Advertisement

Expanded and armed natural killer cells for cancer treatment

Published:August 03, 2016DOI:https://doi.org/10.1016/j.jcyt.2016.06.013

      Abstract

      The capacity of natural killer (NK) cells to recognize and kill transformed cells suggests that their infusion could be used to treat cancer. It is difficult to obtain large numbers of NK cells ex vivo by exposure to cytokines alone but the addition of stimulatory cells to the cultures can induce NK cell proliferation and long-term expansion. Some of these methods have been validated for clinical-grade application and support clinical trials testing feasibility and safety of NK cell administration. Early data indicate that ex vivo expansion of NK cells from healthy donors or from patients with cancer is robust, allowing multiple infusions from a single apheresis. NK cells can transiently expand in vivo after infusion. Allogeneic NK cells are not direct effectors of graft-versus-host disease but this may occur if donor NK cells are infused after allogeneic hematopoietic stem cell transplant, which may activate T cell alloreactivity. NK cells can be directed with antibodies, or engineered using either transient modification by electroporation of mRNA or prolonged gene expression by viral transduction. Thus, expanded NK cells can be armed with activating receptors that enhance their natural anti-tumor capacity or with chimeric antigen receptors that can redirect them towards specific tumor targets. They can also be induced to express cytokines that promote their autonomous growth, further supporting their in vivo expansion. With the implementation of these approaches, expanded and armed NK cells should ultimately become a powerful component of immunotherapy of cancer.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Cytotherapy
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Morvan M.G.
        • Lanier L.L.
        NK cells and cancer: you can teach innate cells new tricks.
        Nat Rev Cancer. 2015; 16: 7-19
        • Vivier E.
        • Raulet D.H.
        • Moretta A.
        • Caligiuri M.A.
        • Zitvogel L.
        • Lanier L.L.
        • et al.
        Innate or adaptive immunity? The example of natural killer cells.
        Science. 2011; 331: 44-49
        • Chang Y.H.
        • Connolly J.
        • Shimasaki N.
        • Mimura K.
        • Kono K.
        • Campana D.
        A chimeric receptor with NKG2D specificity enhances natural killer cell activation and killing of tumor cells.
        Cancer Res. 2013; 73: 1777-1786
        • Orange J.S.
        Formation and function of the lytic NK-cell immunological synapse.
        Nat Rev Immunol. 2008; 8: 713-725
        • Lanier L.L.
        Up on the tightrope: natural killer cell activation and inhibition.
        Nat Immunol. 2008; 9: 495-502
        • Martinet L.
        • Smyth M.J.
        Balancing natural killer cell activation through paired receptors.
        Nat Rev Immunol. 2015; 15: 243-254
        • Gasser S.
        • Raulet D.H.
        Activation and self-tolerance of natural killer cells.
        Immunol Rev. 2006; 214: 130-142
        • Ferris R.L.
        • Jaffee E.M.
        • Ferrone S.
        Tumor antigen-targeted, monoclonal antibody-based immunotherapy: clinical response, cellular immunity, and immunoescape.
        J Clin Oncol. 2010; 28: 4390-4399
        • Comans-Bitter W.M.
        • de Groot R.
        • van den Beemd R.
        • Neijens H.J.
        • Hop W.C.
        • Groeneveld K.
        • et al.
        Immunophenotyping of blood lymphocytes in childhood. Reference values for lymphocyte subpopulations.
        J Pediatr. 1997; 130: 388-393
        • Knorr D.A.
        • Bachanova V.
        • Verneris M.R.
        • Miller J.S.
        Clinical utility of natural killer cells in cancer therapy and transplantation.
        Semin Immunol. 2014; 26: 161-172
        • Kim S.
        • Poursine-Laurent J.
        • Truscott S.M.
        • Lybarger L.
        • Song Y.J.
        • Yang L.
        • et al.
        Licensing of natural killer cells by host major histocompatibility complex class I molecules.
        Nature. 2005; 436: 709-713
        • Fernandez N.C.
        • Treiner E.
        • Vance R.E.
        • Jamieson A.M.
        • Lemieux S.
        • Raulet D.H.
        A subset of natural killer cells achieves self-tolerance without expressing inhibitory receptors specific for self-MHC molecules.
        Blood. 2005; 105: 4416-4423
        • Raulet D.H.
        • Vance R.E.
        Self-tolerance of natural killer cells.
