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Evolution of natural killer cell-targeted therapy for acute myeloid leukemia

  • Progress in Hematology
  • Novel treatment strategies for hematological malignancies in the era of immune therapy
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

In hematologic oncology, acute myeloid leukemia (AML) presents a significant challenge due to its complex genetic landscape and resistance to conventional therapies. Despite advances in treatment, including intensive chemotherapy and hematopoietic stem cell transplantation (HSCT), the prognosis for many patients with AML remains poor. Recently, immunotherapy has emerged as a promising approach to improve outcomes by augmenting existing treatments. Natural killer (NK) cells, a subset of innate lymphoid cells, have garnered attention for their potent cytotoxic capabilities against AML cells. In this review, we discuss the role of NK cells in AML immunosurveillance, their dysregulation in patients with AML, and various therapeutic strategies leveraging NK cells in AML treatment. We explore the challenges and prospects associated with NK cell therapy, including approaches to enhance NK cell function, overcome immune evasion mechanisms, and optimize treatment efficacy. Finally, we emphasize the importance of further research to validate and refine patient-first NK cell-based immunotherapies for AML.

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References

  1. Döhner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015;373(12):1136–52.

    Article  PubMed  Google Scholar 

  2. Kaweme NM, Zhou F. Optimizing NK Cell-Based Immunotherapy In Myeloid Leukemia: Abrogating an immunosuppressive microenvironment. Front Immunol. 2021;12: 683381.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Hussein BA, Hallner A, Wennström L, Brune M, Martner A, Hellstrand K, et al. Impact of NK cell activating receptor gene variants on receptor expression and outcome of immunotherapy in acute myeloid leukemia. Front Immunol. 2021;12: 796072.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Xu J, Niu T. Natural killer cell-based immunotherapy for acute myeloid leukemia. J Hematol Oncol. 2020;13(1):167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Abel AM, Yang C, Thakar MS, Malarkannan S. Natural killer cells: Development, maturation, and clinical utilization. Front Immunol. 2018;9:1869.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Ghaemdoust F, Keshavarz-Fathi M, Rezaei N. Natural killer cells and cancer therapy, what we know and where we are going. Immunotherapy. 2019;11(14):1231–51.

    Article  CAS  PubMed  Google Scholar 

  7. Ames E, Murphy WJ. Advantages and clinical applications of natural killer cells in cancer immunotherapy. Cancer Immunol Immunother. 2014;63(1):21–8.

    Article  PubMed  Google Scholar 

  8. Waldhauer I, Steinle A. NK cells and cancer immunosurveillance. Oncogene. 2008;27(45):5932–43.

    Article  CAS  PubMed  Google Scholar 

  9. Chester C, Fritsch K, Kohrt HE. Natural killer cell immunomodulation: Targeting activating, inhibitory, and co-stimulatory receptor signaling for cancer immunotherapy. Front Immunol. 2015;6:601.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Campbell KS, Hasegawa J. Natural killer cell biology: an update and future directions. J Allergy Clin Immunol. 2013;132(3):536–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Pegram HJ, Andrews DM, Smyth MJ, Darcy PK, Kershaw MH. Activating and inhibitory receptors of natural killer cells. Immunol Cell Biol. 2011;89(2):216–24.

    Article  PubMed  Google Scholar 

  12. Wang W, Erbe AK, Hank JA, Morris ZS, Sondel PM. NK cell-mediated antibody-dependent cellular cytotoxicity in cancer immunotherapy. Front Immunol. 2015;6:368.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Walzer T, Dalod M, Robbins SH, Zitvogel L, Vivier E. Natural-killer cells and dendritic cells: “l’union fait la force.” Blood. 2005;106(7):2252–8.

    Article  CAS  PubMed  Google Scholar 

  14. Fauriat C, Long EO, Ljunggren HG, Bryceson YT. Regulation of human NK-cell cytokine and chemokine production by target cell recognition. Blood. 2010;115(11):2167–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lee HM, Kim KS, Kim J. A comparative study of the effects of inhibitory cytokines on human natural killer cells and the mechanistic features of transforming growth factor-beta. Cell Immunol. 2014;290(1):52–61.

