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Submitted: 23 September 2019 | Approved: 30 September 2019 | Published: 01 October 2019

How to cite this article: Al-Anazi KA. The rising role of natural killer cells in patients with malignant hematological disorders and in recipients of hematopoietic stem cell transplantation. J Stem Cell Ther Transplant. 2019; 3: 023-027.
DOI: 10.29328/journal.jsctt.1001015

Copyright: © 2019 Al-Anazi KA. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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The rising role of natural killer cells in patients with malignant hematological disorders and in recipients of hematopoietic stem cell transplantation

Khalid Ahmed Al-Anazi*

Department of Hematology and Hematopoietic Stem Cell Transplantation, Oncology Center, King Fahad Specialist Hospital, Dammam, Saudi Arabia

*Address for Correspondence: Khalid Ahmed Al-Anazi, Consultant, Hemato-Oncologist and Chairman, Department of Hematology and Hematopoietic Stem Cell Transplantation, Oncology Center, King Fahad Specialist Hospital, P.O. Box: 15215, Dammam 31444, Saudi Arabia, Tel: 966 - 03- 8431111; Fax: 966 -13- 8427420; Email: kaa_alanazi@yahoo.com


Natural killer (NK) cells, the third population of lymphoid cells, comprise 5%-25% of peripheral blood (PB) lymphocytes and represent the first line of defense against infections and tumors [1-7]. They can be derived from: bone marrow, PB, cryopreserved umbilical cord blood (UCB), human embryonic stem cells (hESCs), induced pluripotent stem cells (iPSCs), and various cell lines such as NK-92 and KHYG-1 [1]. NK cells; which have been divided into cytotoxic, tolerant, and regulatory subsets; are classified into: (1) naïve CD56 bright CD 16 dim CD 3 dim cells, (2) mature CD56 dim CD16 bright CD3 dim cells, and (3) lymphoid tissue-resident CD69+/CXCR6+ NK cells [1,2,8-11]. Although NK cells have been traditionally considered as part of the innate immune system, they have recently been shown to exhibit many of the features associated with adaptive immunity [8,12]. The functions of NK cells which are influenced by several cytokines include: elimination of infected cells, destruction of cancer cells, reducing the incidence of graft versus host disease (GVHD) following hematopoietic stem cell transplantation (HSCT), and regulation of pregnancy outcome [10,11,13]. NK cell function is finely tuned by activating and inhibitory receptors that recognize both foreign and self-antigens expressed by NK cell-susceptible targets [7,14]. Activated NK cells interact with dendritic cells (DCs) and mesenchymal stem cells (MSCs) and the complicated crosstalks between NK cells, MSCs, and DCs may alter the functions of any of the 3 cell types [15-27].

NK cells are attractive candidates for adoptive cellular therapy in patients with hematologic malignancies (HMs) and solid tumors, as well as in recipients of allogeneic HSCT by enhancing graft versus leukemia (GVL) effect without causing GVHD [1,28-34]. Approximately 10%-20% of NK cells remain unlicenced and functionally hyporesponsive due to lack of receptors for self-major histocompatibility complex (MHC). However, unlicenced NK cells become alloreactive after adoptive transfer into recipients of HSCT [7]. NK cells express inhibitory inhibitory killer cell immunoglobulin-like receptors (KIRs) to recognize self - HLA (human leukocyte antigen) class I molecules and provide inhibitory signals to preclude killing of the target cells [8].

Multiple myeloma (MM) is characterized by gradual immune dysregulation and myeloma cells exhibit specific immunoevasive strategies to circumvent and attenuate NK cell function [32,35]. Transformed plasma cells in MM are susceptible to NK cell-mediated killing by engagement of tumor ligands for activating receptors or missing self recognition [32,33,35]. Despite the advancements in novel therapies and autologous HSCT, MM remains an incurable and difficult-to-treat HM due to drug resistance predisposed to by the immunosuppressive microenvironment and clonal evolution thus making allogeneic HSCT the only potentially curative therapeutic modality due to its potent graft versus myeloma effect [31,35]. In patients with MM, NK cells have been used in several trials in the setting of autologous as well as allogeneic HSCT as NK cells elicit cytotoxic effects against MM cells and as KIR-ligand mismatch may improve the outcome of allogeneic HSCT [31,32,36-38]. NK cell killing of tumor cells in MM can be augmented by: check point inhibitors (CPIs), therapeutic antibodies such as daratumumab, immunomodulatory agents such as lenalidomide, indoleamine 2,3 dioxygenase inhibitors, and adoptive transfer of unmanipulated or chimeric antigen receptor (CAR)-engineered NK cells [30,35].

