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PMID: 26588681 Published · ppublish English Journal Article Review

Natural Killer Cell Adoptive Transfer Therapy: Exploiting the First Line of Defense Against Cancer.

Cancer journal (Sudbury, Mass.) ·Vol. 21 ·No. 6 ·2015-00-00 ·Pages 486-91

Davis ZB, Felices M, Verneris MR, Miller JS

Abstract

Natural killer (NK) cells constitute an important component of the initial immunological response against transformed cells. However, chronic exposure to the tumor microenvironment can fundamentally alter the ability of NK cells to sufficiently control tumor progression. Thus, the adoptive transfer of healthy, functional NK cells as an interventional therapy has been an area of great interest for improving patient outcomes. Recent developments in the field have provided a better understanding of what makes the NK compartment effective against malignant cells. Moreover, there are now multiple potential sources of NK cell products for infusion as well as techniques to manipulate these cells to enhance their antitumor functions. This review explores the advantages and disadvantages of various sources of NK cells as well as prospective therapeutic enhancements to adoptively transferred NK cells.

MeSH Terms
Adoptive Transfer/methods Humans Immunotherapy, Adoptive/methods Killer Cells, Natural/immunology Neoplasms/therapy
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Davis Zachary B
From the Blood and Marrow Transplant Program, Department of Pediatrics, University of Minnesota, Minneapolis, MN.
Felices Martin
Verneris Michael R
Miller Jeffrey S
References (82)
82 references, click to expand
  1. Human embryonic stem cells differentiate into a homogeneous population of natural killer cells with potent in vivo antitumor activity.
    Blood. 2009 Jun 11;113(24):6094-101 PMID: 19365083
  2. Expansion of a unique CD57⁺NKG2Chi natural killer cell subset during acute human cytomegalovirus infection.
    Proc Natl Acad Sci U S A. 2011 Sep 6;108(36):14725-32 PMID: 21825173
  3. Natural killer cells and regulatory T cells: how to manipulate a graft for optimal GVL.
    Hematology Am Soc Hematol Educ Program. 2013;2013:335-41 PMID: 24319201
  4. Characterization of a cell line, NKL, derived from an aggressive human natural killer cell leukemia.
    Exp Hematol. 1996 Feb;24(3):406-15 PMID: 8599969
  5. Sequential production of interferon-gamma by NK1.1(+) T cells and natural killer cells is essential for the antimetastatic effect of alpha-galactosylceramide.
    Blood. 2002 Feb 15;99(4):1259-66 PMID: 11830474
  6. Cellular immunotherapy of malignancies using the clonal natural killer cell line NK-92.
    J Hematother Stem Cell Res. 2001 Aug;10(4):535-44 PMID: 11522236
  7. Perforin and interferon-gamma activities independently control tumor initiation, growth, and metastasis.
    Blood. 2001 Jan 1;97(1):192-7 PMID: 11133760
  8. Matrix metalloprotease inhibitors restore impaired NK cell-mediated antibody-dependent cellular cytotoxicity in human immunodeficiency virus type 1 infection.
    J Virol. 2009 Sep;83(17):8705-12 PMID: 19553339
  9. Bispecific and trispecific killer cell engagers directly activate human NK cells through CD16 signaling and induce cytotoxicity and cytokine production.
    Mol Cancer Ther. 2012 Dec;11(12):2674-84 PMID: 23075808
  10. NK cell-mediated targeting of human cancer and possibilities for new means of immunotherapy.
    Cancer Immunol Immunother. 2008 Oct;57(10):1541-52 PMID: 18317755
  11. A central role for death receptor-mediated apoptosis in the rejection of tumors by NK cells.
    J Immunol. 2001 Aug 15;167(4):2068-73 PMID: 11489989
  12. Cytokine-induced memory-like natural killer cells.
    Proc Natl Acad Sci U S A. 2009 Feb 10;106(6):1915-9 PMID: 19181844
  13. The IL-15-based superagonist ALT-803 promotes the antigen-independent conversion of memory CD8+ T cells into innate-like effector cells with antitumor activity.
