Challenges of NK cell-based immunotherapy in the new era

Abstract

Natural killer cells (NKs) have a great potential for cancer immunotherapy because they can rapidly and directly kill transformed cells in the absence of antigen presensitization. Various cellular sources, including peripheral blood mononuclear cells (PBMCs), stem cells, and NK cell lines, have been used for producing NK cells. In particular, NK cells that expanded from allogeneic PBMCs exhibit better efficacy than those that did not. However, considering the safety, activities, and reliability of the cell products, researchers must develop an optimal protocol for producing NK cells from PBMCs in the manufacture setting and clinical therapeutic regimen. In this review, the challenges on NK cell-based therapeutic approaches and clinical outcomes are discussed.

Keywords

natural killer cells / immunotherapy / adoptive transfer / genetic modification / immune checkpoint inhibitor

References

[1] Herberman RB, Nunn ME, Lavrin DH. Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic acid allogeneic tumors. I. Distribution of reactivity and specificity. Int J Cancer 1975; 16(2): 216–229

[2] Kiessling R, Klein E, Pross H, Wigzell H. “Natural” killer cells in the mouse. II. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Characteristics of the killer cell. Eur J Immunol 1975; 5(2): 117–121

[3] Béziat V, Hilton HG, Norman PJ, Traherne JA. Deciphering the killer-cell immunoglobulin-like receptor system at super-resolution for natural killer and T-cell biology. Immunology 2017; 150(3): 248–264

[4] Martinet L, Smyth MJ. Balancing natural killer cell activation through paired receptors. Nat Rev Immunol 2015; 15(4): 243–254

[5] 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

[6] He Y, Tian Z. NK cell education via nonclassical MHC and non-MHC ligands. Cell Mol Immunol 2017; 14(4): 321–330

[7] Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S. Functions of natural killer cells. Nat Immunol 2008; 9(5): 503–510

[8] Liu Y, Zheng J, Liu Y, Wen L, Huang L, Xiang Z, Lam KT, Lv A, Mao H, Lau YL, Tu W. Uncompromised NK cell activation is essential for virus-specific CTL activity during acute influenza virus infection. Cell Mol Immunol 2017;14: 1–11

[9] Sun JC, Lanier LL. NK cell development, homeostasis and function: parallels with CD8⁺ T cells. Nat Rev Immunol 2011; 11(10): 645–657

[10] Nair S, Dhodapkar MV. Natural killer T cells in cancer immunotherapy. Front Immunol 2017; 8: 1178

[11] Shissler SC, Bollino DR, Tiper IV, Bates JP, Derakhshandeh R, Webb TJ. Immunotherapeutic strategies targeting natural killer T cell responses in cancer. Immunogenetics 2016; 68(8): 623–638

[12] Davis ZB, Felices M, Verneris MR, Miller JS. Natural killer cell adoptive transfer therapy: exploiting the first line of defense against cancer. Cancer J 2015; 21(6): 486–491

[13] Zhang QF, Yin WW, Xia Y, Yi YY, He QF, Wang X, Ren H, Zhang DZ. Liver-infiltrating CD11b^-CD27⁻ NK subsets account for NK-cell dysfunction in patients with hepatocellular carcinoma and are associated with tumor progression. Cell Mol Immunol 2017; 14(10): 819–829

[14] Krneta T, Gillgrass A, Chew M, Ashkar AA. The breast tumor microenvironment alters the phenotype and function of natural killer cells. Cell Mol Immunol 2016; 13(5): 628–639

[15] Lim O, Jung MY, Hwang YK, Shin EC. Present and future of allogeneic natural killer cell therapy. Front Immunol 2015; 6: 286

[16] Morvan M, David G, Sébille V, Perrin A, Gagne K, Willem C, Kerdudou N, Denis L, Clémenceau B, Folléa G, Bignon JD, Retière C. Autologous and allogeneic HLA KIR ligand environments and activating KIR control KIR NK-cell functions. Eur J Immunol 2008; 38(12): 3474–3486

[17] Wang W, Erbe AK, DeSantes KB, Sondel PM. Donor selection for ex vivo-expanded natural killer cells as adoptive cancer immunotherapy. Future Oncol 2017; 13(12): 1043–1047

[18] Koehl U, Kalberer C, Spanholtz J, Lee DA, Miller JS, Cooley S, Lowdell M, Uharek L, Klingemann H, Curti A, Leung W, Alici E. Advances in clinical NK cell studies: donor selection, manufacturing and quality control. OncoImmunology 2016; 5(4): e1115178

[19] Deng X, Terunuma H, Nieda M, Xiao W, Nicol A. Synergistic cytotoxicity of ex vivo expanded natural killer cells in combination with monoclonal antibody drugs against cancer cells. Int Immunopharmacol 2012; 14(4): 593–605

[20] Li X, He C, Liu C, Ma J, Ma P, Cui H, Tao H, Gao B. Expansion of NK cells from PBMCs using immobilized 4-1BBL and interleukin-21. Int J Oncol 2015; 47(1): 335–342