Allogeneic HSCT has revolutionized the treatment of HMs, but the use of this potentially curative therapy is limited by: GVHD, infections and relapse of the primary disease [29,39-41]. NK cells are the first subset of donor-derived lymphocytes to reconstitute after HSCT thus they may protect against relapse in the early months following HSCT by providing GVL effect without causing GVHD [1,39,42]. Although the initial studies on the use of autologous NK cells were disappointing, the use of allogeneic NK cells has resulted in favorable outcomes in both transplant and non-transplant settings and this led to the advancement of NK immunotherapy over the last decade [1].

Donor NK cells play significant roles in: promotion of hematopoietic engraftment in recipients of HSCT, preventing relapse of HM post-allogeneic HSCT by mediating GVL effects, and regulation of GVHD by suppressing alloreactive T-cell responses [39]. Enhancement of GVL without increasing the incidence of GVHD can be achieved by: optimal donor selection, optimal conditioning therapy, administration of GVHD prophylaxis, and administration of T-cells and donor-derived NK cells which are amenable to ex vivo manipulation and clinical manufacture [40]. Separating GVL effects from GVHD is of special interest in non-specific cell-based immunotherapy which may eradicate molecular disease and prevent relapse following allogeneic HSCT particularly when leukemia burden is low [28,43]. The recognition of missing-self on target cells is crucial for promoting NK cell-mediated GVL effects [8]. NK cells have a central role in tumor-cell surveillance but leukemic cells have great capacity to escape NK cell recognition and killing thus limiting the use of NK cells in immunotherapy [44]. Augmentation of T-cell alloreactivity may be influenced by NK cells in recipients of T-cell deleted allografts, while immunosuppression with sirolimus and expansion of T-regulatory cells may decrease the incidence of acute GVHD by suppressing the development of T-cell mediated alloreactivity [29,45,46]. NK cell infusions derived from PB and UCB contain contaminating T-cells whose stimulation by cytokines that are produced by NK cells may trigger GVHD in vivo thus limiting the safety and efficacy of NK cell infusions in allogeneic HSCT. However, NK cells obtained from iPSCs, hESCs, and NK cell lines are free of contamination with T and B cells thus offering alternative sources of NK cells that can be used in adoptive immunotherapy [47]. Unfortunately, non-specific immunotherapy is dependent on repeat administrations [28].

Invariant NK T (iNKT) cells that are derived from HSCs protect against GVHD and cancer, while cytokine-induced killer (CIK) cells have demonstrated cytotoxicity against a variety of malignant or leukemic cells with no or only minor effects on normal hematopoietic progenitor cells [28,41,48,49]. Allogeneic CIK cells retain the ability to produce GVL effect while generating minimal GVHD [41]. CIK cell infusion comprises a safe and a feasible novel immunotherapeutic approach that targets relapse or minimal residual diseasae following HSCT for HMs [41,50]. In a recently published study that included 91 patients with various HMs relapsing after allogeneic HSCT; conventional donor lymphocyte infusion (DLI) given to 55 patients was compared to CIK given to 36 patients, the outcome of CIK therapy was superior to that of DLI with higher overall survival, less relapses, and less acute GVHD [28]. However, optimal timing and dosage of NK cells need to be determined [50].

