We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine

Leveraging natural killer cells for cancer immunotherapy

    Steven K Grossenbacher

    Department of Dermatology, University of California Davis School of Medicine, CA 95817, USA

    ,
    Ethan G Aguilar

    Department of Dermatology, University of California Davis School of Medicine, CA 95817, USA

    &
    William J Murphy

    *Author for correspondence:

    E-mail Address: wmjmurphy@ucdavis.edu

    Department of Dermatology, University of California Davis School of Medicine, CA 95817, USA

    Department of Internal Medicine, University of California Davis School of Medicine, CA 95817, USA

    Published Online:https://doi.org/10.2217/imt-2017-0013

    Natural killer (NK) cells are potent antitumor effector cells of the innate immune system. Based on their ability to eradicate tumors in vitro and in animal models, significant enthusiasm surrounds the prospect of leveraging human NK cells as vehicles for cancer immunotherapy. While interest in manipulating the effector functions of NK cells has existed for over 30 years, there is renewed optimism for this approach today. Although T cells receive much of the clinical and preclinical attention when it comes to cancer immunotherapy, new strategies are utilizing adoptive NK-cell immunotherapy and monoclonal antibodies and engineered molecules which have been developed to specifically activate NK cells against tumors. Despite the numerous challenges associated with the preclinical and clinical development of NK cell-based therapies for cancer, NK cells possess many unique immunological properties and hold the potential to provide an effective means for cancer immunotherapy.