[21] Denman CJ, Senyukov VV, Somanchi SS, Phatarpekar PV, Kopp LM, Johnson JL, Singh H, Hurton L, Maiti SN, Huls MH, Champlin RE, Cooper LJ, Lee DA. Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. PLoS One 2012; 7(1): e30264

[22] Garg TK, Szmania SM, Khan JA, Hoering A, Malbrough PA, Moreno-Bost A, Greenway AD, Lingo JD, Li X, Yaccoby S, Suva LJ, Storrie B, Tricot G, Campana D, Shaughnessy JD Jr, Nair BP, Bellamy WT, Epstein J, Barlogie B, van Rhee F. Highly activated and expanded natural killer cells for multiple myeloma immunotherapy. Haematologica 2012; 97(9): 1348–1356

[23] Schmidt-Wolf IGH, Lefterova P, Johnston V, Huhn D, Blume KG, Negrin RS. Propagation of large numbers of T cells with natural killer cell markers. Br J Haematol 1994; 87(3): 453–458

[24] Schmidt-Wolf GD, Negrin RS, Schmidt-Wolf IG. Activated T cells and cytokine-induced CD3⁺CD56⁺ killer cells. Ann Hematol 1997; 74(2): 51–56

[25] Granzin M, Wagner J, Köhl U, Cerwenka A, Huppert V, Ullrich E. Shaping of natural killer cell antitumor activity by ex vivo cultivation. Front Immunol 2017; 8: 458

[26] Chabannon C, Mfarrej B, Guia S, Ugolini S, Devillier R, Blaise D, Vivier E, Calmels B. Manufacturing natural killer cells as medicinal products. Front Immunol 2016; 7: 504

[27] Bollino D, Webb TJ. Chimeric antigen receptor-engineered natural killer and natural killer T cells for cancer immunotherapy. Transl Res 2017; 187: 32–43

[28] Song X, Hong SH, Kwon WT, Bailey LM, Basse P, Bartlett DL, Kwon YT, Lee YJ. Secretory trail-armed natural killer cell-based therapy: in vitro and in vivo colorectal peritoneal carcinomatosis xenograft. Mol Cancer Ther 2016; 15(7): 1591–1601

[29] Piscopo NJ, Mueller KP, Das A, Hematti P, Murphy WL, Palecek SP, Capitini CM, Saha K. Bioengineering solutions for manufacturing challenges in CAR T cells. Biotechnol J 2018; 13(2): 1700095

[30] Hartmann J, Schüßler-Lenz M, Bondanza A, Buchholz CJ. Clinical development of CAR T cells-challenges and opportunities in translating innovative treatment concepts. EMBO Mol Med 2017; 9(9): 1183–1197

[31] Ritchie DS, Neeson PJ, Khot A, Peinert S, Tai T, Tainton K, Chen K, Shin M, Wall DM, Hönemann D, Gambell P, Westerman DA, Haurat J, Westwood JA, Scott AM, Kravets L, Dickinson M, Trapani JA, Smyth MJ, Darcy PK, Kershaw MH, Prince HM. Persistence and efficacy of second generation CAR T cell against the LeY antigen in acute myeloid leukemia. Mol Ther 2013; 21(11): 2122–2129

[32] Casucci M, Perna SK, Falcone L, Camisa B, Magnani Z, Bernardi M, Crotta A, Tresoldi C, Fleischhauer K, Ponzoni M, Gregori S, Caligaris Cappio F, Ciceri F, Bordignon C, Cignetti A, Bondanza A, Bonini C. Graft-versus-leukemia effect of HLA-haploidentical central-memory T-cells expanded with leukemic APCs and modified with a suicide gene. Mol Ther 2013; 21(2): 466–475

[33] Leboeuf C, Mailly L, Wu T, Bour G, Durand S, Brignon N, Ferrand C, Borg C, Tiberghien P, Thimme R, Pessaux P, Marescaux J, Baumert TF, Robinet E. In vivo proof of concept of adoptive immunotherapy for hepatocellular carcinoma using allogeneic suicide gene-modified killer cells. Mol Ther 2014; 22(3): 634–644

[34] Kailayangiri S, Altvater B, Spurny C, Jamitzky S, Schelhaas S, Jacobs AH, Wiek C, Roellecke K, Hanenberg H, Hartmann W, Wiendl H, Pankratz S, Meltzer J, Farwick N, Greune L, Fluegge M, Rossig C. Targeting Ewing sarcoma with activated and GD2-specific chimeric antigen receptor-engineered human NK cells induces upregulation of immune-inhibitory HLA-G. OncoImmunology 2017; 6(1): e1250050

[35] Hu Y, Tian ZG, Zhang C. Chimeric antigen receptor (CAR)-transduced natural killer cells in tumor immunotherapy. Acta Pharmacol Sin 2018; 39(2): 167–176

[36] Xu-Monette ZY, Zhang M, Li J, Young KH. PD-1/PD-L1 blockade: have we found the key to unleash the antitumor immune response? Front Immunol 2017; 8: 1597