    Article  CAS  PubMed  Google Scholar 

  16. Park JY, Lee SH, Yoon SR, Park YJ, Jung H, Kim TD, et al. IL-15-induced IL-10 increases the cytolytic activity of human natural killer cells. Mol Cells. 2011;32(3):265–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Littwitz-Salomon E, Malyshkina A, Schimmer S, Dittmer U. The cytotoxic activity of natural killer cells is suppressed by IL-10(+) regulatory t cells during acute retroviral infection. Front Immunol. 2018;9:1947.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Baragaño Raneros A, López-Larrea C, Suárez-Álvarez B. Acute myeloid leukemia and NK cells: Two warriors confront each other. Oncoimmunology. 2019;8(2): e1539617.

    Article  PubMed  Google Scholar 

  19. Sivori S, Meazza R, Quintarelli C, Carlomagno S, Della Chiesa M, Falco M, et al. NK cell-based immunotherapy for hematological malignancies. J Clin Med. 2019;8(10):1702.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Guerra N, Tan YX, Joncker NT, Choy A, Gallardo F, Xiong N, et al. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Immunity. 2008;28(4):571–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Albertsson PA, Basse PH, Hokland M, Goldfarb RH, Nagelkerke JF, Nannmark U, et al. NK cells and the tumour microenvironment: implications for NK-cell function and anti-tumour activity. Trends Immunol. 2003;24(11):603–9.

    Article  CAS  PubMed  Google Scholar 

  22. Sugioka DK, Gonçalves CE, Bicalho MD. KIR repertory in patients with hematopoietic diseases and healthy family members. BMC Hematol. 2016;16:25.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Ahmad M, Rees RC, Ali SA. Escape from immunotherapy: Possible mechanisms that influence tumor regression/progression. Cancer Immunol Immunother. 2004;53(10):844–54.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Vago L, Perna SK, Zanussi M, Mazzi B, Barlassina C, Stanghellini MT, et al. Loss of mismatched HLA in leukemia after stem-cell transplantation. N Engl J Med. 2009;361(5):478–88.

    Article  CAS  PubMed  Google Scholar 

  25. Cornel AM, Mimpen IL, Nierkens S. MHC Class I downregulation in cancer: Underlying mechanisms and potential targets for cancer immunotherapy. Cancers (Basel). 2020;12(7):1760.

    Article  CAS  PubMed  Google Scholar 

  26. Barrett AJ, Le Blanc K. Immunotherapy prospects for acute myeloid leukaemia. Clin Exp Immunol. 2010;161(2):223–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Tratkiewicz JA, Szer J. Loss of natural killer activity as an indicator of relapse in acute leukaemia. Clin Exp Immunol. 1990;80(2):241–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lowdell MW, Craston R, Samuel D, Wood ME, O’Neill E, Saha V, et al. Evidence that continued remission in patients treated for acute leukaemia is dependent upon autologous natural killer cells. Br J Haematol. 2002;117(4):821–7.

    Article  CAS  PubMed  Google Scholar 

  29. Pizzolo G, Trentin L, Vinante F, Agostini C, Zambello R, Masciarelli M, et al. Natural killer cell function and lymphoid subpopulations in acute non-lymphoblastic leukaemia in complete remission. Br J Cancer. 1988;58(3):368–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Rey J, Fauriat C, Kochbati E, Orlanducci F, Charbonnier A, D’Incan E, et al. Kinetics of cytotoxic lymphocytes reconstitution after induction chemotherapy in elderly AML patients reveals progressive recovery of normal phenotypic and functional features in NK cells. Front Immunol. 2017;8:64.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Minculescu L, Marquart HV, Friis LS, Petersen SL, Schiødt I, Ryder LP, et al. Early natural killer cell reconstitution predicts overall survival in T cell-replete allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2016;22(12):2187–93.