The use of post-transplant cyclophosphamide (PTC) as GVHD prophylaxis has revolutionized haploidentical HSCT although PTC eliminates most mature donor NK cells infused in the graft including alloreactive NK cells [51]. NK cell recovery after haploidentical HSCT is greatly influenced by other subsets of immune cells and by drugs used in the post-transplant period [51]. NK cell immunotherapies have the potential to significantly enhace the ability of conventional therapies to eliminate acute myeloid leukemia (AML) after HSCT [43]. Initial reports of haploidentical HSCT in AML patients showed that alloreactive NK cells had favorable effects on relapse and survival by promoting engraftment, enhancing GVL effect and reducing the incidence of GVHD. However, subsequent studies have shown either no defference in the incidence of GVHD or adverse outcomes related to GVHD, infections and disease relapse. Therefore, selecting the most appropriate alloreactive NK cell model and selective expansion of a particular NK cell subset may become vital in restoring NK cell function in the post-HSCT period [52]. Fortunately, acquisition of large numbers of mature and functional NK cells that can be derived and differentiated from UCB-CD3+ HSCs is easily accessible, but optimal clinical protocols for NK cell therapies in leukemia and other cancers are still lacking [53]. Strategies that can be employed to improve NK cell immunotherapies include: optimal donor selection; combination with cytokine stimulation or immune CPIs; drugs that enhance NK cell antitumor activity or sensitize malignant cells to NK cells; bispecific or trispecific killer engagers; adoptively infused allogeneic NK cells in haploidentical transplantation; advancing the field of ex vivo manipulation and genetic engineering; priming of NK cells; and using extracellular vesicles derived from NK cells [1,8,44,45,54-56].

HMs such as: acute lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, and non-Hodgkin lymphoma are associated with immune deficiencies including NK cell dysfunction. Consequently, therapeutic strategies aimed at restoring NK cell function in these HMs are evolving [57-61]. Although the majority of clinical trials involving NK cells have initially focused on AML and MM, trials on the use of NK cell immunotherapies to treat other HMs as well as solid tumors are rapidly expanding. However, certain limitations have to be resolved, quality and safety measures should be taken into consideration, and preparatory as well as therapeutic protocols for specific subsets of NK cells need to be implemented.