[37] Bengsch F, Knoblock DM, Liu A, McAllister F, Beatty GL. CTLA-4/CD80 pathway regulates T cell infiltration into pancreatic cancer. Cancer Immunol Immunother 2017; 66(12): 1609–1617

[38] Li Y, Li D, Du M. TIM-3: a crucial regulator of NK cells in pregnancy. Cell Mol Immunol 2017; 14:948–950

[39] Felices M, Miller JS. Targeting KIR blockade in multiple myeloma: trouble in checkpoint paradise? Clin Cancer Res 2016; 22(21): 5161–5163

[40] Guillerey C, Huntington ND, Smyth MJ. Targeting natural killer cells in cancer immunotherapy. Nat Immunol 2016; 17(9): 1025–1036

[41] McWilliams EM, Mele JM, Cheney C, Timmerman EA, Fiazuddin F, Strattan EJ, Mo X, Byrd JC, Muthusamy N, Awan FT. Therapeutic CD94/NKG2A blockade improves natural killer cell dysfunction in chronic lymphocytic leukemia. OncoImmunology 2016; 5(10): e1226720

[42] Gallois A, Silva I, Osman I, Bhardwaj N. Reversal of natural killer cell exhaustion by TIM-3 blockade. OncoImmunology 2015; 3(12): e946365

[43] Vego H, Sand KL, Høglund RA, Fallang LE, Gundersen G, Holmøy T, Maghazachi AA. Monomethyl fumarate augments NK cell lysis of tumor cells through degranulation and the upregulation of NKp46 and CD107a. Cell Mol Immunol 2016; 13(1): 57–64

[44] Floros T, Tarhini AA. Anticancer cytokines: biology and clinical effects of interferon-α2, interleukin (IL)-2, IL-15, IL-21, and IL-12. Semin Oncol 2015; 42(4): 539–548

[45] Nielsen CM, Wolf AS, Goodier MR, Riley EM. Synergy between common g chain family cytokines and IL-18 potentiates innate and adaptive pathways of NK cell activation. Front Immunol 2016; 7: 101

[46] Srivastava S, Pelloso D, Feng H, Voiles L, Lewis D, Haskova Z, Whitacre M, Trulli S, Chen YJ, Toso J, Jonak ZL, Chang HC, Robertson MJ. Effects of interleukin-18 on natural killer cells: costimulation of activation through Fc receptors for immunoglobulin. Cancer Immunol Immunother 2013; 62(6): 1073–1082

[47] Terme M, Ullrich E, Aymeric L, Meinhardt K, Coudert JD, Desbois M, Ghiringhelli F, Viaud S, Ryffel B, Yagita H, Chen L, Mécheri S, Kaplanski G, Prévost-Blondel A, Kato M, Schultze JL, Tartour E, Kroemer G, Degli-Esposti M, Chaput N, Zitvogel L. Cancer-induced immunosuppression: IL-18-elicited immunoablative NK cells. Cancer Res 2012; 72(11): 2757–2767

[48] Wu D, Wu P, Qiu F, Wei Q, Huang J. Human gdT-cell subsets and their involvement in tumor immunity. Cell Mol Immunol 2017; 14(3): 245–253

[49] 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

[50] Liu J, Cao X. Cellular and molecular regulation of innate inflammatory responses. Cell Mol Immunol 2016; 13(6): 711–721

[51] Mittica G, Capellero S, Genta S, Cagnazzo C, Aglietta M, Sangiolo D, Valabrega G. Adoptive immunotherapy against ovarian cancer. J Ovarian Res 2016; 9(1): 30

[52] Martín-Antonio B, Suñe G, Perez-Amill L, Castella M, Urbano-Ispizua A. Natural killer cells: angels and devils for immunotherapy. Int J Mol Sci 2017; 18(9): E1868

[53] Fang F, Xiao W, Tian Z. NK cell-based immunotherapy for cancer. Semin Immunol 2017; 31: 37–54

[54] Veluchamy JP, Kok N, van der Vliet HJ, Verheul HMW, de Gruijl TD, Spanholtz J. The rise of allogeneic natural killer cells as a platform for cancer immunotherapy: recent innovations and future developments. Front Immunol 2017; 8: 631

[55] Bachanova V, Burns LJ, McKenna DH, Curtsinger J, Panoskaltsis-Mortari A, Lindgren BR, Cooley S, Weisdorf D, Miller JS. Allogeneic natural killer cells for refractory lymphoma. Cancer Immunol Immunother 2010; 59(11): 1739–1744

[56] Hofer E, Koehl U. Natural Killer cell-based cancer immunotherapies: from immune evasion to promising targeted cellular therapies. Front Immunol 2017; 8: 745

[57] Pegram HJ, Haynes NM, Smyth MJ, Kershaw MH, Darcy PK. Characterizing the anti-tumor function of adoptively transferred NK cells in vivo. Cancer Immunol Immunother 2010; 59(8): 1235–1246