        Nat Rev Immunol. 2006; 6: 520-531
        • Elliott J.M.
        • Yokoyama W.M.
        Unifying concepts of MHC-dependent natural killer cell education.
        Trends Immunol. 2011; 32: 364-372
        • Cooley S.
        • Xiao F.
        • Pitt M.
        • Gleason M.
        • McCullar V.
        • Bergemann T.L.
        • et al.
        A subpopulation of human peripheral blood NK cells that lacks inhibitory receptors for self-MHC is developmentally immature.
        Blood. 2007; 110: 578-586
        • Imai C.
        • Iwamoto S.
        • Campana D.
        Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells.
        Blood. 2005; 106: 376-383
        • Wang W.
        • Erbe A.K.
        • Hank J.A.
        • Morris Z.S.
        • Sondel P.M.
        NK cell-mediated antibody-dependent cellular cytotoxicity in cancer immunotherapy.
        Front Immunol. 2015; 6: 368
        • Lanier L.L.
        • Le A.M.
        • Civin C.I.
        • Loken M.R.
        • Phillips J.H.
        The relationship of CD16 (Leu-11) and Leu-19 (NKH-1) antigen expression on human peripheral blood NK cells and cytotoxic T lymphocytes.
        J Immunol. 1986; 136: 4480-4486
        • Lanier L.L.
        • Testi R.
        • Bindl J.
        • Phillips J.H.
        Identity of Leu-19 (CD56) leukocyte differentiation antigen and neural cell adhesion molecule.
        J Exp Med. 1989; 169: 2233-2238
        • Delahaye N.F.
        • Rusakiewicz S.
        • Martins I.
        • Menard C.
        • Roux S.
        • Lyonnet L.
        • et al.
        Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors.
        Nat Med. 2011; 17: 700-707
        • Semeraro M.
        • Rusakiewicz S.
        • Zitvogel L.
        • Kroemer G.
        Natural killer cell mediated immunosurveillance of pediatric neuroblastoma.
        Oncoimmunology. 2015; 4: e1042202
        • Albertsson P.A.
        • Basse P.H.
        • Hokland M.
        • Goldfarb R.H.
        • Nagelkerke J.F.
        • Nannmark U.
        • et al.
        NK cells and the tumour microenvironment: implications for NK-cell function and anti-tumour activity.
        Trends Immunol. 2003; 24: 603-609
        • Groh V.
        • Wu J.
        • Yee C.
        • Spies T.
        Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation.
        Nature. 2002; 419: 734-738
        • Salih H.R.
        • Rammensee H.G.
        • Steinle A.
        Cutting edge: down-regulation of MICA on human tumors by proteolytic shedding.
        J Immunol. 2002; 169: 4098-4102
        • Crane C.A.
        • Austgen K.
        • Haberthur K.
        • Hofmann C.
        • Moyes K.W.
        • Avanesyan L.
        • et al.
        Immune evasion mediated by tumor-derived lactate dehydrogenase induction of NKG2D ligands on myeloid cells in glioblastoma patients.
        Proc Natl Acad Sci USA. 2014; 111: 12823-12828
        • Cerboni C.
        • Mousavi-Jazi M.
        • Wakiguchi H.
        • Carbone E.
        • Karre K.
        • Soderstrom K.
        Synergistic effect of IFN-gamma and human cytomegalovirus protein UL40 in the HLA-E-dependent protection from NK cell-mediated cytotoxicity.
        Eur J Immunol. 2001; 31: 2926-2935
        • Malmberg K.J.
        • Levitsky V.
        • Norell H.
        • de Matos C.T.
        • Carlsten M.
        • Schedvins K.
        • et al.
        IFN-gamma protects short-term ovarian carcinoma cell lines from CTL lysis via a CD94/NKG2A-dependent mechanism.
        J Clin Invest. 2002; 110: 1515-1523
        • Borrego F.
        • Kabat J.
        • Kim D.K.
        • Lieto L.
        • Maasho K.
        • Pena J.
        • et al.
        Structure and function of major histocompatibility complex (MHC) class I specific receptors expressed on human natural killer (NK) cells.
        Mol Immunol. 2002; 38: 637-660
        • Wilson E.B.
        • El-Jawhari J.J.
        • Neilson A.L.
        • Hall G.D.
        • Melcher A.A.
        • Meade J.L.
        • et al.
        Human tumour immune evasion via TGF-beta blocks NK cell activation but not survival allowing therapeutic restoration of anti-tumour activity.
