Advertisement

Improving efficacy of cancer immunotherapy by genetic modification of natural killer cells

      Abstract

      Natural killer (NK) cells are members of the innate immune system that recognize target cells via activating and inhibitory signals received through cell receptors. Derived from the lymphoid lineage, NK cells are able to produce cytokines and exert a cytotoxic effect on viral infected and malignant cells. It is their unique ability to lyse target cells rapidly and without prior education that renders NK cells a promising effector cell for adoptive cell therapy. However, both viruses and tumors employ evasion strategies to avoid attack by NK cells, which represent biological challenges that need to be harnessed to fully exploit the cytolytic potential of NK cells. Using genetic modification, the function of NK cells can be enhanced to improve their homing, cytolytic activity, in vivo persistence and safety. Examples include gene modification to express chemokine, high-affinity Fc receptor and chimeric antigen receptors, suicide genes and the forced expression of cytokines such as interleukin (IL)-2 and IL-15. Preclinical studies have clearly demonstrated that such approaches are effective in improving NK-cell function, homing and safety. In this review, we summarize the recent advances in the genetic manipulations of NK cells and their application for cellular immunotherapeutic strategies.

      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

        • Hellstrom I.
        • Hellstrom K.E.
        • Pierce G.E.
        • Yang J.P.
        Cellular and humoral immunity to different types of human neoplasms.
        Nature. 1968; 220 (Epub 1968/12/28): 1352-1354
        • Herberman R.B.
        • Nunn M.E.
        • Holden H.T.
        • Lavrin D.H.
        Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic tumors. II. Characterization of effector cells.
        Int J Cancer. 1975; 16 (Epub 1975/08/15): 230-239
        • Herberman R.B.
        • Nunn M.E.
        • Lavrin D.H.
        Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic acid allogeneic tumors. I. Distribution of reactivity and specificity.
        Int J Cancer. 1975; 16 (Epub 1975/08/15): 216-229
        • 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 (Epub 1975/02/01): 117-121https://doi.org/10.1002/eji.1830050209
        • Kiessling R.
        • Klein E.
        • Wigzell H.
        “Natural” killer cells in the mouse. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Specificity and distribution according to genotype.
        Eur J Immunol. 1975; 5 (Epub 1975/02/01): 112-117https://doi.org/10.1002/eji.1830050208
        • Carotta S.
        • Pang S.H.
        • Nutt S.L.
        • Belz G.T.
        Identification of the earliest NK-cell precursor in the mouse BM.
        Blood. 2011; 117 (Epub 2011/03/23) (blood-2010-11-318956 [pii]): 5449-5452https://doi.org/10.1182/blood-2010-11-318956
        • Boos M.D.
        • Yokota Y.
        • Eberl G.
        • Kee B.L.
        Mature natural killer cell and lymphoid tissue-inducing cell development requires Id2-mediated suppression of E protein activity.
        J Exp Med. 2007; 204 (Epub 2007/04/25) (jem.20061959 [pii]; PubMed Central PMCID: PMC2118569): 1119-1130https://doi.org/10.1084/jem.20061959
        • Carson W.E.
        • Giri J.G.
        • Lindemann M.J.
        • Linett M.L.
        • Ahdieh M.
        • Paxton R.
        • et al.
        Interleukin (IL) 15 is a novel cytokine that activates human natural killer cells via components of the IL-2 receptor.
        J Exp Med. 1994; 180 (Epub 1994/10/01) (PubMed Central PMCID: PMC2191697): 1395-1403
        • Iannello A.
        • Debbeche O.
        • Samarani S.
        • Ahmad A.
        Antiviral NK cell responses in HIV infection: I. NK cell receptor genes as determinants of HIV resistance and progression to AIDS.
        J Leukoc Biol. 2008; 84 (Epub 2008/04/05) (jlb.0907650 [pii]): 1-26https://doi.org/10.1189/jlb.0907650
        • Dahlberg C.I.
        • Sarhan D.
        • Chrobok M.
        • Duru A.D.
        • Alici E.
        Natural killer cell-based therapies targeting cancer: possible strategies to gain and sustain anti-tumor activity.
        Front Immunol. 2015; 6 (Epub 2015/12/10) (PubMed Central PMCID: PMC4663254): 605https://doi.org/10.3389/fimmu.2015.00605
        • Fauriat C.
        • Long E.O.
        • Ljunggren H.G.
        • Bryceson Y.T.
        Regulation of human NK-cell cytokine and chemokine production by target cell recognition.
        Blood. 2010; 115 (Epub 2009/12/08) (blood-2009-08-238469 [pii]; PubMed Central PMCID: PMC2844017): 2167-2176https://doi.org/10.1182/blood-2009-08-238469
        • Carrega P.