[58] Romee R, Rosario M, Berrien-Elliott MM, Wagner JA, Jewell BA, Schappe T, Leong JW, Abdel-Latif S, Schneider SE, Willey S, Neal CC, Yu L, Oh ST, Lee YS, Mulder A, Claas F, Cooper MA, Fehniger TA. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. Sci Transl Med 2016; 8(357): 357ra123

[59] Knorr DA, Bachanova V, Verneris MR, Miller JS. Clinical utility of natural killer cells in cancer therapy and transplantation. Semin Immunol 2014; 26(2): 161–172

[60] Dahlberg CI, Sarhan D, Chrobok M, Duru AD, Alici E. Natural killer cell-based therapies targeting cancer: possible strategies to gain and sustain anti-tumor activity. Front Immunol 2015; 6: 605

[61] Cheng M, Chen Y, Xiao W, Sun R, Tian Z. NK cell-based immunotherapy for malignant diseases. Cell Mol Immunol 2013; 10(3): 230–252

[62] Dolstra H, Roeven MWH, Spanholtz J, Hangalapura BN, Tordoir M, Maas F, Leenders M, Bohme F, Kok N, Trilsbeek C, Paardekooper J, van der Waart AB, Westerweel PE, Snijders TJF, Cornelissen JJ, Bos GMJ, Pruijt HFM, De Graaf AO, van der Reijden B, Jansen JH, van der Meer A, Huls G, Cany J, Preijers F, Blijlevens NMA, Schaap NM. 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):4107–4118

[63] Rubnitz JE, Inaba H, Ribeiro RC, Pounds S, Rooney B, Bell T, Pui CH, Leung W. 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): 955–959

[64] Curti A, Ruggeri L, D’Addio A, Bontadini A, Dan E, Motta MR, Trabanelli S, Giudice V, Urbani E, Martinelli G, Paolini S, Fruet F, Isidori A, Parisi S, Bandini G, Baccarani M, Velardi A, Lemoli RM. Successful transfer of alloreactive haploidentical KIR ligand-mismatched natural killer cells after infusion in elderly high risk acute myeloid leukemia patients. Blood 2011; 118(12): 3273–3279

[65] Klingemann H, Grodman C, Cutler E, Duque M, Kadidlo D, Klein AK, Sprague KA, Miller KB, Comenzo RL, Kewalramani T, Yu N, Van Etten RA, McKenna DH. Autologous stem cell transplant recipients tolerate haploidentical related-donor natural killer cell-enriched infusions. Transfusion 2013; 53(2): 412–418, quiz 411

[66] Kottaridis PD, North J, Tsirogianni M, Marden C, Samuel ER, Jide-Banwo S, Grace S, Lowdell MW. Two-stage priming of allogeneic natural killer cells for the treatment of patients with acute myeloid leukemia: a phase I trial. PLoS One 2015; 10(6): e0123416

[67] Bachanova V, Cooley S, Defor TE, Verneris MR, Zhang B, McKenna DH, Curtsinger J, Panoskaltsis-Mortari A, Lewis D, Hippen K, McGlave P, Weisdorf DJ, Blazar BR, Miller JS. Clearance of acute myeloid leukemia by haploidentical natural killer cells is improved using IL-2 diphtheria toxin fusion protein. Blood 2014; 123(25): 3855–3863

[68] Ciurea SO, Schafer JR, Bassett R, Denman CJ, Cao K, Willis D, Rondon G, Chen J, Soebbing D, Kaur I, Gulbis A, Ahmed S, Rezvani K, Shpall EJ, Lee DA, Champlin RE. Phase 1 clinical trial using mbIL21 ex vivo-expanded donor-derived NK cells after haploidentical transplantation. Blood 2017; 130(16): 1857–1868

[69] Choi I, Yoon SR, Park SY, Kim H, Jung SJ, Jang YJ, Kang M, Yeom YI, Lee JL, Kim DY, Lee YS, Kang YA, Jeon M, Seol M, Lee JH, Lee JH, Kim HJ, Yun SC, Lee KH. Donor-derived natural killer cells infused after human leukocyte antigen-haploidentical hematopoietic cell transplantation: a dose-escalation study. Biol Blood Marrow Transplant 2014; 20(5): 696–704

[70] Killig M, Friedrichs B, Meisig J, Gentilini C, Blüthgen N, Loddenkemper C, Labopin M, Basara N, Pfrepper C, Niederwieser DW, Uharek L, Romagnani C. Tracking in vivo dynamics of NK cells transferred in patients undergoing stem cell transplantation. Eur J Immunol 2014; 44(9): 2822–2834

[71] Shah N, Li L, McCarty J, Kaur I, Yvon E, Shaim H, Muftuoglu M, Liu E, Orlowski RZ, Cooper L, Lee D, Parmar S, Cao K, Sobieiski C, Saliba R, Hosing C, Ahmed S, Nieto Y, Bashir Q, Patel K, Bollard C, Qazilbash M, Champlin R, Rezvani K, Shpall EJ. 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): 457–466