  1. Mehta RS, Randolph B, Daher M, Rezvani K. NK cell therapy for hematologic malignancies. Int J Hematol. 2018; 107: 262-270. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29383623
  2. Crinier A, Milpied P, Escalière B, Piperoglou C, Galluso J, et al. High-dimensional single-cell analysis identifies organ-specific signatures and conserved NK cell subsets in humans and mice. Immunity. 2018; 49: 971-986. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30413361
  3. Freud AG, Mundy-Bosse BL, Yu J, Caligiuri MA. The broad spectrum of human natural killer cell diversity. Immunity. 2017; 47: 820-833. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29166586
  4. Orr MT, Lanier LL. Natural killer cell education and tolerance. Cell. 2010; 142: 847-856. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/20850008
  5. Abel AM, Yang C, Thakar MS, Malarkannan S. Natural killer cells: development, maturation, and clinical utilization. Front Immunol. 2018; 9: 1869. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30150991
  6. van Erp EA, van Kampen MR, van Kasteren PB, de Wit J. Viral infection of human natural killer cells. Viruses. 2019; 11: 243. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466310/
  7. Pittari G, Filippini P, Gentilcore G, Grivel JC, Rutella S. Revving up natural killer cells and cytokine-induced killer cells against hematological malignancies. Front Immunol. 2015; 6: 230. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26029215
  8. Handgretinger R, Lang P, André MC. Exploitation of natural killer cells for the treatment of acute leukemia. Blood. 2016; 127: 3341-3349. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27207791
  9. Robertson MJ. Role of chemokines in the biology of natural killer cells. J Leukoc Biol. 2002; 71: 173-183. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/11818437
  10. Maghazachi AA. Role of chemokines in the biology of natural killer cells. Curr Top Microbiol Immunol. 2010; 341: 37-58. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/20369317
  11. Wu Y, Tian Z, Wei H. Developmental and functional control of natural killer cells by cytokines. Front Immunol. 2017; 8: 930. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28824650
  12. Tesi B, Schlums H, Cichocki F, Bryceson YT. Epigenetic regulation of adaptive NK cell diversification. Trends Immunol. 2016; 37(7): 451-461. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27160662
  13. Chiossone L, Vacca P, Orecchia P, Croxatto D, Damonte P, et al. In vivo generation of decidual natural killer cells from resident hematopoietic progenitors. Haematologica. 2014; 99: 448-57. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24179150
  14. Mavers M, Bertaina A. High-risk leukemia: past, present, and future role of NK cells. J Immunol Res. 2018; 2018: 1586905. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29850617
  15. Ferlazzo G, Morandi B. Cross-talks between natural killer cells and distinct subsets of dendritic cells. Front Immunol. 2014; 5: 159. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3989561/
  16. Moretta A. Natural killer cells and dendritic cells: rendezvous in abused tissues. Nat Rev Immunol. 2002; 2: 957-964. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/12461568
  17. Sanabria MX, Vargas-Inchaustegui DA, Xin L, Soong L. Role of natural killer cells in modulating dendritic cell responses to Leishmania amazonensis infection. Infect Immun. 2008; 76: 5100-5109. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/18794295
  18. Van Elssen CH, Oth T, Germeraad WT, Bos GM, Vanderlocht J. Natural killer cells: the secret weapon in dendritic cell vaccination strategies. Clin Cancer Res. 2014; 20:1095-1103. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24590885
  19. Harizi H. Reciprocal crosstalk between dendritic cells and natural killer cells under the effects of PGE2 in immunity and immunopathology. Cell Mol Immunol. 2013; 10: 213-221. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23524652
  20. Calmeiro J, Carrascal M, Gomes C, Falcão A, Cruz MT, et al. Heighlighting the role of DC-NK cell interplay in immunobiology and immunotherapy. In: Dendritic cells. Edited by: Chapoval SP. Intech Open 2018.
  21. Gerosa F, Baldani-Guerra B, Nisii C, Marchesini V, Carra G, et al. Reciprocal activating interaction between natural killer cells and dendritic cells. J Exp Med. 2002; 195: 327-333. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/11828007
  22. Piccioli D, Sbrana S, Melandri E, Valiante NM. Contact-dependent stimulation and inhibition of dendritic cells by natural killer cells. J Exp Med. 2002; 195(3): 335-341. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/11828008
  23. Galland S, Vuille J, Martin P, Letovanec I, Caignard A, et al. Tumor-derived mesenchymal stem cells use distinct mechanisms to block the activity of natural killer cell subsets. Cell Rep. 2017; 20: 2891-2905. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28930684
  24. Najar M, Fayyad-Kazan M, Merimi M, Burny A, Bron D, et al. Mesenchymal stromal cells and natural killer cells: a complex story of love and hate. Curr Stem Cell Res Ther. 2019; 14: 14-21. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30207245