        • Bonaccorsi I.
        • Di Carlo E.
        • Morandi B.
        • Paul P.
        • Rizzello V.
        • et al.
        CD56(bright)perforin(low) noncytotoxic human NK cells are abundant in both healthy and neoplastic solid tissues and recirculate to secondary lymphoid organs via afferent lymph.
        J Immunol. 2014; 192 (Epub 2014/03/22) (jimmunol.1301889 [pii]): 3805-3815https://doi.org/10.4049/jimmunol.1301889
        • Ferlazzo G.
        • Thomas D.
        • Lin S.L.
        • Goodman K.
        • Morandi B.
        • Muller W.A.
        • et al.
        The abundant NK cells in human secondary lymphoid tissues require activation to express killer cell Ig-like receptors and become cytolytic.
        J Immunol. 2004; 172 (Epub 2004/01/22): 1455-1462
        • De Maria A.
        • Bozzano F.
        • Cantoni C.
        • Moretta L.
        Revisiting human natural killer cell subset function revealed cytolytic CD56(dim)CD16+ NK cells as rapid producers of abundant IFN-gamma on activation.
        Proc Natl Acad Sci USA. 2011; 108 (Epub 2010/12/29) (1012356108 [pii]; PubMed Central PMCID: PMC3021076): 728-732https://doi.org/10.1073/pnas.1012356108
        • Carrega P.
        • Ferlazzo G.
        Natural killer cell distribution and trafficking in human tissues.
        Front Immunol. 2012; 3 (Epub 2012/12/12) (PubMed Central PMCID: PMC3515878): 347https://doi.org/10.3389/fimmu.2012.00347
        • Parolini S.
        • Santoro A.
        • Marcenaro E.
        • Luini W.
        • Massardi L.
        • Facchetti F.
        • et al.
        The role of chemerin in the colocalization of NK and dendritic cell subsets into inflamed tissues.
        Blood. 2007; 109 (Epub 2007/01/05) (blood-2006-08-038844 [pii]): 3625-3632https://doi.org/10.1182/blood-2006-08-038844
        • Juelke K.
        • Killig M.
        • Luetke-Eversloh M.
        • Parente E.
        • Gruen J.
        • Morandi B.
        • et al.
        CD62L expression identifies a unique subset of polyfunctional CD56dim NK cells.
        Blood. 2010; 116 (Epub 2010/05/28) (blood-2009-11-253286 [pii]): 1299-1307https://doi.org/10.1182/blood-2009-11-253286
        • Mavilio D.
        • Lombardo G.
        • Benjamin J.
        • Kim D.
        • Follman D.
        • Marcenaro E.
        • et al.
        Characterization of CD56-/CD16+ natural killer (NK) cells: a highly dysfunctional NK subset expanded in HIV-infected viremic individuals.
        Proc Natl Acad Sci USA. 2005; 102 (Epub 2005/02/09) (0409872102 [pii]; PubMed Central PMCID: PMC549494): 2886-2891https://doi.org/10.1073/pnas.0409872102
        • Scott-Algara D.
        • Paul P.
        NK cells and HIV infection: lessons from other viruses.
        Curr Mol Med. 2002; 2 (Epub 2002/12/05): 757-768
        • Pyo C.W.
        • Guethlein L.A.
        • Vu Q.
        • Wang R.
        • Abi-Rached L.
        • Norman P.J.
        • et al.
        Different patterns of evolution in the centromeric and telomeric regions of group A and B haplotypes of the human killer cell Ig-like receptor locus.
        PLoS ONE. 2010; 5 (Epub 2011/01/06) (PubMed Central PMCID: PMC3012066): e15115https://doi.org/10.1371/journal.pone.0015115
        • Koch J.
        • Steinle A.
        • Watzl C.
        • Mandelboim O.
        Activating natural cytotoxicity receptors of natural killer cells in cancer and infection.
        Trends Immunol. 2013; 34 (Epub 2013/02/19) (S1471-4906(13)00012-4 [pii]): 182-191https://doi.org/10.1016/j.it.2013.01.003
        • Fauriat C.
        • Ivarsson M.A.
        • Ljunggren H.G.
        • Malmberg K.J.
        • Michaelsson J.
        Education of human natural killer cells by activating killer cell immunoglobulin-like receptors.
        Blood. 2010; 115 (Epub 2009/11/12) (blood-2009-09-245746 [pii]): 1166-1174https://doi.org/10.1182/blood-2009-09-245746
        • Lodoen M.B.
        • Lanier L.L.
        Viral modulation of NK cell immunity.
        Nat Rev Microbiol. 2005; 3 (Epub 2004/12/21) (nrmicro1066 [pii]): 59-69https://doi.org/10.1038/nrmicro1066
        • Wallin R.P.