    Article  CAS  PubMed  Google Scholar 

  32. Dunbar EM, Buzzeo MP, Levine JB, Schold JD, Meier-Kriesche HU, Reddy V. The relationship between circulating natural killer cells after reduced intensity conditioning hematopoietic stem cell transplantation and relapse-free survival and graft-versus-host disease. Haematologica. 2008;93(12):1852–8.

    Article  PubMed  Google Scholar 

  33. Freud AG, Yokohama A, Becknell B, Lee MT, Mao HC, Ferketich AK, et al. Evidence for discrete stages of human natural killer cell differentiation in vivo. J Exp Med. 2006;203(4):1033–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Chretien AS, Fauriat C, Orlanducci F, Galseran C, Rey J, Bouvier Borg G, et al. Natural killer defective maturation is associated with adverse clinical outcome in patients with acute myeloid leukemia. Front Immunol. 2017;8:573.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Szczepanski MJ, Szajnik M, Welsh A, Foon KA, Whiteside TL, Boyiadzis M. Interleukin-15 enhances natural killer cell cytotoxicity in patients with acute myeloid leukemia by upregulating the activating NK cell receptors. Cancer Immunol Immunother. 2010;59(1):73–9.

    Article  CAS  PubMed  Google Scholar 

  36. Sanchez-Correa B, Gayoso I, Bergua JM, Casado JG, Morgado S, Solana R, et al. Decreased expression of DNAM-1 on NK cells from acute myeloid leukemia patients. Immunol Cell Biol. 2012;90(1):109–15.

    Article  CAS  PubMed  Google Scholar 

  37. Fauriat C, Just-Landi S, Mallet F, Arnoulet C, Sainty D, Olive D, et al. Deficient expression of NCR in NK cells from acute myeloid leukemia: Evolution during leukemia treatment and impact of leukemia cells in NCRdull phenotype induction. Blood. 2007;109(1):323–30.

    Article  CAS  PubMed  Google Scholar 

  38. Verheyden S, Bernier M, Demanet C. Identification of natural killer cell receptor phenotypes associated with leukemia. Leukemia. 2004;18(12):2002–7.

    Article  CAS  PubMed  Google Scholar 

  39. Sandoval-Borrego D, Moreno-Lafont MC, Vazquez-Sanchez EA, Gutierrez-Hoya A, López-Santiago R, Montiel-Cervantes LA, et al. Overexpression of CD158 and NKG2A inhibitory receptors and underexpression of NKG2D and NKp46 activating receptors on NK cells in acute myeloid leukemia. Arch Med Res. 2016;47(1):55–64.

    Article  CAS  PubMed  Google Scholar 

  40. Farag SS, Bacigalupo A, Eapen M, Hurley C, Dupont B, Caligiuri MA, et al. The effect of KIR ligand incompatibility on the outcome of unrelated donor transplantation: A report from the center for international blood and marrow transplant research, the European blood and marrow transplant registry, and the Dutch registry. Biol Blood Marrow Transplant. 2006;12(8):876–84.

    Article  CAS  PubMed  Google Scholar 

  41. Verheyden S, Demanet C. NK cell receptors and their ligands in leukemia. Leukemia. 2008;22(2):249–57.

    Article  CAS  PubMed  Google Scholar 

  42. Nguyen S, Beziat V, Dhedin N, Kuentz M, Vernant JP, Debre P, et al. HLA-E upregulation on IFN-gamma-activated AML blasts impairs CD94/NKG2A-dependent NK cytolysis after haplo-mismatched hematopoietic SCT. Bone Marrow Transplant. 2009;43(9):693–9.

    Article  CAS  PubMed  Google Scholar 

  43. Beldi-Ferchiou A, Caillat-Zucman S. Control of NK cell activation by immune checkpoint molecules. Int J Mol Sci. 2017;18(10):2129.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Goltz D, Gevensleben H, Grünen S, Dietrich J, Kristiansen G, Landsberg J, et al. PD-L1 (CD274) promoter methylation predicts survival in patients with acute myeloid leukemia. Leukemia. 2017;31(3):738–43.

