma activity of natural killer cells as monotherapy and in combination with anti-CD20 antibodies. Blood. 2014;123:678–86.

    Article  CAS  Google Scholar 

  33. Borrego F, Masilamani M, Kabat J, Sanni TB, Coligan JE. The cell biology of the human natural killer cell CD94/NKG2A inhibitory receptor. Mol Immunol. 2005;42:485–8.

    Article  CAS  Google Scholar 

  34. Figueiredo C, Seltsam A, Blasczyk R. Permanent silencing of NKG2A expression for cell-based therapeutics. J Mol Med. 2009;87:199–210.

    Article  CAS  Google Scholar 

  35. Ochoa MC, Minute L, Rodriguez I, Garasa S, Perez-Ruiz E, Inoges S, et al. Antibody-dependent cell cytotoxicity: immunotherapy strategies enhancing effector NK cells. Immunol Cell Biol. 2017;95:347–55.

    Article  CAS  Google Scholar 

  36. Mehta RS, Rezvani K. Chimeric antigen receptor expressing natural killer cells for the immunotherapy of cancer. Front Immunol. 2018;9:283.

    Article  Google Scholar 

  37. Rezvani K, Rouce R, Liu E, Shpall E. Engineering natural killer cells for cancer immunotherapy. Mol Ther. 2017;25:1769–81.

    Article  CAS  Google Scholar 

  38. Klingemann H, Boissel L, Toneguzzo F. Natural killer cells for immunotherapy - advantages of the NK-92 cell line over blood NK cells. Front Immunol. 2016;7:91.

    Article  Google Scholar 

Download references

Funding

Publication of this supplement was sponsored by Gilead Sciences Europe Ltd, Cell Source, Inc., The Chorafas Institute for Scientific Exchange of the Weizmann Institute of Science, Kiadis Pharma, Miltenyi Biotec, Celgene, Centro Servizi Congressuali, Almog Diagnostic. The author’s research are funded in part by grants from the Leukemia Lymphoma Society (LLS Grant ID: 6555-18), the NIH (R01 CA211044-01), the Cancer Prevention Research Institute of Texas (RSG-15-218-01-LIB), the American Cancer Society (ACS RSG-15-218-01-LIB) and the generous philanthropic support of the MD Anderson Cancer Center Moon Shots programs.

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Correspondence to Katayoun Rezvani.

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Rezvani, K. Adoptive cell therapy using engineered natural killer cells. Bone Marrow Transplant 54 (Suppl 2), 785–788 (2019). https://doi.org/10.1038/s41409-019-0601-6

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