        • Screpanti V.
        • Michaelsson J.
        • Grandien A.
        • Ljunggren H.G.
        Regulation of perforin-independent NK cell-mediated cytotoxicity.
        Eur J Immunol. 2003; 33 (Epub 2003/09/30): 2727-2735https://doi.org/10.1002/eji.200324070
        • Titus J.A.
        • Perez P.
        • Kaubisch A.
        • Garrido M.A.
        • Segal D.M.
        Human K/natural killer cells targeted with hetero-cross-linked antibodies specifically lyse tumor cells in vitro and prevent tumor growth in vivo.
        J Immunol. 1987; 139 (Epub 1987/11/01): 3153-3158
        • Garrido M.A.
        • Perez P.
        • Titus J.A.
        • Valdayo M.J.
        • Winkler D.F.
        • Barbieri S.A.
        • et al.
        Targeted cytotoxic cells in human peripheral blood lymphocytes.
        J Immunol. 1990; 144 (Epub 1990/04/15): 2891-2898
        • Lim O.
        • Jung M.Y.
        • Hwang Y.K.
        • Shin E.C.
        Present and future of allogeneic natural killer cell therapy.
        Front Immunol. 2015; 6 (PubMed Central PMCID: PMCPMC4453480): 286https://doi.org/10.3389/fimmu.2015.00286
        • Costello R.T.
        • Sivori S.
        • Marcenaro E.
        • Lafage-Pochitaloff M.
        • Mozziconacci M.J.
        • Reviron D.
        • et al.
        Defective expression and function of natural killer cell-triggering receptors in patients with acute myeloid leukemia.
        Blood. 2002; 99 (Epub 2002/05/03): 3661-3667
        • Sconocchia G.
        • Lau M.
        • Provenzano M.
        • Rezvani K.
        • Wongsena W.
        • Fujiwara H.
        • et al.
        The antileukemia effect of HLA-matched NK and NK-T cells in chronic myelogenous leukemia involves NKG2D-target-cell interactions.
        Blood. 2005; 106 (PubMed Central PMCID: PMC1895055): 3666-3672https://doi.org/10.1182/blood-2005-02-0479
        • 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
        • Salih H.R.
        • Goehlsdorf D.
        • Steinle A.
        Release of MICB molecules by tumor cells: mechanism and soluble MICB in sera of cancer patients.
        Hum Immunol. 2006; 67: 188-195https://doi.org/10.1016/j.humimm.2006.02.008
        • Wang B.
        • Niu D.
        • Lai L.
        • Ren E.C.
        p53 increases MHC class I expression by upregulating the endoplasmic reticulum aminopeptidase ERAP1.
        Nat Commun. 2013; 4 (Epub 2013/08/24) (ncomms3359 [pii]; PubMed Central PMCID: PMC3759077)https://doi.org/10.1038/ncomms3359
        • Rouas-Freiss N.
        • Moreau P.
        • Ferrone S.
        • Carosella E.D.
        HLA-G proteins in cancer: do they provide tumor cells with an escape mechanism?.
        Cancer Res. 2005; 65 (Epub 2005/11/17) (65/22/10139 [pii]): 10139-10144https://doi.org/10.1158/0008-5472.CAN-05-0097
        • Urosevic M.
        • Dummer R.
        Human leukocyte antigen-G and cancer immunoediting.
        Cancer Res. 2008; 68 (Epub 2008/02/05) (68/3/627 [pii]): 627-630https://doi.org/10.1158/0008-5472.CAN-07-2704
        • Veuillen C.
        • Aurran-Schleinitz T.
        • Castellano R.
        • Rey J.
        • Mallet F.
        • Orlanducci F.
        • et al.
        Primary B-CLL resistance to NK cell cytotoxicity can be overcome in vitro and in vivo by priming NK cells and monoclonal antibody therapy.
        J Clin Immunol. 2012; 32 (Epub 2012/02/10): 632-646https://doi.org/10.1007/s10875-011-9624-5
        • Stringaris K.
        • Sekine T.
        • Khoder A.
        • Alsuliman A.
        • Razzaghi B.
        • Sargeant R.
        • et al.
        Leukemia-induced phenotypic and functional defects in natural killer cells predict failure to achieve remission in acute myeloid leukemia.
        Haematologica. 2014; 99 (PubMed Central PMCID: PMC4008119): 836-847https://doi.org/10.3324/haematol.2013.087536
        • Pietra G.
        • Manzini C.
        • Rivara S.
        • Vitale M.
        • Cantoni C.
        • Petretto A.
        • et al.
        Melanoma cells inhibit natural killer cell function by modulating the expression of activating receptors and cytolytic activity.