    References

    • 1 Cerwenka A, Lanier LL. Natural killer cell memory in infection, inflammation and cancer. Nat. Rev. Immunol. 16(2), 112–123 (2016).
    • 2 Guillerey C, Huntington ND, Smyth MJ. Targeting natural killer cells in cancer immunotherapy. Nat. Immunol. 17(9), 1025–1036 (2016).
    • 3 Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S. Functions of natural killer cells. Nat. Immunol. 9(5), 503–510 (2008).
    • 4 Morvan MG, Lanier LL. NK cells and cancer: you can teach innate cells new tricks. Nat. Rev. Cancer 16(1), 7–19 (2016).
    • 5 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. 6, 605 (2015).
    • 6 Kumar V, Mcnerney ME. A new self: MHC-class-I-independent natural-killer-cell self-tolerance. Nat. Rev. Immunol. 5(5), 363–374 (2005).
    • 7 Pegram HJ, Andrews DM, Smyth MJ, Darcy PK, Kershaw MH. Activating and inhibitory receptors of natural killer cells. Immunol. Cell Biol. 89(2), 216–224 (2011).
    • 8 Long EO. Negative signaling by inhibitory receptors: the NK cell paradigm. Immunol. Rev. 224, 70–84 (2008).
    • 9 Husain Z, Alper CA, Yunis EJ, Dubey DP. Complex expression of natural killer receptor genes in single natural killer cells. Immunology 106(3), 373–380 (2002).
    • 10 Kim S, Poursine-Laurent J, Truscott SM et al. Licensing of natural killer cells by host major histocompatibility complex class I molecules. Nature 436(7051), 709–713 (2005).
    • 11 Tarek N, Le Luduec JB, Gallagher MM et al. Unlicensed NK cells target neuroblastoma following anti-GD2 antibody treatment. J. Clin. Invest. 122(9), 3260–3270 (2012).
    • 12 Long EO, Kim HS, Liu D, Peterson ME, Rajagopalan S. Controlling natural killer cell responses: integration of signals for activation and inhibition. Annu. Rev. Immunol. 31, 227–258 (2013).
    • 13 Shevtsov M, Multhoff G. Immunological and translational aspects of NK cell-based antitumor immunotherapies. Front. Immunol. 7, 492 (2016).
    • 14 Sun JC, Beilke JN, Lanier LL. Adaptive immune features of natural killer cells. Nature 457(7229), 557–561 (2009).
    • 15 Schlums H, Cichocki F, Tesi B et al. Cytomegalovirus infection drives adaptive epigenetic diversification of NK cells with altered signaling and effector function. Immunity 42(3), 443–456 (2015).
    • 16 Van Den Boorn JG, Jakobs C, Hagen C et al. Inflammasome-dependent induction of adaptive NK cell memory. Immunity 44(6), 1406–1421 (2016).
    • 17 Cichocki F, Cooley S, Davis Z et al. CD56dimCD57+NKG2C+ NK cell expansion is associated with reduced leukemia relapse after reduced intensity HCT. Leukemia 30(2), 456–463 (2016).
    • 18 Lee J, Zhang T, Hwang I et al. Epigenetic modification and antibody-dependent expansion of memory-like NK cells in human cytomegalovirus-infected individuals. Immunity 42(3), 431–442 (2015).
    • 19 Della Chiesa M, Pesce S, Muccio L et al. Features of memory-like and PD-1(+) human NK cell subsets. Front. Immunol. 7, 351 (2016).
    • 20 Miller JS, Soignier Y, Panoskaltsis-Mortari A et al. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Blood 105(8), 3051–3057 (2005).
    • 21 Burns LJ, Weisdorf DJ, Defor TE et al. IL-2-based immunotherapy after autologous transplantation for lymphoma and breast cancer induces immune activation and cytokine release: a Phase I/II trial. Bone Marrow Transplant. 32(2), 177–186 (2003).
    • 22 Gasteiger G, Hemmers S, Bos PD, Sun JC, Rudensky AY. IL-2-dependent adaptive control of NK cell homeostasis. J. Exp. Med. 210(6), 1179–1187 (2013).
    • 23 Gasteiger G, Hemmers S, Firth MA et al. IL-2-dependent tuning of NK cell sensitivity for target cells is controlled by regulatory T cells. J. Exp. Med. 210(6), 1167–1178 (2013).
    • 24 Ghiringhelli F, Menard C, Terme M et al. CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-beta-dependent manner. J. Exp. Med. 202(8), 1075–1085 (2005).
    • 25 Smyth MJ, Teng MW, Swann J, Kyparissoudis K, Godfrey DI, Hayakawa Y. CD4+CD25+ T regulatory cells suppress NK cell-mediated immunotherapy of cancer. J. Immunol. 176(3), 1582–1587 (2006).