    Article  CAS  PubMed  Google Scholar 

  45. Zhang Q, Bi J, Zheng X, Chen Y, Wang H, Wu W, et al. Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity. Nat Immunol. 2018;19(7):723–32.

    Article  CAS  PubMed  Google Scholar 

  46. Sakamoto N, Ishikawa T, Kokura S, Okayama T, Oka K, Ideno M, et al. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. J Transl Med. 2015;13:277.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Parkhurst MR, Riley JP, Dudley ME, Rosenberg SA. Adoptive transfer of autologous natural killer cells leads to high levels of circulating natural killer cells but does not mediate tumor regression. Clin Cancer Res. 2011;17(19):6287–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Guillerey C, Huntington ND, Smyth MJ. Targeting natural killer cells in cancer immunotherapy. Nat Immunol. 2016;17(9):1025–36.

    Article  CAS  PubMed  Google Scholar 

  49. Allison M, Mathews J, Gilliland T, Mathew SO. Natural killer cell-mediated immunotherapy for leukemia. Cancers (Basel). 2022;14(3):843.

    Article  CAS  PubMed  Google Scholar 

  50. 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(8):3051–7.

    Article  CAS  PubMed  Google Scholar 

  51. Franks SE, Wolfson B, Hodge JW. Natural born killers: NK cells in cancer therapy. Cancers (Basel). 2020;12(8):2131.

    Article  CAS  PubMed  Google Scholar 

  52. Rubnitz JE, Inaba H, Ribeiro RC, Pounds S, Rooney B, Bell T, et al. NKAML: A pilot study to determine the safety and feasibility of haploidentical natural killer cell transplantation in childhood acute myeloid leukemia. J Clin Oncol. 2010;28(6):955–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Handgretinger R, Lang P, André MC. Exploitation of natural killer cells for the treatment of acute leukemia. Blood. 2016;127(26):3341–9.

    Article  CAS  PubMed  Google Scholar 

  54. Huang J, Liu Y, Au BC, Barber DL, Arruda A, Schambach A, et al. Preclinical validation: LV/IL-12 transduction of patient leukemia cells for immunotherapy of AML. Mol Ther Methods Clin Dev. 2016;3:16074.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Shi Y, Dincheva-Vogel L, Ayemoba CE, Fung JP, Bergamaschi C, Pavlakis GN, et al. IL-15/IL-15Rα/CD80-expressing AML cell vaccines eradicate minimal residual disease in leukemic mice. Blood Adv. 2018;2(22):3177–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Zhao X, Cai L, Hu Y, Wang H. Cord-blood natural killer cell-based immunotherapy for cancer. Front Immunol. 2020;11: 584099.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Sarvaria A, Jawdat D, Madrigal JA, Saudemont A. Umbilical cord blood natural killer cells, their characteristics, and potential clinical applications. Front Immunol. 2017;8:329.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Dolstra H, Roeven MWH, Spanholtz J, Hangalapura BN, Tordoir M, Maas F, et al. Successful transfer of umbilical cord blood CD34(+) hematopoietic stem and progenitor-derived NK cells in older acute myeloid leukemia patients. Clin Cancer Res. 2017;23(15):4107–18.

    Article  CAS  PubMed  Google Scholar 

  59. 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(3):457–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Gunesch JT, Angelo LS, Mahapatra S, Deering RP, Kowalko JE, Sleiman P, et al. Genome-wide analyses and functional profiling of human NK cell lines. Mol Immunol. 2019;115:64–75.

    Article  CAS  PubMed  Google Scholar 

  61. Zhang J, Zheng H, Diao Y. Natural killer cells and current applications of chimeric antigen receptor-modified NK-92 cells in tumor immunotherapy. Int J Mol Sci. 2019;20(2):317.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Suck G, Odendahl M, Nowakowska P, Seidl C, Wels WS, Klingemann HG, et al. NK-92: An “off-the-shelf therapeutic” for adoptive natural killer cell-based cancer immunotherapy. Cancer Immunol Immunother. 2016;65(4):485–92.