        Cancer Res. 2012; 72: 1407-1415https://doi.org/10.1158/0008-5472.CAN-11-2544
        • Van Elssen C.H.
        • Vanderlocht J.
        • Oth T.
        • Senden-Gijsbers B.L.
        • Germeraad W.T.
        • Bos G.M.
        Inflammation-restraining effects of prostaglandin E2 on natural killer-dendritic cell (NK-DC) interaction are imprinted during DC maturation.
        Blood. 2011; 118: 2473-2482https://doi.org/10.1182/blood-2010-09-307835
        • 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 (PubMed Central PMCID: PMC4012770): 213-221https://doi.org/10.1038/cmi.2013.1
        • Romero A.I.
        • Thoren F.B.
        • Brune M.
        • Hellstrand K.
        NKp46 and NKG2D receptor expression in NK cells with CD56dim and CD56bright phenotype: regulation by histamine and reactive oxygen species.
        Br J Haematol. 2006; 132: 91-98https://doi.org/10.1111/j.1365-2141.2005.05842.x
        • Ghiringhelli F.
        • Menard C.
        • Terme M.
        • Flament C.
        • Taieb J.
        • Chaput N.
        • et al.
        CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-beta-dependent manner.
        J Exp Med. 2005; 202 (PubMed Central PMCID: PMC2213209): 1075-1085https://doi.org/10.1084/jem.20051511
        • Ghiringhelli F.
        • Menard C.
        • Puig P.E.
        • Ladoire S.
        • Roux S.
        • Martin F.
        • et al.
        Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients.
        Cancer Immunol Immunother. 2007; 56: 641-648https://doi.org/10.1007/s00262-006-0225-8
        • Bachanova V.
        • Cooley S.
        • Defor T.E.
        • Verneris M.R.
        • Zhang B.
        • McKenna D.H.
        • et al.
        Clearance of acute myeloid leukemia by haploidentical natural killer cells is improved using IL-2 diphtheria toxin fusion protein.
        Blood. 2014; 123 (PubMed Central PMCID: PMC4064329): 3855-3863https://doi.org/10.1182/blood-2013-10-532531
        • Gill S.
        • June C.H.
        Going viral: chimeric antigen receptor T-cell therapy for hematological malignancies.
        Immunol Rev. 2015; 263: 68-89https://doi.org/10.1111/imr.12243
        • Lee D.W.
        • Kochenderfer J.N.
        • Stetler-Stevenson M.
        • Cui Y.K.
        • Delbrook C.
        • Feldman S.A.
        • et al.
        T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial.
        Lancet. 2015; 385: 517-528https://doi.org/10.1016/S0140-6736(14)61403-3
        • Pule M.A.
        • Savoldo B.
        • Myers G.D.
        • Rossig C.
        • Russell H.V.
        • Dotti G.
        • et al.
        Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma.
        Nat Med. 2008; 14 (PubMed Central PMCID: PMC2749734): 1264-1270https://doi.org/10.1038/nm.1882
        • 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 (PubMed Central PMCID: PMC3261192): e30264https://doi.org/10.1371/journal.pone.0030264
        • Carlsten M.
        • Childs R.W.
        Genetic manipulation of NK cells for cancer immunotherapy: techniques and clinical implications.
        Front Immunol. 2015; 6 (PubMed Central PMCID: PMC4462109): 266https://doi.org/10.3389/fimmu.2015.00266
        • Rezvani K.
        • Rouce R.H.
        The application of natural killer cell immunotherapy for the treatment of cancer.
        Front Immunol. 2015; 6 (PubMed Central PMCID: PMC4648067): 578https://doi.org/10.3389/fimmu.2015.00578
        • Spanholtz J.
        • Preijers F.
        • Tordoir M.
        • Trilsbeek C.
        • Paardekooper J.
        • de Witte T.
        • et al.
        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 (PubMed Central PMCID: PMC3116834): e20740https://doi.org/10.1371/journal.pone.0020740
        • Tonn T.
        • Schwabe D.
        • Klingemann H.G.
        • Becker S.
        • Esser R.
        • Koehl U.
        • et al.
        Treatment of patients with advanced cancer with the natural killer cell line NK-92.
        Cytotherapy. 2013; 15: 1563-1570https://doi.org/10.1016/j.jcyt.2013.06.017
        • Inngjerdingen M.
        • Damaj B.
        • Maghazachi A.A.
        Expression and regulation of chemokine receptors in human natural killer cells.
        Blood. 2001; 97: 367-375
        • Miller J.S.
        • Rooney C.M.
        • Curtsinger J.
        • McElmurry R.
        • McCullar V.
        • Verneris M.R.
        • et al.
        Expansion and homing of adoptively transferred human natural killer cells in immunodeficient mice varies with product preparation and in vivo cytokine administration: implications for clinical therapy.