    Oncoimmunology. 2013 Nov 1;2(11):e26442 PMID: 24404427
  14. CD16xCD33 bispecific killer cell engager (BiKE) activates NK cells against primary MDS and MDSC CD33+ targets.
    Blood. 2014 May 8;123(19):3016-26 PMID: 24652987
  15. Natural killer cell alloreactivity for leukemia therapy.
    J Immunother. 2005 May-Jun;28(3):175-82 PMID: 15838373
  16. Interleukin 2 and interleukin 15 differentially predispose natural killer cells to apoptosis mediated by endothelial and tumour cells.
    Br J Haematol. 2001 Nov;115(2):442-50 PMID: 11703348
  17. A Phase I Trial of the Anti-KIR Antibody IPH2101 and Lenalidomide in Patients with Relapsed/Refractory Multiple Myeloma.
    Clin Cancer Res. 2015 Sep 15;21(18):4055-61 PMID: 25999435
  18. Downregulation of Fc gamma receptor IIIA alpha (CD16-II) on natural killer cells induced by anti-CD16 mAb is independent of protein tyrosine kinases and protein kinase C.
    Cell Immunol. 1994 Oct 1;158(1):208-17 PMID: 8087866
  19. CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-beta-dependent manner.
    J Exp Med. 2005 Oct 17;202(8):1075-85 PMID: 16230475
  20. The biology of natural killer cells in cancer, infection, and pregnancy.
    Exp Hematol. 2001 Oct;29(10):1157-68 PMID: 11602317
  21. Pluripotent stem cell-derived natural killer cells for cancer therapy.
    Transl Res. 2010 Sep;156(3):147-54 PMID: 20801411
  22. Cytokine activation induces human memory-like NK cells.
    Blood. 2012 Dec 6;120(24):4751-60 PMID: 22983442
  23. 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 May;28(4):274-82 PMID: 23611188
  24. Clearance of acute myeloid leukemia by haploidentical natural killer cells is improved using IL-2 diphtheria toxin fusion protein.
    Blood. 2014 Jun 19;123(25):3855-63 PMID: 24719405
  25. "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 Feb;5(2):112-7 PMID: 1234049
  26. Activating and inhibitory NK cell receptors.
    Adv Exp Med Biol. 1998;452:13-8 PMID: 9889954
  27. NK cell CD16 surface expression and function is regulated by a disintegrin and metalloprotease-17 (ADAM17).
    Blood. 2013 May 2;121(18):3599-608 PMID: 23487023
  28. NK-cell reconstitution after haploidentical hematopoietic stem-cell transplantations: immaturity of NK cells and inhibitory effect of NKG2A override GvL effect.
    Blood. 2005 May 15;105(10):4135-42 PMID: 15687235
  29. Human embryonic stem cell-derived NK cells acquire functional receptors and cytolytic activity.
    J Immunol. 2005 Oct 15;175(8):5095-103 PMID: 16210613
  30. Melanoma cells inhibit natural killer cell function by modulating the expression of activating receptors and cytolytic activity.
    Cancer Res. 2012 Mar 15;72(6):1407-15 PMID: 22258454
  31. A phase 1 trial of the anti-KIR antibody IPH2101 in patients with relapsed/refractory multiple myeloma.
    Blood. 2012 Nov 22;120(22):4324-33 PMID: 23033266
  32. Natural killer cell-based immunotherapeutic strategies.
    Cytotherapy. 2005;7(1):16-22 PMID: 16040380
  33. Human cytomegalovirus (CMV)-induced memory-like NKG2C(+) NK cells are transplantable and expand in vivo in response to recipient CMV antigen.
    J Immunol. 2012 Nov 15;189(10):5082-8 PMID: 23077239
  34. Donors with group B KIR haplotypes improve relapse-free survival after unrelated hematopoietic cell transplantation for acute myelogenous leukemia.
    Blood. 2009 Jan 15;113(3):726-32 PMID: 18945962
  35. Increased susceptibility to tumor initiation and metastasis in TNF-related apoptosis-inducing ligand-deficient mice.
    J Immunol. 2002 Feb 1;168(3):1356-61 PMID: 11801676
  36. Prospects for the use of NK cells in immunotherapy of human cancer.
    Nat Rev Immunol. 2007 May;7(5):329-39 PMID: 17438573
  37. Irradiated KHYG-1 retains cytotoxicity: potential for adoptive immunotherapy with a natural killer cell line.
    Int J Radiat Biol. 2006 May;82(5):355-61 PMID: 16782653
  38. 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. 2010 Sep 30;116(13):2286-94 PMID: 20460501
  39. Role of spontaneous and interleukin-2-induced natural killer cell activity in the cytotoxicity and rejection of Fas+ and Fas- tumor cells.