    Article  CAS  PubMed  Google Scholar 

  63. Boyiadzis M, Agha M, Redner RL, Sehgal A, Im A, Hou JZ, et al. Phase 1 clinical trial of adoptive immunotherapy using “off-the-shelf” activated natural killer cells in patients with refractory and relapsed acute myeloid leukemia. Cytotherapy. 2017;19(10):1225–32.

    Article  CAS  PubMed  Google Scholar 

  64. Kang S, Gao X, Zhang L, Yang E, Li Y, Yu L. The advances and challenges of NK cell-based cancer immunotherapy. Curr Oncol. 2021;28(2):1077–93.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Kaito Y, Sugimoto E, Nakamura F, Tsukune Y, Sasaki M, Yui S, et al. Immune checkpoint molecule DNAM-1/CD112 axis is a novel target for NK-cell therapy in acute myeloid leukemia. Haematologica. 2023;109(4):1107–20.

    PubMed Central  Google Scholar 

  66. Matsubara H, Niwa A, Nakahata T, Saito MK. Induction of human pluripotent stem cell-derived natural killer cells for immunotherapy under chemically defined conditions. Biochem Biophys Res Commun. 2019;515(1):1–8.

    Article  CAS  PubMed  Google Scholar 

  67. Romee R, Rosario M, Berrien-Elliott MM, Wagner JA, Jewell BA, Schappe T, et al. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. Sci Transl Med. 2016;8(357):357ra123.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Cooper MA, Elliott JM, Keyel PA, Yang L, Carrero JA, Yokoyama WM. Cytokine-induced memory-like natural killer cells. Proc Natl Acad Sci U S A. 2009;106(6):1915–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Bednarski JJ, Zimmerman C, Berrien-Elliott MM, Foltz JA, Becker-Hapak M, Neal CC, et al. Donor memory-like NK cells persist and induce remissions in pediatric patients with relapsed AML after transplant. Blood. 2022;139(11):1670–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. 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(8):725–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507–17.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Malmberg KJ, Carlsten M, Björklund A, Sohlberg E, Bryceson YT, Ljunggren HG. Natural killer cell-mediated immunosurveillance of human cancer. Semin Immunol. 2017;31:20–9.

    Article  CAS  PubMed  Google Scholar 

  73. Lanier LL. Up on the tightrope: Natural killer cell activation and inhibition. Nat Immunol. 2008;9(5):495–502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Shimasaki N, Jain A, Campana D. NK cells for cancer immunotherapy. Nat Rev Drug Discov. 2020;19(3):200–18.

    Article  CAS  PubMed  Google Scholar 

  75. Klingemann H. Are natural killer cells superior CAR drivers? Oncoimmunology. 2014;3: e28147.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Christodoulou I, Ho WJ, Marple A, Ravich JW, Tam A, Rahnama R, et al. Engineering CAR-NK cells to secrete IL-15 sustains their anti-AML functionality but is associated with systemic toxicities. J Immunother Cancer. 2021;9(12): e003894.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Morgan MA, Kloos A, Lenz D, Kattre N, Nowak J, Bentele M, et al. Improved activity against acute myeloid leukemia with chimeric antigen receptor (CAR)-NK-92 cells designed to target CD123. Viruses. 2021;13(7):1365.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Salman H, Pinz KG, Wada M, Shuai X, Yan LE, Petrov JC, et al. Preclinical targeting of human acute myeloid leukemia using CD4-specific chimeric antigen receptor (CAR) T cells and NK cells. J Cancer. 2019;10(18):4408–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Ureña-Bailén G, Dobrowolski JM, Hou Y, Dirlam A, Roig-Merino A, Schleicher S, et al. Preclinical evaluation of CRISPR-edited CAR-NK-92 cells for off-the-shelf treatment of AML and B-ALL. Int J Mol Sci. 2022;23(21):12828.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Du Z, Ng YY, Zha S, Wang S. piggyBac system to co-express NKG2D CAR and IL-15 to augment the in vivo persistence and anti-AML activity of human peripheral blood NK cells. Mol Ther Methods Clin Dev. 2021;23:582–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Tang X, Yang L, Li Z, Nalin AP, Dai H, Xu T, et al. First-in-man clinical trial of CAR NK-92 cells: Safety test of CD33-CAR NK-92 cells in patients with relapsed and refractory acute myeloid leukemia. Am J Cancer Res. 2018;8(6):1083–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Cronk RJ, Zurko J, Shah NN. Bispecific chimeric antigen receptor T cell therapy for B cell malignancies and multiple myeloma. Cancers (Basel). 2020;12(9):2523.