        Biol Blood Marrow Transplant. 2014; 20 (PubMed Central PMCID: PMC4099265): 1252-1257https://doi.org/10.1016/j.bbmt.2014.05.004
        • Somanchi S.S.
        • Somanchi A.
        • Cooper L.J.
        • Lee D.A.
        Engineering lymph node homing of ex vivo-expanded human natural killer cells via trogocytosis of the chemokine receptor CCR7.
        Blood. 2012; 119 (PubMed Central PMCID: PMC3418772): 5164-5172https://doi.org/10.1182/blood-2011-11-389924
        • Peng W.
        • Ye Y.
        • Rabinovich B.A.
        • Liu C.
        • Lou Y.
        • Zhang M.
        • et al.
        Transduction of tumor-specific T cells with CXCR2 chemokine receptor improves migration to tumor and antitumor immune responses.
        Clin Cancer Res. 2010; 16 (PubMed Central PMCID: PMC3476703): 5458-5468https://doi.org/10.1158/1078-0432.CCR-10-0712
        • Pule M.
        • Finney H.
        • Lawson A.
        Artificial T-cell receptors.
        Cytotherapy. 2003; 5: 211-226https://doi.org/10.1080/14653240310001488
        • Haynes N.M.
        • Trapani J.A.
        • Teng M.W.
        • Jackson J.T.
        • Cerruti L.
        • Jane S.M.
        • et al.
        Single-chain antigen recognition receptors that costimulate potent rejection of established experimental tumors.
        Blood. 2002; 100: 3155-3163https://doi.org/10.1182/blood-2002-04-1041
        • Pule M.A.
        • Straathof K.C.
        • Dotti G.
        • Heslop H.E.
        • Rooney C.M.
        • Brenner M.K.
        A chimeric T cell antigen receptor that augments cytokine release and supports clonal expansion of primary human T cells.
        Mol Ther. 2005; 12: 933-941https://doi.org/10.1016/j.ymthe.2005.04.016
        • Long A.H.
        • Haso W.M.
        • Shern J.F.
        • Wanhainen K.M.
        • Murgai M.
        • Ingaramo M.
        • et al.
        4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors.
        Nat Med. 2015; 21 (PubMed Central PMCID: PMC4458184): 581-590https://doi.org/10.1038/nm.3838
        • 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: 1777-1786https://doi.org/10.1158/0008-5472.CAN-12-3558
        • 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 (PubMed Central PMCID: PMC2771629): 4857-4866https://doi.org/10.1158/1078-0432.CCR-08-2810
        • Topfer K.
        • Cartellieri M.
        • Michen S.
        • Wiedemuth R.
        • Muller N.
        • Lindemann D.
        • et al.
        DAP12-based activating chimeric antigen receptor for NK cell tumor immunotherapy.
        J Immunol. 2015; 194: 3201-3212https://doi.org/10.4049/jimmunol.1400330
        • Boissel L.
        • Betancur-Boissel M.
        • Lu W.
        • Krause D.S.
        • Van Etten R.A.
        • Wels W.S.
        • et al.
        Retargeting NK-92 cells by means of CD19- and CD20-specific chimeric antigen receptors compares favorably with antibody-dependent cellular cytotoxicity.
        Oncoimmunology. 2013; 2 (PubMed Central PMCID: PMC3881109): e26527https://doi.org/10.4161/onci.26527
        • Cho F.N.
        • Chang T.H.
        • Shu C.W.
        • Ko M.C.
        • Liao S.K.
        • Wu K.H.
        • et al.
        Enhanced cytotoxicity of natural killer cells following the acquisition of chimeric antigen receptors through trogocytosis.
        PLoS ONE. 2014; 9 (PubMed Central PMCID: PMC4196898): e109352https://doi.org/10.1371/journal.pone.0109352
        • Gill S.
        • Porter D.L.
        CAR-modified anti-CD19 T cells for the treatment of B-cell malignancies: rules of the road.
        Expert Opin Biol Ther. 2014; 14: 37-49https://doi.org/10.1517/14712598.2014.860442
        • Chu J.
        • Deng Y.
        • Benson D.M.
        • He S.
        • Hughes T.
        • Zhang J.
        • et al.
        CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma.
        Leukemia. 2014; 28 (PubMed Central PMCID: PMC3967004): 917-927https://doi.org/10.1038/leu.2013.279
        • Jiang H.
        • Zhang W.
        • Shang P.
        • Zhang H.
        • Fu W.
        • Ye F.
        • et al.
        Transfection of chimeric anti-CD138 gene enhances natural killer cell activation and killing of multiple myeloma cells.
        Mol Oncol. 2014; 8: 297-310https://doi.org/10.1016/j.molonc.2013.12.001
        • Schirrmann T.