    • 26 Lodolce JP, Boone DL, Chai S et al. IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation. Immunity 9(5), 669–676 (1998).
    • 27 Kennedy MK, Glaccum M, Brown SN et al. Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice. J. Exp. Med. 191(5), 771–780 (2000).
    • 28 Porrata LF, Inwards DJ, Micallef IN et al. Interleukin-15 affects patient survival through natural killer cell recovery after autologous hematopoietic stem cell transplantation for non-Hodgkin lymphomas. Clin. Dev. Immunol. 2010, 914945 (2010).
    • 29 Conlon KC, Lugli E, Welles HC 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. 33(1), 74–82 (2015).
    • 30 Perez-Martinez A, Fernandez L, Valentin J et al. 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 17(11), 1594–1603 (2015).
    • 31 Cooley S, Verneris MR, Curtsinger J et al. Recombinant human IL-15 promotes in vivo expansion of adoptively transferred NK cells in a first-in-human Phase I dose escalation study in patients with AML. Blood 120(21), 894 (2012).
    • 32 Allavena P, Paganin C, Zhou D, Bianchi G, Sozzani S, Mantovani A. Interleukin-12 is chemotactic for natural killer cells and stimulates their interaction with vascular endothelium. Blood 84(7), 2261–2268 (1994).
    • 33 Gollob JA, Mier JW, Veenstra K et al. Phase I trial of twice-weekly intravenous interleukin 12 in patients with metastatic renal cell cancer or malignant melanoma: ability to maintain IFN-gamma induction is associated with clinical response. Clin. Cancer Res. 6(5), 1678–1692 (2000).
    • 34 Kim PS, Kwilas AR, Xu W et al. IL-15 superagonist/IL-15RalphaSushi-Fc fusion complex (IL-15SA/IL-15RalphaSu-Fc; ALT-803) markedly enhances specific subpopulations of NK and memory CD8+ T cells, and mediates potent anti-tumor activity against murine breast and colon carcinomas. Oncotarget 7(13), 16130–16145 (2016).
    • 35 Cooper MA, Elliott JM, Keyel PA, Yang L, Carrero JA, Yokoyama WM. Cytokine-induced memory-like natural killer cells. Proc. Natl Acad Sci. USA 106(6), 1915–1919 (2009).
    • 36 Romee R, Rosario M, Berrien-Elliott MM et al. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. Sci. Transl. Med. 8(357), 357ra123 (2016).
    • 37 Adib-Conquy M, Scott-Algara D, Cavaillon JM, Souza-Fonseca-Guimaraes F. TLR-mediated activation of NK cells and their role in bacterial/viral immune responses in mammals. Immunol. Cell Biol. 92(3), 256–262 (2014).
    • 38 Brackett CM, Kojouharov B, Veith J et al. Toll-like receptor-5 agonist, entolimod, suppresses metastasis and induces immunity by stimulating an NK-dendritic-CD8+ T-cell axis. Proc. Natl Acad Sci. USA 113(7), E874–883 (2016).
    • 39 Yang H, Brackett CM, Morales-Tirado VM et al. The Toll-like receptor 5 agonist entolimod suppresses hepatic metastases in a murine model of ocular melanoma via an NK cell-dependent mechanism. Oncotarget 7(3), 2936–2950 (2016).
    • 40 Reddy N, Hernandez-Ilizaliturri FJ, Deeb G et al. Immunomodulatory drugs stimulate natural killer-cell function, alter cytokine production by dendritic cells, and inhibit angiogenesis enhancing the anti-tumour activity of rituximab in vivo. Br. J. Haematol. 140(1), 36–45 (2008).
    • 41 Chanan-Khan AA, Chitta K, Ersing N et al. Biological effects and clinical significance of lenalidomide-induced tumour flare reaction in patients with chronic lymphocytic leukaemia: in vivo evidence of immune activation and antitumour response. Br. J. Haematol. 155(4), 457–467 (2011).
    • 42 Wang W, Erbe AK, Hank JA, Morris ZS, Sondel PM. NK Cell-mediated antibody-dependent cellular cytotoxicity in cancer immunotherapy. Front. Immunol. 6, 368 (2015).
    • 43 Seidel UJ, Schlegel P, Lang P. Natural killer cell mediated antibody-dependent cellular cytotoxicity in tumor immunotherapy with therapeutic antibodies. Front. Immunol. 4, 76 (2013).
    • 44 Mandelboim O, Malik P, Davis DM, Jo CH, Boyson JE, Strominger JL. Human CD16 as a lysis receptor mediating direct natural killer cell cytotoxicity. Proc. Natl Acad Sci. USA 96(10), 5640–5644 (1999).
    • 45 Sondel PM, Hank JA. Combination therapy with interleukin-2 and antitumor monoclonal antibodies. Cancer J. Sci. Am. 3(Suppl. 1), S121–127 (1997).