        PLoS ONE. 2011; 6: e22842
        • Viel S.
        • Marcais A.
        • Guimaraes F.S.
        • Loftus R.
        • Rabilloud J.
        • Grau M.
        • et al.
        TGF-beta inhibits the activation and functions of NK cells by repressing the mTOR pathway.
        Sci Signal. 2016; 9: ra19
        • Ruggeri L.
        • Capanni M.
        • Urbani E.
        • Perruccio K.
        • Shlomchik W.D.
        • Tosti A.
        • et al.
        Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants.
        Science. 2002; 295: 2097-2100
        • Giebel S.
        • Locatelli F.
        • Lamparelli T.
        • Velardi A.
        • Davies S.
        • Frumento G.
        • et al.
        Survival advantage with KIR ligand incompatibility in hematopoietic stem cell transplantation from unrelated donors.
        Blood. 2003; 102: 814-819
        • Leung W.
        • Iyengar R.
        • Turner V.
        • Lang P.
        • Bader P.
        • Conn P.
        • et al.
        Determinants of antileukemia effects of allogeneic NK cells.
        J Immunol. 2004; 172: 644-650
        • Hsu K.C.
        • Keever-Taylor C.A.
        • Wilton A.
        • Pinto C.
        • Heller G.
        • Arkun K.
        • et al.
        Improved outcome in HLA-identical sibling hematopoietic stem-cell transplantation for acute myelogenous leukemia predicted by KIR and HLA genotypes.
        Blood. 2005; 105: 4878-4884
        • Cooley S.
        • Weisdorf D.J.
        • Guethlein L.A.
        • Klein J.P.
        • Wang T.
        • Le C.T.
        • et al.
        Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia.
        Blood. 2010; 116: 2411-2419
        • Miller J.S.
        Therapeutic applications: natural killer cells in the clinic.
        Hematology Am Soc Hematol Educ Program. 2013; 2013: 247-253
        • Miller J.S.
        • Soignier Y.
        • Panoskaltsis-Mortari A.
        • McNearney S.A.
        • Yun G.H.
        • Fautsch S.K.
        • et al.
        Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in cancer patients.
        Blood. 2005; 105: 3051-3057
        • Iyengar R.
        • Handgretinger R.
        • Babarin-Dorner A.
        • Leimig T.
        • Otto M.
        • Geiger T.L.
        • et al.
        Purification of human natural killer cells using a clinical-scale immunomagnetic method.
        Cytotherapy. 2003; 5: 479-484
        • Lee D.A.
        • Verneris M.R.
        • Campana D.
        Acquisition, preparation, and functional assessment of human NK cells for adoptive immunotherapy.
        Methods Mol Biol. 2010; 651: 61-77
        • Tomchuck S.L.
        • Leung W.H.
        • Dallas M.H.
        Enhanced cytotoxic function of natural killer and CD3+CD56+ cells in cord blood after culture.
        Biol Blood Marrow Transplant. 2015; 21: 39-49
        • Hermanson D.L.
        • Bendzick L.
        • Pribyl L.
        • McCullar V.
        • Vogel R.I.
        • Miller J.S.
        • et al.
        Induced pluripotent stem cell-derived natural killer cells for treatment of ovarian cancer.
        Stem Cells. 2016; 34: 93-101
        • James A.M.
        • Hsu H.T.
        • Dongre P.
        • Uzel G.
        • Mace E.M.
        • Banerjee P.P.
        • et al.
        Rapid activation receptor- or IL-2-induced lytic granule convergence in human natural killer cells requires Src, but not downstream signaling.
        Blood. 2013; 121: 2627-2637
        • Romee R.
        • Schneider S.E.
        • Leong J.W.
        • Chase J.M.
        • Keppel C.R.
        • Sullivan R.P.
        • et al.
        Cytokine activation induces human memory-like NK cells.
        Blood. 2012; 120: 4751-4760
        • Ni J.
        • Miller M.
        • Stojanovic A.
        • Garbi N.
        • Cerwenka A.
        Sustained effector function of IL-12/15/18-preactivated NK cells against established tumors.
        J Exp Med. 2012; 209: 2351-2365
        • London L.
        • Perussia B.
        • Trinchieri G.
        Induction of proliferation in vitro of resting human natural killer cells: IL 2 induces into cell cycle most peripheral blood NK cells, but only a minor subset of low density T cells.