    Article  CAS  PubMed  Google Scholar 

  83. Hope KJ, Jin L, Dick JE. Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity. Nat Immunol. 2004;5(7):738–43.

    Article  CAS  PubMed  Google Scholar 

  84. Sutherland HJ, Blair A, Zapf RW. Characterization of a hierarchy in human acute myeloid leukemia progenitor cells. Blood. 1996;87(11):4754–61.

    Article  CAS  PubMed  Google Scholar 

  85. Schmidt P, Raftery MJ, Pecher G. Engineering NK cells for CAR therapy-recent advances in gene transfer methodology. Front Immunol. 2020;11: 611163.

    Article  CAS  PubMed  Google Scholar 

  86. Davis ZB, Vallera DA, Miller JS, Felices M. Natural killer cells unleashed: Checkpoint receptor blockade and BiKE/TriKE utilization in NK-mediated anti-tumor immunotherapy. Semin Immunol. 2017;31:64–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Allan DSJ, Chakraborty M, Waller GC, Hochman MJ, Poolcharoen A, Reger RN, et al. Systematic improvements in lentiviral transduction of primary human natural killer cells undergoing ex vivo expansion. Mol Ther Methods Clin Dev. 2021;20:559–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Mensali N, Dillard P, Hebeisen M, Lorenz S, Theodossiou T, Myhre MR, et al. NK cells specifically TCR-dressed to kill cancer cells. EBioMedicine. 2019;40:106–17.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Ågerstam H, Karlsson C, Hansen N, Sandén C, Askmyr M, von Palffy S, et al. Antibodies targeting human IL1RAP (IL1R3) show therapeutic effects in xenograft models of acute myeloid leukemia. Proc Natl Acad Sci U S A. 2015;112(34):10786–91.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Koerner SP, André MC, Leibold JS, Kousis PC, Kübler A, Pal M, et al. An Fc-optimized CD133 antibody for induction of NK cell reactivity against myeloid leukemia. Leukemia. 2017;31(2):459–69.

    Article  CAS  PubMed  Google Scholar 

  91. Vasu S, He S, Cheney C, Gopalakrishnan B, Mani R, Lozanski G, et al. Decitabine enhances anti-CD33 monoclonal antibody BI 836858-mediated natural killer ADCC against AML blasts. Blood. 2016;127(23):2879–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Krupka C, Lichtenegger FS, Köhnke T, Bögeholz J, Bücklein V, Roiss M, et al. Targeting CD157 in AML using a novel Fc-engineered antibody construct. Oncotarget. 2017;8(22):35707–17.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Mani R, Rajgolikar G, Nunes J, Zapolnik K, Wasmuth R, Mo X, et al. Fc-engineered anti-CD33 monoclonal antibody potentiates cytotoxicity of membrane-bound interleukin-21 expanded natural killer cells in acute myeloid leukemia. Cytotherapy. 2020;22(7):369–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Khan M, Arooj S, Wang H. NK cell-based immune checkpoint inhibition. Front Immunol. 2020;11:167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Coles SJ, Wang EC, Man S, Hills RK, Burnett AK, Tonks A, et al. CD200 expression suppresses natural killer cell function and directly inhibits patient anti-tumor response in acute myeloid leukemia. Leukemia. 2011;25(5):792–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Vey N, Bourhis JH, Boissel N, Bordessoule D, Prebet T, Charbonnier A, et al. A phase 1 trial of the anti-inhibitory KIR mAb IPH2101 for AML in complete remission. Blood. 2012;120(22):4317–23.