    • 46 Gleason MK, Verneris MR, Todhunter DA et al. Bispecific and trispecific killer cell engagers directly activate human NK cells through CD16 signaling and induce cytotoxicity and cytokine production. Mol. Cancer Ther. 11(12), 2674–2684 (2012).
    • 47 Schmohl JU, Felices M, Taras E, Miller JS, Vallera DA. Enhanced ADCC and NK cell activation of an anticarcinoma bispecific antibody by genetic insertion of a modified IL-15 cross-linker. Mol. Ther. 24(7), 1312–1322 (2016).
    • 48 Vallera DA, Felices M, Mcelmurry R et al. 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. 22(14), 3440–3450 (2016).
    • 49 Gleason MK, Ross JA, Warlick ED et al. CD16xCD33 bispecific killer cell engager (BiKE) activates NK cells against primary MDS and MDSC CD33+ targets. Blood 123(19), 3016–3026 (2014).
    • 50 Romee R, Foley B, Lenvik T et al. NK cell CD16 surface expression and function is regulated by a disintegrin and metalloprotease-17 (ADAM17). Blood 121(18), 3599–3608 (2013).
    • 51 Chester C, Fritsch K, Kohrt HE. Natural killer cell immunomodulation: targeting activating, inhibitory, and co-stimulatory receptor signaling for cancer immunotherapy. Front. Immunol. 6, 601 (2015).
    • 52 Benson DM Jr, Bakan CE, Mishra A et al. The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti-PD-1 antibody. Blood 116(13), 2286–2294 (2010).
    • 53 Carlsten M, Korde N, Kotecha R et al. Checkpoint inhibition of KIR2D with the monoclonal antibody IPH2101 induces contraction and hyporesponsiveness of NK cells in patients with myeloma. Clin. Cancer Res. 22(21), 5211–5222 (2016).
    • 54 Childs RW, Carlsten M. Therapeutic approaches to enhance natural killer cell cytotoxicity against cancer: the force awakens. Nat. Rev. Drug Discov. 14(7), 487–498 (2015).
    • 55 Seggewiss R, Einsele H. Immune reconstitution after allogeneic transplantation and expanding options for immunomodulation: an update. Blood 115(19), 3861–3868 (2010).
    • 56 Savani BN, Mielke S, Adams S et al. Rapid natural killer cell recovery determines outcome after T-cell-depleted HLA-identical stem cell transplantation in patients with myeloid leukemias but not with acute lymphoblastic leukemia. Leukemia 21(10), 2145–2152 (2007).
    • 57 Ruggeri L, Capanni M, Urbani E et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 295(5562), 2097–2100 (2002).
    • 58 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. 17(19), 6287–6297 (2011).
    • 59 Kim JY, Son YO, Park SW et al. Increase of NKG2D ligands and sensitivity to NK cell-mediated cytotoxicity of tumor cells by heat shock and ionizing radiation. Exp. Mol. Med. 38(5), 474–484 (2006).
    • 60 Ames E, Canter RJ, Grossenbacher SK et al. Enhanced targeting of stem-like solid tumor cells with radiation and natural killer cells. Oncoimmunology 4(9), e1036212 (2015).
    • 61 Gasser S, Orsulic S, Brown EJ, Raulet DH. The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature 436(7054), 1186–1190 (2005).
    • 62 Gerlinger M, Rowan AJ, Horswell S et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 366(10), 883–892 (2012).
    • 63 Wicha MS, Liu S, Dontu G. Cancer stem cells: an old idea – a paradigm shift. Cancer Res. 66(4), 1883–1890, discussion 1895–1886 (2006).
    • 64 Ames E, Canter RJ, Grossenbacher SK et al. NK cells preferentially target tumor cells with a cancer stem cell phenotype. J. Immunol. 195(8), 4010–4019 (2015).
    • 65 Castriconi R, Daga A, Dondero A et al. NK cells recognize and kill human glioblastoma cells with stem cell-like properties. J. Immunol. 182(6), 3530–3539 (2009).
    • 66 Ferreira-Teixeira M, Paiva-Oliveira D, Parada B et al. Natural killer cell-based adoptive immunotherapy eradicates and drives differentiation of chemoresistant bladder cancer stem-like cells. BMC Med. 14(1), 163 (2016).
    • 67 Lundqvist A, Berg M, Smith A, Childs RW. Bortezomib treatment to potentiate the anti-tumor immunity of ex-vivo expanded adoptively infused autologous natural killer cells. J. Cancer 2, 383–385 (2011).