[72] Passweg JR, Tichelli A, Meyer-Monard S, Heim D, Stern M, Kühne T, Favre G, Gratwohl A. Purified donor NK-lymphocyte infusion to consolidate engraftment after haploidentical stem cell transplantation. Leukemia 2004; 18(11): 1835–1838

[73] Yoon SR, Lee YS, Yang SH, Ahn KH, Lee JH, Lee JH, Kim DY, Kang YA, Jeon M, Seol M, Ryu SG, Chung JW, Choi I, Lee KH. Generation of donor natural killer cells from CD34(+) progenitor cells and subsequent infusion after HLA-mismatched allogeneic hematopoietic cell transplantation: a feasibility study. Bone Marrow Transplant 2010; 45(6): 1038–1046

[74] Rizzieri DA, Storms R, Chen DF, Long G, Yang Y, Nikcevich DA, Gasparetto C, Horwitz M, Chute J, Sullivan K, Hennig T, Misra D, Apple C, Baker M, Morris A, Green PG, Hasselblad V, Chao NJ. Natural killer cell-enriched donor lymphocyte infusions from A 3-6/6 HLA matched family member following nonmyeloablative allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2010; 16(8): 1107–1114

[75] Schmeel LC, Schmeel FC, Coch C, Schmidt-Wolf IG. Cytokine-induced killer (CIK) cells in cancer immunotherapy: report of the international registry on CIK cells (IRCC). J Cancer Res Clin Oncol 2015; 141(5): 839–849

[76] Hölsken O, Miller M, Cerwenka A. Exploiting natural killer cells for therapy of melanoma. J Dtsch Dermatol Ges 2015; 13(1): 23–29

[77] Braumüller H, Wieder T, Brenner E, Aßmann S, Hahn M, Alkhaled M, Schilbach K, Essmann F, Kneilling M, Griessinger C, Ranta F, Ullrich S, Mocikat R, Braungart K, Mehra T, Fehrenbacher B, Berdel J, Niessner H, Meier F, van den Broek M, Häring HU, Handgretinger R, Quintanilla-Martinez L, Fend F, Pesic M, Bauer J, Zender L, Schaller M, Schulze-Osthoff K, Röcken M. T-helper-1-cell cytokines drive cancer into senescence. Nature 2013; 494(7437): 361–365

[78] Geller MA, Cooley S, Judson PL, Ghebre R, Carson LF, Argenta PA, Jonson AL, Panoskaltsis-Mortari A, Curtsinger J, McKenna D, Dusenbery K, Bliss R, Downs LS, Miller JS. A phase II study of allogeneic natural killer cell therapy to treat patients with recurrent ovarian and breast cancer. Cytotherapy 2011; 13(1): 98–107

[79] Iliopoulou EG, Kountourakis P, Karamouzis MV, Doufexis D, Ardavanis A, Baxevanis CN, Rigatos G, Papamichail M, Perez SA. A phase I trial of adoptive transfer of allogeneic natural killer cells in patients with advanced non-small cell lung cancer. Cancer Immunol Immunother 2010; 59(12): 1781–1789

[80] Yang Y, Lim O, Kim TM, Ahn YO, Choi H, Chung H, Min B, Her JH, Cho SY, Keam B, Lee SH, Kim DW, Hwang YK, Heo DS. Phase I study of random healthy donor-derived allogeneic natural killer cell therapy in patients with malignant lymphoma or advanced solid tumors. Cancer Immunol Res 2016; 4(3): 215–224

[81] Tonn T, Schwabe D, Klingemann HG, Becker S, Esser R, Koehl U, Suttorp M, Seifried E, Ottmann OG, Bug G. Treatment of patients with advanced cancer with the natural killer cell line NK-92. Cytotherapy 2013; 15(12): 1563–1570

[82] Miller JS, Soignier Y, Panoskaltsis-Mortari A, McNearney SA, Yun GH, Fautsch SK, McKenna D, Le C, Defor TE, Burns LJ, Orchard PJ, Blazar BR, Wagner JE, Slungaard A, Weisdorf DJ, Okazaki IJ, McGlave PB. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood 2005; 105(8): 3051–3057

[83] Sadozai H, Gruber T, Hunger RE, Schenk M. Recent successes and future directions in immunotherapy of cutaneous melanoma. Front Immunol 2017; 8: 1617

[84] Overacre-Delgoffe AE, Chikina M, Dadey RE, Yano H, Brunazzi EA, Shayan G, Horne W, Moskovitz JM, Kolls JK, Sander C, Shuai Y, Normolle DP, Kirkwood JM, Ferris RL, Delgoffe GM, Bruno TC, Workman CJ, Vignali DAA. Interferon-g drives T_reg fragility to promote anti-tumor immunity. Cell 2017; 169(6): 1130–1141.e11

[85] Tallerico R, Garofalo C, Carbone E. A new biological feature of natural killer cells: the recognition of solid tumor-derived cancer stem cells. Front Immunol 2016; 7: 179

[86] Langers I, Renoux VM, Thiry M, Delvenne P, Jacobs N. Natural killer cells: role in local tumor growth and metastasis. Biologics 2012; 6: 73–82