  25. Najar M, Fayyad-Kazan M, Meuleman N, Bron D, Fayyad-Kazan H, et al. Mesenchymal stromal cells of the bone marrow and natural killer cells: cell interactions and cross modulation. J Cell Commun Signal. 2018; 12: 673-688. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29350342
  26. Thomas H, Jäger M, Mauel K, Brandau S, Lask S, et al. Interaction with mesenchymal stem cells provokes natural killer cells for enhanced IL-12/IL-18-induced interferon-gamma secretion. Mediators Inflamm. 2014; 2014: 143463. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24876666
  27. Sotiropoulou PA, Perez SA, Gritzapis AD, Baxevanis CN, Papamichail M. Interactions between human mesenchymal stem cells and natural killer cells. Stem Cells. 2006; 24: 74-85. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16099998
  28. Merker M, Salzmann-Manrique E, Katzki V, Huenecke S, Bremm M, et al. Clearance of hematologic malignancies by allogeneic cytokine-induced killer cell or donor lymphocyte infusions. Biol Blood Marrow Transplant. 2019; 25: 1281-1292. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30878607
  29. Chan YLT, Zuo J, Inman C, Croft W, Begum J, et al. NK cells produce high levels of IL-10 early after allogeneic stem cell transplantation and suppress development of acute GVHD. Eur J Immunol. 2018; 48: 316-329. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28944953
  30. Carlsten M, Korde N, Kotecha R, Reger R, Bor S, et al. Checkpoint inhibition of KIR2D with the monoclonal antibody IPH2101 induces contraction and hyporesponsiveness of NK Cells in patients with myeloma. Clin Cancer Res. 2016; 22: 5211-5222. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27307594
  31. Gabriel IH, Sergeant R, Szydlo R, Apperley JF, DeLavallade H, et al. Interaction between KIR3DS1 and HLA-Bw4 predicts for progression-free survival after autologous stem cell transplantation in patients with multiple myeloma. Blood. 2010; 116: 2033-2039. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/20562327
  32. Benson DM Jr, Hofmeister CC, Padmanabhan S, Suvannasankha A, Jagannath S, et al. A phase 1 trial of the anti-KIR antibody IPH2101 in patients with relapsed/refractory multiple myeloma. Blood 2012; 120: 4324-4333. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23033266
  33. Hoteit R, Bazarbachi A, Antar A, Salem Z, Shammaa D, et al. KIR genotype distribution among patients with multiple myeloma: Higher prevalence of KIR 2DS4 and KIR 2DS5 genes. Meta Gene 2014; 2: 730-736. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25606456
  34. Petri RM, Hackel A, Hahnel K, Dumitru CA, Bruderek K, et al. Activated tissue-resident mesenchymal stromal cells regulate natural killer cell immune and tissue-regenerative function. Stem Cell Rep. 2017; 9: 985-998. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28781075
  35. Pittari G, Vago L, Festuccia M, Bonini C, Mudawi D, et al. Restoring natural killer cell immunity against multiple myeloma in the era of new drugs. Front Immunol. 2017; 8: 1444. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5682004/
  36. Shah N, Li L, McCarty J, Kaur I, Yvon E, 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. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28295190
  37. Kröger N, Shaw B, Iacobelli S, Zabelina T, Peggs K, et al; Clinical Trial Committee of the British Society of Blood and Marrow Transplantation and the German Cooperative Transplant Group. Comparison between antithymocyte globulin and alemtuzumab and the possible impact of KIR-ligand mismatch after dose-reduced conditioning and unrelated stem cell transplantation in patients with multiple myeloma. Br J Haematol. 2005; 129: 631-643. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15916686
  38. Shi J, Tricot G, Szmania S, Rosen N, Garg TK, et al. Infusion of haplo-identical killer immunoglobulin-like receptor ligand mismatched NK cells for relapsed myeloma in the setting of autologous stem cell transplantation. Br J Haematol. 2008; 143: 641-653. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/18950462
  39. Simonetta F, Alvarez M, Negrin RS. Natural killer cells in graft-versus-host-disease after allogeneic hematopoietic cell transplantation. Front Immunol. 2017; 8:465. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28487696
  40. Cruz CR, Bollard CM. T-cell and natural killer cell therapies for hematologic malignancies after hematopoietic stem cell transplantation: enhancing the graft-versus-leukemia effect. Haematologica. 2015; 100(6): 709-719. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26034113
  41. Yang XY, Zeng H, Chen FP. Cytokine-induced killer cells: a novel immunotherapy strategy for leukemia. Oncol Lett. 2015; 9: 535-541. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4301482/
  42. Mavers M, Bertaina A. High-risk leukemia: past, present, and future role of NK cells. J Immunol Res. 2018; 2018: 1586905. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29850617