        • Pecher G.
        Specific targeting of CD33(+) leukemia cells by a natural killer cell line modified with a chimeric receptor.
        Leuk Res. 2005; 29: 301-306https://doi.org/10.1016/j.leukres.2004.07.005
        • Schirrmann T.
        • Pecher G.
        Human natural killer cell line modified with a chimeric immunoglobulin T-cell receptor gene leads to tumor growth inhibition in vivo.
        Cancer Gene Ther. 2002; 9: 390-398https://doi.org/10.1038/sj.cgt.7700453
        • Esser R.
        • Muller T.
        • Stefes D.
        • Kloess S.
        • Seidel D.
        • Gillies S.D.
        • et al.
        NK cells engineered to express a GD2 -specific antigen receptor display built-in ADCC-like activity against tumour cells of neuroectodermal origin.
        J Cell Mol Med. 2012; 16 (PubMed Central PMCID: PMC3822932): 569-581https://doi.org/10.1111/j.1582-4934.2011.01343.x
        • Zhang G.
        • Liu R.
        • Zhu X.
        • Wang L.
        • Ma J.
        • Han H.
        • et al.
        Retargeting NK-92 for anti-melanoma activity by a TCR-like single-domain antibody.
        Immunol Cell Biol. 2013; 91: 615-624https://doi.org/10.1038/icb.2013.45
        • Sahm C.
        • Schonfeld K.
        • Wels W.S.
        Expression of IL-15 in NK cells results in rapid enrichment and selective cytotoxicity of gene-modified effectors that carry a tumor-specific antigen receptor.
        Cancer Immunol Immunother. 2012; 61: 1451-1461https://doi.org/10.1007/s00262-012-1212-x
        • 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 (PubMed Central PMCID: PMC2582261): 17481-17486https://doi.org/10.1073/pnas.0804788105
        • Schonfeld K.
        • Sahm C.
        • Zhang C.
        • Naundorf S.
        • Brendel C.
        • Odendahl M.
        • et al.
        Selective inhibition of tumor growth by clonal NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor.
        Mol Ther. 2015; 23 (PubMed Central PMCID: PMC4445620): 330-338https://doi.org/10.1038/mt.2014.219
        • Tassev D.V.
        • Cheng M.
        • Cheung N.K.
        Retargeting NK92 cells using an HLA-A2-restricted, EBNA3C-specific chimeric antigen receptor.
        Cancer Gene Ther. 2012; 19: 84-100https://doi.org/10.1038/cgt.2011.66
        • Kobayashi E.
        • Kishi H.
        • Ozawa T.
        • Hamana H.
        • Nakagawa H.
        • Jin A.
        • et al.
        A chimeric antigen receptor for TRAIL-receptor 1 induces apoptosis in various types of tumor cells.
        Biochem Biophys Res Commun. 2014; 453: 798-803https://doi.org/10.1016/j.bbrc.2014.10.024
        • Wu J.
        • Edberg J.C.
        • Redecha P.B.
        • Bansal V.
        • Guyre P.M.
        • Coleman K.
        • et al.
        A novel polymorphism of FcgammaRIIIa (CD16) alters receptor function and predisposes to autoimmune disease.
        J Clin Invest. 1997; 100 (PubMed Central PMCID: PMC508280): 1059-1070https://doi.org/10.1172/JCI119616
        • Binyamin L.
        • Alpaugh R.K.
        • Hughes T.L.
        • Lutz C.T.
        • Campbell K.S.
        • Weiner L.M.
        Blocking NK cell inhibitory self-recognition promotes antibody-dependent cellular cytotoxicity in a model of anti-lymphoma therapy.
        J Immunol. 2008; 180 (PubMed Central PMCID: PMC2810560): 6392-6401
        • Weng W.K.
        • Levy R.
        Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma.
        J Clin Oncol. 2003; 21: 3940-3947https://doi.org/10.1200/JCO.2003.05.013
        • 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 (PubMed Central PMCID: PMC3167809): e22842https://doi.org/10.1371/journal.pone.0022842
        • Beier C.P.
        • Kumar P.
        • Meyer K.
        • Leukel P.
        • Bruttel V.
        • Aschenbrenner I.
        • et al.
        The cancer stem cell subtype determines immune infiltration of glioblastoma.
        Stem Cells Dev. 2012; 21 (PubMed Central PMCID: PMC3464079): 2753-2761https://doi.org/10.1089/scd.2011.0660
        • 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: ra19https://doi.org/10.1126/scisignal.aad1884
        • Bollard C.M.
        • Rossig C.
        • Calonge M.J.
        • Huls M.H.
        • Wagner H.J.
        • Massague J.
        • et al.