    Blood. 1998 Dec 1;92(11):4248-55 PMID: 9834230
  40. A phase II trial of pan-KIR2D blockade with IPH2101 in smoldering multiple myeloma.
    Haematologica. 2014 Jun;99(6):e81-3 PMID: 24658821
  41. Sustained effector function of IL-12/15/18-preactivated NK cells against established tumors.
    J Exp Med. 2012 Dec 17;209(13):2351-65 PMID: 23209317
  42. 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. 2003 Jul;32(2):177-86 PMID: 12838283
  43. CD56(dim)CD16(+) NK cells downregulate CD16 following target cell induced activation of matrix metalloproteinases.
    Leukemia. 2007 Feb;21(2):356-9; author reply 359 PMID: 17251901
  44. IPH2101, a novel anti-inhibitory KIR antibody, and lenalidomide combine to enhance the natural killer cell versus multiple myeloma effect.
    Blood. 2011 Dec 8;118(24):6387-91 PMID: 22031859
  45. Natural killer cells, viruses and cancer.
    Nat Rev Immunol. 2001 Oct;1(1):41-9 PMID: 11905813
  46. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer.
    Blood. 2005 Apr 15;105(8):3051-7 PMID: 15632206
  47. Follow the leader: NK cell receptors for classical and nonclassical MHC class I.
    Cell. 1998 Mar 20;92(6):705-7 PMID: 9529246
  48. Natural killer cell killing of acute myelogenous leukemia and acute lymphoblastic leukemia blasts by killer cell immunoglobulin-like receptor-negative natural killer cells after NKG2A and LIR-1 blockade.
    Biol Blood Marrow Transplant. 2010 May;16(5):612-21 PMID: 20139023
  49. The biology of the human natural killer cell.
    J Clin Immunol. 1982 Oct;2(4):249-63 PMID: 6292259
  50. Genetic Manipulation of NK Cells for Cancer Immunotherapy: Techniques and Clinical Implications.
    Front Immunol. 2015 Jun 10;6:266 PMID: 26113846
  51. A novel bispecific antibody format enables simultaneous bivalent and monovalent co-engagement of distinct target antigens.
    MAbs. 2011 Nov-Dec;3(6):546-57 PMID: 22123055
  52. Human NK cell education by inhibitory receptors for MHC class I.
    Immunity. 2006 Aug;25(2):331-42 PMID: 16901727
  53. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants.
    Science. 2002 Mar 15;295(5562):2097-100 PMID: 11896281
  54. Natural killer-cell differentiation by myeloid progenitors.
    Blood. 2011 Mar 31;117(13):3548-58 PMID: 21173117
  55. Interleukin-2 and the development of immunotherapy for the treatment of patients with cancer.
    Cancer J Sci Am. 2000 Feb;6 Suppl 1:S2-7 PMID: 10685650
  56. New aspects of natural-killer-cell surveillance and therapy of cancer.
    Nat Rev Cancer. 2002 Nov;2(11):850-61 PMID: 12415255
  57. Role of interleukin-15 in the development of human CD56+ natural killer cells from CD34+ hematopoietic progenitor cells.
    Blood. 1996 Apr 1;87(7):2632-40 PMID: 8639878
  58. Matrix metalloproteinases inhibition promotes the polyfunctionality of human natural killer cells in therapeutic antibody-based anti-tumour immunotherapy.
    Clin Exp Immunol. 2013 Jul;173(1):131-9 PMID: 23607800
  59. Effect of tumor cells and tumor microenvironment on NK-cell function.
    Eur J Immunol. 2014 Jun;44(6):1582-92 PMID: 24777896
  60. KHYG-1, a model for the study of enhanced natural killer cell cytotoxicity.
    Exp Hematol. 2005 Oct;33(10):1160-71 PMID: 16219538
  61. Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic tumors. II. Characterization of effector cells.
    Int J Cancer. 1975 Aug 15;16(2):230-9 PMID: 1080480
  62. Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells.
    Nat Med. 2001 Jan;7(1):94-100 PMID: 11135622
  63. Cytomegalovirus reactivation after allogeneic transplantation promotes a lasting increase in educated NKG2C+ natural killer cells with potent function.