        J Immunol. 1986; 137: 3845-3854
        • Alici E.
        • Sutlu T.
        • Bjorkstrand B.
        • Gilljam M.
        • Stellan B.
        • Nahi H.
        • et al.
        Autologous antitumor activity by NK cells expanded from myeloma patients using GMP-compliant components.
        Blood. 2008; 111: 3155-3162
        • Satwani P.
        • van de Ven C.
        • Ayello J.
        • Cairo D.
        • Simpson L.L.
        • Baxi L.
        • et al.
        Interleukin (IL)-15 in combination with IL-2, fms-like tyrosine kinase-3 ligand and anti-CD3 significantly enhances umbilical cord blood natural killer (NK) cell and NK-cell subset expansion and NK function.
        Cytotherapy. 2011; 13: 730-738
        • 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: 4010-4017
        • Berg M.
        • Lundqvist A.
        • McCoy Jr, P.
        • Samsel L.
        • Fan Y.
        • Tawab A.
        • et al.
        Clinical-grade ex vivo-expanded human natural killer cells up-regulate activating receptors and death receptor ligands and have enhanced cytolytic activity against tumor cells.
        Cytotherapy. 2009; 11: 341-355
        • Harada H.
        • Watanabe S.
        • Saijo K.
        • Ishiwata I.
        • Ohno T.
        A Wilms tumor cell line, HFWT, can greatly stimulate proliferation of CD56+ human natural killer cells and their novel precursors in blood mononuclear cells.
        Exp Hematol. 2004; 32: 614-621
        • Kottaridis P.D.
        • North J.
        • Tsirogianni M.
        • Marden C.
        • Samuel E.R.
        • Jide-Banwo S.
        • et al.
        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: e0123416
        • Phillips J.H.
        • Lanier L.L.
        A model for the differentiation of human natural killer cells. Studies on the in vitro activation of Leu-11+ granular lymphocytes with a natural killer-sensitive tumor cell, K562.
        J Exp Med. 1985; 161: 1464-1482
        • Kobayashi H.
        • Dubois S.
        • Sato N.
        • Sabzevari H.
        • Sakai Y.
        • Waldmann T.A.
        • et al.
        Role of trans-cellular IL-15 presentation in the activation of NK cell-mediated killing, which leads to enhanced tumor immunosurveillance.
        Blood. 2005; 105: 721-727
        • Melero I.
        • Johnston J.V.
        • Shufford W.W.
        • Mittler R.S.
        • Chen L.
        NK1.1 cells express 4-1BB (CDw137) costimulatory molecule and are required for tumor immunity elicited by anti-4-1BB monoclonal antibodies.
        Cell Immunol. 1998; 190: 167-172
        • Fujisaki H.
        • Kakuda H.
        • Imai C.
        • Mullighan C.G.
        • Campana D.
        Replicative potential of human natural killer cells.
        Br J Haematol. 2009; 145: 606-613
        • Lapteva N.
        • Durett A.G.
        • Sun J.
        • Rollins L.A.
        • Huye L.L.
        • Fang J.
        • et al.
        Large-scale ex vivo expansion and characterization of natural killer cells for clinical applications.
        Cytotherapy. 2012; 14: 1131-1143
        • Suhoski M.M.
        • Golovina T.N.
        • Aqui N.A.
        • Tai V.C.
        • Varela-Rohena A.
        • Milone M.C.
        • et al.
        Engineering artificial antigen-presenting cells to express a diverse array of co-stimulatory molecules.
        Mol Ther. 2007; 15: 981-988
        • Zhang H.
        • Cui Y.
        • Voong N.
        • Sabatino M.
        • Stroncek D.F.
        • Morisot S.
        • et al.
        Activating signals dominate inhibitory signals in CD137L/IL-15 activated natural killer cells.
        J Immunother. 2011; 34: 187-195
        • Shah N.N.
        • Baird K.
        • Delbrook C.P.
        • Fleisher T.A.
        • Kohler M.E.
        • Rampertaap S.
        • 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
        • Denman C.J.
        • Senyukov V.V.
        • Somanchi S.S.
        • Phatarpekar P.V.
        • Kopp L.M.
        • Johnson J.L.
        • et al.
        Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells.
        PLoS ONE. 2012; 7: e30264
        • Tam Y.K.
        • Martinson J.A.
        • Doligosa K.
        • Klingemann H.G.