[87] Krasnova Y, Putz EM, Smyth MJ, Souza-Fonseca-Guimaraes F. Bench to bedside: NK cells and control of metastasis. Clin Immunol 2017; 177: 50–59

[88] Ames E, Canter RJ, Grossenbacher SK, Mac S, Smith RC, Monjazeb AM, Chen M, Murphy WJ. Enhanced targeting of stem-like solid tumor cells with radiation and natural killer cells. OncoImmunology 2015; 4(9): e1036212

[89] Specht HM, Ahrens N, Blankenstein C, Duell T, Fietkau R, Gaipl US, Günther C, Gunther S, Habl G, Hautmann H, Hautmann M, Huber RM, Molls M, Offner R, Rödel C, Rödel F, Schütz M, Combs SE, Multhoff G. Heat shock protein 70 (Hsp70) peptide activated natural killer (NK) cells for the treatment of patients with non-small cell lung cancer (NSCLC) after radiochemotherapy (RCTx) — from preclinical studies to a clinical phase II trial. Front Immunol 2015; 6: 162

[90] Suck G, Linn YC, Tonn T. Natural killer cells for therapy of leukemia. Transfus Med Hemother 2016; 43(2): 89–95

[91] Li L, Li W, Wang C, Yan X, Wang Y, Niu C, Zhang X, Li M, Tian H, Yao C, Jin H, Han F, Xu D, Han W, Li D, Cui J. Adoptive transfer of natural killer cells in combination with chemotherapy improves outcomes of patients with locally advanced colon carcinoma. Cytotherapy 2018; 20(1): 134–148

[92] Fine JH, Chen P, Mesci A, Allan DSJ, Gasser S, Raulet DH, Carlyle JR. Chemotherapy-induced genotoxic stress promotes sensitivity to natural killer cell cytotoxicity by enabling missing-self recognition. Cancer Res 2010; 70(18): 7102–7113

[93] Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, Royal RE, Kammula U, White DE, Mavroukakis SA, Rogers LJ, Gracia GJ, Jones SA, Mangiameli DP, Pelletier MM, Gea-Banacloche J, Robinson MR, Berman DM, Filie AC, Abati A, Rosenberg SA. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol 2005; 23(10): 2346–2357

[94] Federico SM, McCarville MB, Shulkin BL, Sondel PM, Hank JA, Hutson P, Meagher M, Shafer A, Ng CY, Leung W, Janssen WE, Wu J, Mao S, Brennan RC, Santana VM, Pappo AS, Furman WL. A pilot trial of humanized anti-GD2 monoclonal antibody (hu14.18K322A) with chemotherapy and natural killer cells in children with recurrent/refractory neuroblastoma. Clin Cancer Res 2017; 23(21): 6441–6449

[95] Benson DM Jr, Hofmeister CC, Padmanabhan S, Suvannasankha A, Jagannath S, Abonour R, Bakan C, Andre P, Efebera Y, Tiollier J, Caligiuri MA, Farag SS. A phase 1 trial of the anti-KIR antibody IPH2101 in patients with relapsed/refractory multiple myeloma. Blood 2012; 120(22): 4324–4333

[96] Sanmamed MF, Pastor F, Rodriguez A, Perez-Gracia JL, Rodriguez-Ruiz ME, Jure-Kunkel M, Melero I. Agonists of co-stimulation in cancer immunotherapy directed against CD137, OX40, GITR, CD27, CD28, and ICOS. Semin Oncol 2015; 42(4): 640–655

[97] Anderson AC, Joller N, Kuchroo VK. Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity 2016; 44(5): 989–1004

[98] Vallera DA, Felice M, McElmurry R, McCullar V, Zhou X, Schmohl JU, Zhang B, Lenvik AJ, Panoskaltsis-Mortari A, Verneris MR, Tolar J, Cooley S, Weisdorf DJ, Blazar BR, Miller JS. IL15 Trispecific killer engagers (TriKE) make natural killer cells specific to CD33⁺ targets while also inducing persistence, in vivo expansion, and enhanced function. Clin Cancer Res 2016; 22(14):3440–3450

[99] Chen S, Li J, Li Q, Wang Z. Bispecific antibodies in cancer immunotherapy. Hum Vaccin Immunother 2016; 12(10): 2491–2500

[100] Liu D, Tian S, Zhang K, Xiong W, Lubaki NM, Chen Z, Han W. Chimeric antigen receptor (CAR)-modified natural killer cell-based immunotherapy and immunological synapse formation in cancer and HIV. Protein Cell 2017; 8(12): 861–877

[101] Carlsten M, Childs RW. Genetic manipulation of NK cells for cancer immunotherapy: techniques and clinical implications. Front Immunol 2015; 6: 266

[102] Sutlu T, Nyström S, Gilljam M, Stellan B, Applequist SE, Alici E. Inhibition of intracellular antiviral defense mechanisms augments lentiviral transduction of human natural killer cells: implications for gene therapy. Hum Gene Ther 2012; 23(10): 1090–1100