    Blood. 2012 Mar 15;119(11):2665-74 PMID: 22180440
  64. Natural killer cell lines in tumor immunotherapy.
    Front Med. 2012 Mar;6(1):56-66 PMID: 22460449
  65. Cytokine modulation of the innate immune system in the treatment of leukemia and lymphoma.
    Adv Pharmacol. 2004;51:295-318 PMID: 15464915
  66. Natural killer cell-based immunotherapy in cancer: current insights and future prospects.
    J Intern Med. 2009 Aug;266(2):154-81 PMID: 19614820
  67. NK cells and cancer immunosurveillance.
    Oncogene. 2008 Oct 6;27(45):5932-43 PMID: 18836474
  68. Targeting of T or NK lymphocytes against tumor cells by bispecific monoclonal antibodies: role of different triggering molecules.
    Int J Cancer Suppl. 1992;7:15-8 PMID: 1428398
  69. 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 Jul 15;19(14):3844-55 PMID: 23690482
  70. Up on the tightrope: natural killer cell activation and inhibition.
    Nat Immunol. 2008 May;9(5):495-502 PMID: 18425106
  71. Interleukin-2, interleukin-15, and their roles in human natural killer cells.
    Adv Immunol. 2005;86:209-39 PMID: 15705423
  72. Involvement of a metalloprotease in spontaneous and phorbol ester-induced release of natural killer cell-associated Fc gamma RIII (CD16-II).
    J Immunol. 1991 Nov 15;147(10):3459-65 PMID: 1834741
  73. Cytokines in cancer immunity and immunotherapy.
    Immunol Rev. 2004 Dec;202:275-93 PMID: 15546400
  74. Differentiation of natural killer (NK) cells from human primitive marrow progenitors in a stroma-based long-term culture system: identification of a CD34+7+ NK progenitor.
    Blood. 1994 May 1;83(9):2594-601 PMID: 7513206
  75. Effects of IL-2 on MMP expression in freshly isolated human NK cells and the IL-2-independent NK cell line YT.
    J Immunother. 2010 Jun;33(5):475-81 PMID: 20463600
  76. Adaptive Natural Killer Cell and Killer Cell Immunoglobulin-Like Receptor-Expressing T Cell Responses are Induced by Cytomegalovirus and Are Associated with Protection against Cytomegalovirus Reactivation after Allogeneic Donor Hematopoietic Cell Transplantation.
    Biol Blood Marrow Transplant. 2015 Sep;21(9):1653-62 PMID: 26055301
  77. In vivo role of natural killer cells: involvement of large granular lymphocytes in the clearance of tumor cells in anti-asialo GM1-treated rats.
    J Immunol. 1983 Aug;131(2):1024-7 PMID: 6863925
  78. The tryptophan catabolite L-kynurenine inhibits the surface expression of NKp46- and NKG2D-activating receptors and regulates NK-cell function.
    Blood. 2006 Dec 15;108(13):4118-25 PMID: 16902152
  79. In vivo natural reactivity of mice against tumor cells.
    Int J Cancer. 1980 Apr 15;25(4):475-86 PMID: 6154658
  80. The biology of NK cells and their receptors affects clinical outcomes after hematopoietic cell transplantation (HCT).
    Immunol Rev. 2014 Mar;258(1):45-63 PMID: 24517425
  81. Utilizing chimeric antigen receptors to direct natural killer cell activity.
    Front Immunol. 2015 Apr 28;6:195 PMID: 25972867
  82. Adaptive immune features of natural killer cells.
    Nature. 2009 Jan 29;457(7229):557-61 PMID: 19136945
Article Info
Journal
Cancer journal (Sudbury, Mass.)
Abbr.
Cancer J
ISSN
1540-336X
DOI
10.1097/PPO.0000000000000156
Published
2015-00-00
Pages
486-91
Language
English
Region
United States
NLM ID
100931981
PMCID
PMC4763946
Subset
IM
Grants
NCI NIH HHS · P30 CA077598 · United States
NHLBI NIH HHS · T32 HL007062 · United States
NCI NIH HHS · P01 CA065493 · United States
NCI NIH HHS · R35 CA197292 · United States
NCI NIH HHS · P01 CA111412 · United States
External Links
PubMed source DOI: 10.1097/PPO.0000000000000156 PMC Full Text View journal details
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