    Article  CAS  PubMed  Google Scholar 

  97. Godal R, Bachanova V, Gleason M, McCullar V, Yun GH, Cooley S, et al. Natural killer cell killing of acute myelogenous leukemia and acute lymphoblastic leukemia blasts by killer cell immunoglobulin-like receptor-negative natural killer cells after NKG2A and LIR-1 blockade. Biol Blood Marrow Transplant. 2010;16(5):612–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Ruggeri L, Urbani E, André P, Mancusi A, Tosti A, Topini F, et al. Effects of anti-NKG2A antibody administration on leukemia and normal hematopoietic cells. Haematologica. 2016;101(5):626–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Lanuza PM, Pesini C, Arias MA, Calvo C, Ramirez-Labrada A, Pardo J. Recalling the biological significance of immune checkpoints on NK cells: A chance to overcome LAG3, PD1, and CTLA4 inhibitory pathways by adoptive NK cell transfer? Front Immunol. 2019;10:3010.

    Article  CAS  PubMed  Google Scholar 

  100. Sanchez-Correa B, Valhondo I, Hassouneh F, Lopez-Sejas N, Pera A, Bergua JM, et al. DNAM-1 and the TIGIT/PVRIG/TACTILE axis: Novel immune checkpoints for natural killer cell-based cancer immunotherapy. Cancers (Basel). 2019;11(6):877.

    Article  CAS  PubMed  Google Scholar 

  101. Berger R, Rotem-Yehudar R, Slama G, Landes S, Kneller A, Leiba M, et al. Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin Cancer Res. 2008;14(10):3044–51.

    Article  CAS  PubMed  Google Scholar 

  102. Davids MS, Kim HT, Bachireddy P, Costello C, Liguori R, Savell A, et al. Ipilimumab for patients with relapse after allogeneic transplantation. N Engl J Med. 2016;375(2):143–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Gallois A, Silva I, Osman I, Bhardwaj N. Reversal of natural killer cell exhaustion by TIM-3 blockade. Oncoimmunology. 2014;3(12): e946365.

    Article  PubMed  PubMed Central  Google Scholar 

  104. Xu L, Huang Y, Tan L, Yu W, Chen D, Lu C, et al. Increased Tim-3 expression in peripheral NK cells predicts a poorer prognosis and Tim-3 blockade improves NK cell-mediated cytotoxicity in human lung adenocarcinoma. Int Immunopharmacol. 2015;29(2):635–41.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Hematology, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-Ku, Tokyo, 113-8602, Japan

    Yuta Kaito

  2. Department of Hematology and Oncology, Dokkyo Medical University, Tochigi, Japan

    Yoichi Imai

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  1. Yuta Kaito
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  2. Yoichi Imai
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YK and YI wrote the manuscript. YI supervised the project. All the authors have read and approved the final manuscript.

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Correspondence to Yuta Kaito.

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Conflict of interest

YI received research funding from JSPS KAKENHI (Grant Number 20K08726), Takeda Pharma, and Bristol Myers Squibb. YI received an honorarium from Bristol Myers Squibb, Takeda Pharma, Janssen Pharmaceutical, and Sanofi. The remaining authors declare no competing financial interests.

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Kaito, Y., Imai, Y. Evolution of natural killer cell-targeted therapy for acute myeloid leukemia. Int J Hematol (2024). https://doi.org/10.1007/s12185-024-03778-0

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  • DOI: https://doi.org/10.1007/s12185-024-03778-0

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