        Adapting a transforming growth factor beta-related tumor protection strategy to enhance antitumor immunity.
        Blood. 2002; 99: 3179-3187
        • Foster A.E.
        • Dotti G.
        • Lu A.
        • Khalil M.
        • Brenner M.K.
        • Heslop H.E.
        • et al.
        Antitumor activity of EBV-specific T lymphocytes transduced with a dominant negative TGF-beta receptor.
        J Immunother. 2008; 31 (PubMed Central PMCID: PMC2745436): 500-505https://doi.org/10.1097/CJI.0b013e318177092b
        • Yang B.
        • Liu H.
        • Shi W.
        • Wang Z.
        • Sun S.
        • Zhang G.
        • et al.
        Blocking transforming growth factor-beta signaling pathway augments antitumor effect of adoptive NK-92 cell therapy.
        Int Immunopharmacol. 2013; 17: 198-204https://doi.org/10.1016/j.intimp.2013.06.003
        • Zwirner N.W.
        • Fuertes M.B.
        • Girart M.V.
        • Domaica C.I.
        • Rossi L.E.
        Cytokine-driven regulation of NK cell functions in tumor immunity: role of the MICA-NKG2D system.
        Cytokine Growth Factor Rev. 2007; 18: 159-170https://doi.org/10.1016/j.cytogfr.2007.01.013
        • Mattei F.
        • Schiavoni G.
        • Belardelli F.
        • Tough D.F.
        IL-15 is expressed by dendritic cells in response to type I IFN, double-stranded RNA, or lipopolysaccharide and promotes dendritic cell activation.
        J Immunol. 2001; 167: 1179-1187
        • Rosenberg S.A.
        • Lotze M.T.
        • Muul L.M.
        • Leitman S.
        • Chang A.E.
        • Ettinghausen S.E.
        • et al.
        Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer.
        N Engl J Med. 1985; 313: 1485-1492https://doi.org/10.1056/NEJM198512053132327
        • Rosenberg S.A.
        • Lotze M.T.
        • Yang J.C.
        • Aebersold P.M.
        • Linehan W.M.
        • Seipp C.A.
        • et al.
        Experience with the use of high-dose interleukin-2 in the treatment of 652 cancer patients.
        Ann Surg. 1989; 210 (discussion 84-5) (PubMed Central PMCID: PMC1357927): 474-484
        • Astoul P.
        • Viallat J.R.
        • Laurent J.C.
        • Brandely M.
        • Boutin C.
        Intrapleural recombinant IL-2 in passive immunotherapy for malignant pleural effusion.
        Chest. 1993; 103: 209-213
        • Goey S.H.
        • Eggermont A.M.
        • Punt C.J.
        • Slingerland R.
        • Gratama J.W.
        • Oosterom R.
        • et al.
        Intrapleural administration of interleukin 2 in pleural mesothelioma: a phase I-II study.
        Br J Cancer. 1995; 72 (PubMed Central PMCID: PMC2033917): 1283-1288
        • Conlon K.C.
        • Lugli E.
        • Welles H.C.
        • Rosenberg S.A.
        • Fojo A.T.
        • Morris J.C.
        • et al.
        Redistribution, hyperproliferation, activation of natural killer cells and CD8 T cells, and cytokine production during first-in-human clinical trial of recombinant human interleukin-15 in patients with cancer.
        J Clin Oncol. 2015; 33 (PubMed Central PMCID: PMC4268254): 74-82https://doi.org/10.1200/JCO.2014.57.3329
        • Nagashima S.
        • Mailliard R.
        • Kashii Y.
        • Reichert T.E.
        • Herberman R.B.
        • Robbins P.
        • et al.
        Stable transduction of the interleukin-2 gene into human natural killer cell lines and their phenotypic and functional characterization in vitro and in vivo.
        Blood. 1998; 91: 3850-3861
        • 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: 1081-1088https://doi.org/10.1182/blood-2014-02-556837
        • Maus M.V.
        • Grupp S.A.
        • Porter D.L.
        • June C.H.
        Antibody-modified T cells: CARs take the front seat for hematologic malignancies.
        Blood. 2014; 123 (PubMed Central PMCID: PMC3999751): 2625-2635https://doi.org/10.1182/blood-2013-11-492231
        • Bonini C.
        • Ferrari G.
        • Verzeletti S.
        • Servida P.
        • Zappone E.
        • Ruggieri L.
        • et al.
        HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia.
        Science. 1997; 276: 1719-1724
        • Bonini C.
        • Bordignon C.
        Potential and limitations of HSV-TK-transduced donor peripheral blood lymphocytes after allo-BMT.
        Hematol Cell Ther. 1997; 39: 273-274
        • Vogler I.
        • Newrzela S.