    • 68 Lundqvist A, Su S, Rao S, Childs R. Cutting edge: bortezomib-treated tumors sensitized to NK-cell apoptosis paradoxically acquire resistance to antigen-specific T cells. J. Immunol. 184(3), 1139–1142 (2010).
    • 69 Hallett WH, Ames E, Motarjemi M et al. Sensitization of tumor cells to NK cell-mediated killing by proteasome inhibition. J. Immunol. 180(1), 163–170 (2008).
    • 70 Yoo JY, Jaime-Ramirez AC, Bolyard C et al. Bortezomib treatment sensitizes oncolytic HSV-1-treated tumors to NK-cell immunotherapy. Clin. Cancer Res. 22(21), 5265–5276 (2016).
    • 71 Zhu S, Denman CJ, Cobanoglu ZS et al. The narrow-spectrum HDAC inhibitor entinostat enhances NKG2D expression without NK-cell toxicity, leading to enhanced recognition of cancer cells. Pharm. Res. 32(3), 779–792 (2015).
    • 72 Diermayr S, Himmelreich H, Durovic B et al. NKG2D ligand expression in AML increases in response to HDAC inhibitor valproic acid and contributes to allorecognition by NK-cell lines with single KIR-HLA class I specificities. Blood 111(3), 1428–1436 (2008).
    • 73 Maude SL, Teachey DT, Porter DL, Grupp SA. CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Blood 125(26), 4017–4023 (2015).
    • 74 Ramos CA, Savoldo B, Dotti G. CD19-CAR trials. Cancer J. 20(2), 112–118 (2014).
    • 75 Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood 127(26), 3321–3330 (2016).
    • 76 Beatty GL, Gladney WL. Immune escape mechanisms as a guide for cancer immunotherapy. Clin. Cancer Res. 21(4), 687–692 (2015).
    • 77 Khong HT, Restifo NP. Natural selection of tumor variants in the generation of ‘tumor escape’ phenotypes. Nat. Immunol. 3(11), 999–1005 (2002).
    • 78 Sahm C, Schonfeld K, Wels WS. 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. 61(9), 1451–1461 (2012).
    • 79 Carlsten M, Childs RW. Genetic manipulation of NK cells for cancer immunotherapy: techniques and clinical implications. Front. Immunol. 6, 266 (2015).
    • 80 Romanski A, Uherek C, Bug G et al. CD19-CAR engineered NK-92 cells are sufficient to overcome NK cell resistance in B-cell malignancies. J. Cell. Mol. Med. 20(7), 1287–1294 (2016).
    • 81 Han J, Chu J, Keung Chan W et al. CAR-engineered NK cells targeting wild-type EGFR and EGFRvIII enhance killing of glioblastoma and patient-derived glioblastoma stem cells. Sci. Rep. 5, 11483 (2015).
    • 82 Schonfeld K, Sahm C, Zhang C et al. Selective inhibition of tumor growth by clonal NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor. Mol. Ther. 23(2), 330–338 (2015).
    • 83 Jochems C, Hodge JW, Fantini M et al. An NK cell line (haNK) expressing high levels of granzyme and engineered to express the high affinity CD16 allele. Oncotarget 7(52), 86359–86373 (2016).
    • 84 Mamessier E, Sylvain A, Thibult ML et al. Human breast cancer cells enhance self tolerance by promoting evasion from NK cell antitumor immunity. J. Clin. Invest. 121(9), 3609–3622 (2011).
    • 85 Melero I, Rouzaut A, Motz GT, Coukos G. T-cell and NK-cell infiltration into solid tumors: a key limiting factor for efficacious cancer immunotherapy. Cancer Discov. 4(5), 522–526 (2014).
    • 86 Somanchi SS, Somanchi A, Cooper LJ, Lee DA. Engineering lymph node homing of ex vivo-expanded human natural killer cells via trogocytosis of the chemokine receptor CCR7. Blood 119(22), 5164–5172 (2012).
    • 87 Suzuki E, Kataoka TR, Hirata M et al. Trogocytosis-mediated expression of HER2 on immune cells may be associated with a pathological complete response to trastuzumab-based primary systemic therapy in HER2-overexpressing breast cancer patients. BMC Cancer 15, 39 (2015).
    • 88 Cho FN, Chang TH, Shu CW et al. Enhanced cytotoxicity of natural killer cells following the acquisition of chimeric antigen receptors through trogocytosis. PLoS One 9(10), e109352 (2014).
    • 89 Miner CA, Giri TK, Meyer CE, Shabsovich M, Tripathy SK. Acquisition of activation receptor ligand by trogocytosis renders NK cells hyporesponsive. J. Immunol. 194(4), 1945–1953 (2015).
    • 90 Denman CJ, Senyukov VV, Somanchi SS et al. Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. PLoS One 7(1), e30264 (2012).