[103] Boyiadzis M, Agha M, Redner RL, Sehgal A, Im A, Hou JZ, Farah R, Dorritie KA, Raptis A, Lim SH, Wang H, Lapteva N, Mei Z, Butterfield LH, Rooney CM, Whiteside TL. 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): 1225–1232

[104] Ayello J, Hochberg J, Flower A, Chu Y, Baxi LV, Quish W, van de Ven C, Cairo MS. Genetically re-engineered K562 cells significantly expand and functionally activate cord blood natural killer cells: potential for adoptive cellular immunotherapy. Exp Hematol 2017; 46: 38–47

[105] Shah N, Martin-Antonio B, Yang H, Ku S, Lee DA, Cooper LJ, Decker WK, Li S, Robinson SN, Sekine T, Parmar S, Gribben J, Wang M, Rezvani K, Yvon E, Najjar A, Burks J, Kaur I, Champlin RE, Bollard CM, Shpall EJ. Antigen presenting cell-mediated expansion of human umbilical cord blood yields log-scale expansion of natural killer cells with anti-myeloma activity. PLoS One 2013; 8(10): e76781

[106] Cany J, van der Waart AB, Tordoir M, Franssen GM, Hangalapura BN, de Vries J, Boerman O, Schaap N, van der Voort R, Spanholtz J, Dolstra H. Natural killer cells generated from cord blood hematopoietic progenitor cells efficiently target bone marrow-residing human leukemia cells in NOD/SCID/IL2Rg(null) mice. PLoS One 2013; 8(6): e64384

[107] Knorr DA, Ni Z, Hermanson D, Hexum MK, Bendzick L, Cooper LJN, Lee DA, Kaufman DS. Clinical-scale derivation of natural killer cells from human pluripotent stem cells for cancer therapy. Stem Cells Transl Med 2013; 2(4): 274–283

[108] Hermanson DL, Bendzick L, Pribyl L, McCullar V, Vogel RI, Miller JS, Geller MA, Kaufman DS. Induced pluripotent stem cell-derived natural killer cells for treatment of ovarian cancer. Stem Cells 2016; 34(1): 93–101

[109] Veluchamy JP, Heeren AM, Spanholtz J, van Eendenburg JDH, Heideman DAM, Kenter GG, Verheul HM, van der Vliet HJ, Jordanova ES, de Gruijl TD. High-efficiency lysis of cervical cancer by allogeneic NK cells derived from umbilical cord progenitors is independent of HLA status. Cancer Immunol Immunother 2017; 66(1): 51–61

[110] Spanholtz J, Preijers F, Tordoir M, Trilsbeek C, Paardekooper J, de Witte T, Schaap N, Dolstra H. Clinical-grade generation of active NK cells from cord blood hematopoietic progenitor cells for immunotherapy using a closed-system culture process. PLoS One 2011; 6(6): e20740

[111] Tanaka J, Sugita J, Shiratori S, Shigematu A, Asanuma S, Fujimoto K, Nishio M, Kondo T, Imamura M. Expansion of NK cells from cord blood with antileukemic activity using GMP-compliant substances without feeder cells. Leukemia 2012; 26(5): 1149–1152

[112] Boerman GH, van Ostaijen-ten Dam MM, Kraal KCJM, Santos SJ, Ball LM, Lankester AC, Schilham MW, Egeler RM, van Tol MJD. Role of NKG2D, DNAM-1 and natural cytotoxicity receptors in cytotoxicity toward rhabdomyosarcoma cell lines mediated by resting and IL-15-activated human natural killer cells. Cancer Immunol Immunother 2015; 64(5): 573–583

[113] van Ostaijen-ten Dam MM, Prins HJ, Boerman GH, Vervat C, Pende D, Putter H, Lankester A, van Tol MJD, Zwaginga JJ, Schilham MW. Preparation of cytokine-activated NK cells for use in adoptive cell therapy in cancer patients: protocol optimization and therapeutic potential. J Immunother 2016; 39(2): 90–100

[114] Wendt K, Wilk E, Buyny S, Schmidt RE, Jacobs R. Interleukin-21 differentially affects human natural killer cell subsets. Immunology 2007; 122(4): 486–495

[115] Koehl U, Sörensen J, Esser R, Zimmermann S, Grüttner HP, Tonn T, Seidl C, Seifried E, Klingebiel T, Schwabe D. IL-2 activated NK cell immunotherapy of three children after haploidentical stem cell transplantation. Blood Cells Mol Dis 2004; 33(3): 261–266

[116] Torelli GF, Rozera C, Santodonato L, Peragine N, D’agostino G, Montefiore E, Napolitano MR, Monque DM, Carlei D, Mariglia P, Pauselli S, Gozzer M, Bafti MS, Girelli G, Guarini A, Belardelli F, Foà R. A good manufacturing practice method to ex vivo expand natural killer cells for clinical use. Blood Transfus 2015; 13(3): 464–471