        • Hartmann S.
        • Schneider N.
        • von Laer D.
        • Koehl U.
        • et al.
        An improved bicistronic CD20/tCD34 vector for efficient purification and in vivo depletion of gene-modified T cells for adoptive immunotherapy.
        Mol Ther. 2010; 18 (PubMed Central PMCID: PMC2911262): 1330-1338https://doi.org/10.1038/mt.2010.83
        • Straathof K.C.
        • Pule M.A.
        • Yotnda P.
        • Dotti G.
        • Vanin E.F.
        • Brenner M.K.
        • et al.
        An inducible caspase 9 safety switch for T-cell therapy.
        Blood. 2005; 105 (PubMed Central PMCID: PMC1895037): 4247-4254https://doi.org/10.1182/blood-2004-11-4564
        • Di Stasi A.
        • Tey S.K.
        • Dotti G.
        • Fujita Y.
        • Kennedy-Nasser A.
        • Martinez C.
        • et al.
        Inducible apoptosis as a safety switch for adoptive cell therapy.
        N Engl J Med. 2011; 365 (PubMed Central PMCID: PMC3236370): 1673-1683https://doi.org/10.1056/NEJMoa1106152
        • Leboeuf C.
        • Mailly L.
        • Wu T.
        • Bour G.
        • Durand S.
        • Brignon N.
        • et al.
        In vivo proof of concept of adoptive immunotherapy for hepatocellular carcinoma using allogeneic suicide gene-modified killer cells.
        Mol Ther. 2014; 22 (PubMed Central PMCID: PMC3944343): 634-644https://doi.org/10.1038/mt.2013.277
        • Hoyos V.
        • Savoldo B.
        • Quintarelli C.
        • Mahendravada A.
        • Zhang M.
        • Vera J.
        • et al.
        Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety.
        Leukemia. 2010; 24 (PubMed Central PMCID: PMC2888148): 1160-1170https://doi.org/10.1038/leu.2010.75
        • Boissel L.
        • Betancur M.
        • Wels W.S.
        • Tuncer H.
        • Klingemann H.
        Transfection with mRNA for CD19 specific chimeric antigen receptor restores NK cell mediated killing of CLL cells.
        Leuk Res. 2009; 33 (PubMed Central PMCID: PMC3047414): 1255-1259https://doi.org/10.1016/j.leukres.2008.11.024
        • Muller T.
        • Uherek C.
        • Maki G.
        • Chow K.U.
        • Schimpf A.
        • Klingemann H.G.
        • et al.
        Expression of a CD20-specific chimeric antigen receptor enhances cytotoxic activity of NK cells and overcomes NK-resistance of lymphoma and leukemia cells.
        Cancer Immunol Immunother. 2008; 57: 411-423https://doi.org/10.1007/s00262-007-0383-3
        • 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 (PubMed Central PMCID: PMC2821468): 147-154https://doi.org/10.1038/cgt.2009.61
        • 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: 830-840https://doi.org/10.3109/14653249.2012.671519
        • Boissel L.
        • Betancur M.
        • Lu W.
        • Wels W.S.
        • Marino T.
        • Van Etten R.A.
        • et al.
        Comparison of mRNA and lentiviral based transfection of natural killer cells with chimeric antigen receptors recognizing lymphoid antigens.
        Leuk Lymphoma. 2012; 53 (PubMed Central PMCID: PMC3491067): 958-965https://doi.org/10.3109/10428194.2011.634048
        • Chu Y.
        • Hochberg J.
        • Yahr A.
        • Ayello J.
        • van de Ven C.
        • Barth M.
        • et al.
        Targeting CD20+ aggressive B-cell non-hodgkin lymphoma by Anti-CD20 CAR mRNA-modified expanded natural killer cells in vitro and in NSG mice.
        Cancer Immunol Res. 2015; 3: 333-344https://doi.org/10.1158/2326-6066.CIR-14-0114
        • Lee J.M.
        • Yoon S.H.
        • Kim H.S.
        • Kim S.Y.
        • Sohn H.J.
        • Oh S.T.
        • et al.
        Direct and indirect antitumor effects by human peripheral blood lymphocytes expressing both chimeric immune receptor and interleukin-2 in ovarian cancer xenograft model.
        Cancer Gene Ther. 2010; 17: 742-750https://doi.org/10.1038/cgt.2010.30
        • Jiang W.
        • Zhang C.
        • Tian Z.
        • Zhang J.
        hIL-15 gene-modified human natural killer cells (NKL-IL15) augments the anti-human hepatocellular carcinoma effect in vivo.
        Immunobiology. 2014; 219: 547-553https://doi.org/10.1016/j.imbio.2014.03.007

      CHORUS Manuscript

      View Open Manuscript