        Ex vivo expansion of the highly cytotoxic human natural killer-92 cell-line under current good manufacturing practice conditions for clinical adoptive cellular immunotherapy.
        Cytotherapy. 2003; 5: 259-272
        • Cho D.
        • Shook D.R.
        • Shimasaki N.
        • Chang Y.H.
        • Fujisaki H.
        • Campana D.
        Cytotoxicity of activated natural killer cells against pediatric solid tumors.
        Clin Cancer Res. 2010; 16: 3901-3909
        • Mimura K.
        • Kamiya T.
        • Shiraishi K.
        • Kua L.F.
        • Shabbir A.
        • So J.
        • et al.
        Therapeutic potential of highly cytotoxic natural killer cells for gastric cancer.
        Int J Cancer. 2014; 135: 1390-1398
        • Kamiya T.
        • Chang Y.H.
        • Campana D.
        Expanded and activated natural killer cells for immunotherapy of hepatocellular carcinoma.
        Cancer Immunol Res. 2016; 4: 574-581
        • Ho E.L.
        • Heusel J.W.
        • Brown M.G.
        • Matsumoto K.
        • Scalzo A.A.
        • Yokoyama W.M.
        Murine Nkg2d and Cd94 are clustered within the natural killer complex and are expressed independently in natural killer cells.
        Proc Natl Acad Sci USA. 1998; 95: 6320-6325
        • Bauer S.
        • Groh V.
        • Wu J.
        • Steinle A.
        • Phillips J.H.
        • Lanier L.L.
        • et al.
        Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA.
        Science. 1999; 285: 727-729
        • Gasser S.
        • Orsulic S.
        • Brown E.J.
        • Raulet D.H.
        The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor.
        Nature. 2005; 436: 1186-1190
        • Champsaur M.
        • Lanier L.L.
        Effect of NKG2D ligand expression on host immune responses.
        Immunol Rev. 2010; 235: 267-285
        • Wu J.
        • Song Y.
        • Bakker A.B.
        • Bauer S.
        • Spies T.
        • Lanier L.L.
        • et al.
        An activating immunoreceptor complex formed by NKG2D and DAP10.
        Science. 1999; 285: 730-732
        • Diefenbach A.
        • Tomasello E.
        • Lucas M.
        • Jamieson A.M.
        • Hsia J.K.
        • Vivier E.
        • et al.
        Selective associations with signaling proteins determine stimulatory versus costimulatory activity of NKG2D.
        Nat Immunol. 2002; 3: 1142-1149
        • Garrity D.
        • Call M.E.
        • Feng J.
        • Wucherpfennig K.W.
        The activating NKG2D receptor assembles in the membrane with two signaling dimers into a hexameric structure.
        Proc Natl Acad Sci USA. 2005; 102: 7641-7646
        • Smyth M.J.
        • Swann J.
        • Cretney E.
        • Zerafa N.
        • Yokoyama W.M.
        • Hayakawa Y.
        NKG2D function protects the host from tumor initiation.
        J Exp Med. 2005; 202: 583-588
        • Raulet D.H.
        Roles of the NKG2D immunoreceptor and its ligands.
        Nat Rev Immunol. 2003; 3: 781-790
        • Romagne F.
        • Andre P.
        • Spee P.
        • Zahn S.
        • Anfossi N.
        • Gauthier L.
        • et al.
        Preclinical characterization of 1-7F9, a novel human anti-KIR receptor therapeutic antibody that augments natural killer-mediated killing of tumor cells.
        Blood. 2009; 114: 2667-2677
        • Benson Jr, D.M.
        • Bakan C.E.
        • Zhang S.
        • Collins S.M.
        • Liang J.
        • Srivastava S.
        • et al.
        IPH2101, a novel anti-inhibitory KIR antibody, and lenalidomide combine to enhance the natural killer cell versus multiple myeloma effect.
        Blood. 2011; 118: 6387-6391
        • Ruggeri L.
        • Urbani E.
        • Andre P.
        • Mancusi A.
        • Tosti A.
        • Topini F.
        • et al.
        Effects of anti-NKG2A antibody administration on leukemia and normal hematopoietic cells.
        Haematologica. 2016; 101: 626-633
        • Imamura M.
        • Shook D.
        • Kamiya T.
        • Shimasaki N.
        • Chai S.M.
        • Coustan-Smith E.
        • et al.
        Autonomous growth and increased cytotoxicity of natural killer cells expressing membrane-bound interleukin-15.