[117] Granzin M, Stojanovic A, Miller M, Childs R, Huppert V, Cerwenka A. Highly efficient IL-21 and feeder cell-driven ex vivo expansion of human NK cells with therapeutic activity in a xenograft mouse model of melanoma. OncoImmunology 2016; 5(9): e1219007

[118] Kim EK, Ahn YO, Kim S, Kim TM, Keam B, Heo DS .Ex vivo activation and expansion of natural killer cells from patients with advanced cancer with feeder cells from healthy volunteers. Cytotherapy 2013; 15(2): 231–241.e1

[119] Zhang H, Cui Y, Voong N, Sabatino M, Stroncek DF, Morisot S, Civin CI, Wayne AS, Levine BL, Mackall CL. Activating signals dominate inhibitory signals in CD137L/IL-15 activated natural killer cells. J Immunother 2011; 34(2): 187–195

[120] Childs RW, Berg M. Bringing natural killer cells to the clinic: ex vivo manipulation. Hematology Am Soc Hematol Educ Program 2013; 2013: 234–246

[121] Oyer JL, Igarashi RY, Kulikowski AR, Colosimo DA, Solh MM, Zakari A, Khaled YA, Altomare DA, Copik AJ. Generation of highly cytotoxic natural killer cells for treatment of acute myelogenous leukemia using a feeder-free, particle-based approach. Biol Blood Marrow Transplant 2015; 21(4): 632–639

[122] Sakamoto N, Ishikawa T, Kokura S, Okayama T, Oka K, Ideno M, Sakai F, Kato A, Tanabe M, Enoki T, Mineno J, Naito Y, Itoh Y, Yoshikawa T. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. J Transl Med 2015; 13(1): 277

[123] Lapteva N, Durett AG, Sun J, Rollins LA, Huye LL, Fang J, Dandekar V, Mei Z, Jackson K, Vera J, Ando J, Ngo MC, Coustan-Smith E, Campana D, Szmania S, Garg T, Moreno-Bost A, Vanrhee F, Gee AP, Rooney CM. Large-scale ex vivo expansion and characterization of natural killer cells for clinical applications. Cytotherapy 2012; 14(9): 1131–1143

[124] Williams BA, Law AD, Routy B, denHollander N, Gupta V, Wang XH, Chaboureau A, Viswanathan S, Keating A. A phase I trial of NK-92 cells for refractory hematological malignancies relapsing after autologous hematopoietic cell transplantation shows safety and evidence of efficacy. Oncotarget 2017; 8(51): 89256 –89268

[125] Arai S, Meagher R, Swearingen M, Myint H, Rich E, Martinson J, Klingemann H. Infusion of the allogeneic cell line NK-92 in patients with advanced renal cell cancer or melanoma: a phase I trial. Cytotherapy 2008; 10(6): 625–632

[126] Shah N, Li L, McCarty J, Kaur I, Yvon E, Shaim H, Muftuoglu M, Liu E, Orlowski RZ, Cooper L, Lee D, Parmar S, Cao K, Sobieiski C, Saliba R, Hosing C, Ahmed S, Nieto Y, Bashir Q, Patel K, Bollard C, Qazilbash M, Champlin R, Rezvani K, Shpall EJ. 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): 457–466

[127] 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): 6287–6297

[128] Liang S, Xu K, Niu L, Wang X, Liang Y, Zhang M, Chen J, Lin M. Comparison of autogeneic and allogeneic natural killer cells immunotherapy on the clinical outcome of recurrent breast cancer. Onco Targets Ther 2017; 10: 4273–4281

[129] Leivas A, Perez-Martinez A, Blanchard MJ, Martín-Clavero E, Fernández L, Lahuerta JJ, Martinez-Lopez J. Novel treatment strategy with autologous activated and expanded natural killer cells plus anti-myeloma drugs for multiple myeloma. OncoImmunology 2016; 5(12): e1250051

[130] Szmania S, Lapteva N, Garg T, Greenway A, Lingo J, Nair B, Stone K, Woods E, Khan J, Stivers J, Panozzo S, Campana D, Bellamy WT, Robbins M, Epstein J, Yaccoby S, Waheed S, Gee A, Cottler-Fox M, Rooney C, Barlogie B, van Rhee F. Ex vivo-expanded natural killer cells demonstrate robust proliferation in vivo in high-risk relapsed multiple myeloma patients. J Immunother 2015; 38(1): 24–36

[131] Pérez-Martínez A, Fernández L, Valentín J, Martínez-Romera I, Corral MD, Ramírez M, Abad L, Santamaría S, González-Vicent M, Sirvent S, Sevilla J, Vicario JL, de Prada I, Diaz MA. A phase I/II trial of interleukin-15—stimulated natural killer cell infusion after haplo-identical stem cell transplantation for pediatric refractory solid tumors. Cytotherapy 2015; 17(11): 1594–1603

[132] Shaffer BC, Le Luduec JB, Forlenza C, Jakubowski AA, Perales MA, Young JW, Hsu KC. Phase II study of haploidentical natural killer cell infusion for treatment of relapsed or persistent myeloid malignancies following allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2016; 22(4): 705–709

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