  43. Hattori N, Nakamaki T. Natural killer immunotherapy for minimal residual disease eradication following allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia. Int J Mol Sci. 2019; 20: E2057. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31027331
  44. Chouaib S, Pittari G, Nanbakhsh A, El Ayoubi H, Amsellem S, et al. Improving the outcome of leukemia by natural killer cell-based immunotherapeutic strategies. Front Immunol. 2014; 5: 95. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3956082/
  45. Shah NN, Baird K, Delbrook CP, Fleisher TA, Kohler ME, et al. Acute GVHD in patients receiving IL-15/4-1BBL activated NK cells following T-cell-depleted stem cell transplantation. Blood 2015; 125: 784-792. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25452614
  46. Chen YB, Efebera YA, Johnston L, Ball ED, Avigan D, et al. Increased Foxp3+Helios+ regulatory T cells and decreased acute graft-versus-host disease after allogeneic bone marrow transplantation in patients receiving sirolimus and RGI-2001, an activator of invariant natural killer T cells. Biol Blood Marrow Transplant. 2017; 23: 625-634. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28104514
  47. Lupo KB, Matosevic S. Natural killer cells as allogeneic effectors in adoptive cancer immunotherapy. Cancers (Basel). 2019; 11: E769. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31163679
  48. Du J, Paz K, Thangavelu G, Schneidawind D, Baker J, et al. Invariant natural killer T cells ameliorate murine chronic GVHD by expanding donor regulatory T cells. Blood. 2017; 129: 3121-3125. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28416503
  49. Sun W, Wang Y, East JE, Kimball AS, Tkaczuk K, et al. Invariant natural killer T cells generated from human adult hematopoietic stem-progenitor cells are poly-functional. Cytokine. 2015; 72: 48-57. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25569376
  50. Rettinger E, Huenecke S, Bonig H, Merker M, Jarisch A, et al. Interleukin-15-activated cytokine-induced killer cells may sustain remission in leukemia patients after allogeneic stem cell transplantation: feasibility, safety and first insights on efficacy. Haematologica. 2016; 101: e153-6. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004389/
  51. Russo A, Oliveira G, Berglund S, Greco R, Gambacorta V, et al. NK cell recovery after haploidentical HSCT with posttransplant cyclophosphamide: dynamics and clinical implications. Blood. 2018; 131(2): 247-262. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28986344
  52. Gill S, Olson JA, Negrin RS. Natural killer cells in allogeneic transplantation: effect on engraftment, graft- versus-tumor, and graft-versus-host responses. Biol Blood Marrow Transplant. 2009; 15: 765-776. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19539207
  53. Herrera L, Salcedo JM, Santos S, Vesga MÁ, Borrego F, et al. OP9 feeder cells are superior to M2-10B4 cells for the generation of mature and functional natural killer cells from umbilical cord hematopoietic progenitors. Front Immunol. 2017; 8: 755. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28713379
  54. Bassani B, Baci D, Gallazzi M, Poggi A, Bruno A, et al. Natural killer cells as key players of tumor progression and angiogenesis: old and novel tools to divert their pro-tumor activities into otent anti-tumor effects. Cancers (Basel) 2019; 11(4). pii: E461. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30939820
  55. Veluchamy JP, Kok N, van der Vliet HJ, Verheul HMW, de Gruijl TD, et al. The rise of allogeneic natural killer cells as a platform for cancer immunotherapy: recent innovations and future developments. Front Immunol. 2017; 8: 631. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28620386
  56. Hu W, Wang G, Huang D, Sui M, Xu Y. Cancer immunotherapy based on natural killer cells: current progress and new opportunities. Front Immunol. 2019; 10: 1205. PubMed: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6554437/
  57. Liu LL, Béziat V, Oei VYS, Pfefferle A, Schaffer M, et al. Ex vivo expanded adaptive NK cells effectively kill primary acute lymphoblastic leukemia cells. Cancer Immunol Res. 2017; 5: 654-665. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28637877
  58. MacFarlane AW, Jillab M, Smith MR, Katherine Alpaugh R, Cole ME, et al. Natural killer cell dysfunction in chronic lymphocytic leukemia is associated with loss of the mature KIR3DL1+ subset. Blood. 2014; 124: 3318.
  59. Chen CI, Koschmieder S, Kerstiens L, Schemionek M, Altvater B, et al. NK cells are dysfunctional in human chronic myelogenous leukemia before and on imatinib treatment and in BCR-ABL-positive mice. Leukemia. 2012; 26(3): 465-474. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21904381
  60. Chiu J, Ernst DM, Keating A. Acquired natural killer cell dysfunction in the tumor microenvironment of classic Hodgkin lymphoma. Front Immunol. 2018; 9: 267. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29491867
  61. Kohrt HE, Thielens A, Marabelle A, Sagiv-Barfi I, Sola C, 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(5): 678-686. PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24326534