        Blood. 2014; 124: 1081-1088
        • Rubnitz J.E.
        • Inaba H.
        • Ribeiro R.C.
        • 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: 955-959
        • Torikai H.
        • Reik A.
        • Soldner F.
        • Warren E.H.
        • Yuen C.
        • Zhou Y.
        • et al.
        Toward eliminating HLA class I expression to generate universal cells from allogeneic donors.
        Blood. 2013; 122: 1341-1349
        • Valton J.
        • Guyot V.
        • Marechal A.
        • Filhol J.M.
        • Juillerat A.
        • Duclert A.
        • et al.
        A multidrug-resistant engineered CAR T cell for allogeneic combination immunotherapy.
        Mol Ther. 2015; 23: 1507-1518
        • Shimasaki N.
        • Fujisaki H.
        • Cho D.
        • Masselli M.
        • Lockey T.
        • Eldridge P.
        • et al.
        A clinically adaptable method to enhance the cytotoxicity of natural killer cells against B-cell malignancies.
        Cytotherapy. 2012; 14: 830-840
        • Li L.
        • Liu L.N.
        • Feller S.
        • Allen C.
        • Shivakumar R.
        • Fratantoni J.
        • et al.
        Expression of chimeric antigen receptors in natural killer cells with a regulatory-compliant non-viral method.
        Cancer Gene Ther. 2010; 17: 147-154
        • Shimasaki N.
        • Campana D.
        Natural killer cell reprogramming with chimeric immune receptors.
        Methods Mol Biol. 2013; 969: 203-220
        • Kruschinski A.
        • Moosmann A.
        • Poschke I.
        • Norell H.
        • Chmielewski M.
        • Seliger B.
        • et al.
        Engineering antigen-specific primary human NK cells against HER-2 positive carcinomas.
        Proc Natl Acad Sci USA. 2008; 105: 17481-17486
        • Altvater B.
        • Landmeier S.
        • Pscherer S.
        • Temme J.
        • Schweer K.
        • Kailayangiri S.
        • et al.
        2B4 (CD244) signaling by recombinant antigen-specific chimeric receptors costimulates natural killer cell activation to leukemia and neuroblastoma cells.
        Clin Cancer Res. 2009; 15: 4857-4866
        • Wiernik A.
        • Foley B.
        • Zhang B.
        • Verneris M.R.
        • Warlick E.
        • Gleason M.K.
        • et al.
        Targeting natural killer cells to acute myeloid leukemia in vitro with a CD16 x 33 bispecific killer cell engager and ADAM17 inhibition.
        Clin Cancer Res. 2013; 19: 3844-3855
        • Vallera D.A.
        • Zhang B.
        • Gleason M.K.
        • Oh S.
        • Weiner L.M.
        • Kaufman D.S.
        • et al.
        Heterodimeric bispecific single-chain variable-fragment antibodies against EpCAM and CD16 induce effective antibody-dependent cellular cytotoxicity against human carcinoma cells.
        Cancer Biother Radiopharm. 2013; 28: 274-282
        • Szmania S.
        • Lapteva N.
        • Garg T.
        • Greenway A.
        • Lingo J.
        • Nair B.
        • et al.
        Ex vivo-expanded natural killer cells demonstrate robust proliferation in vivo in high-risk relapsed multiple myeloma patients.
        J Immunother. 2015; 38: 24-36
        • Garg T.K.
        • Szmania S.M.
        • Khan J.A.
        • Hoering A.
        • Malbrough P.A.
        • Moreno-Bost A.
        • et al.
        Highly activated and expanded natural killer cells for multiple myeloma immunotherapy.
        Haematologica. 2012; 97: 1348-1356
        • Dudley M.E.
        • Wunderlich J.R.
        • Robbins P.F.
        • Yang J.C.
        • Hwu P.
        • Schwartzentruber D.J.
        • et al.
        Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes.
        Science. 2002; 298: 850-854
        • Hamelik R.M.
        • Krishan A.
        Click-iT assay with improved DNA distribution histograms.
        Cytometry A. 2009; 75: 862-865
        • Hank J.A.
        • Surfus J.
        • Gan J.
        • Albertini M.
        • Lindstrom M.
        • Schiller J.H.
        • et al.
        Distinct clinical and laboratory activity of two recombinant interleukin-2 preparations.
        Clin Cancer Res. 1999; 5: 281-289