Skip to main content

Advertisement

Log in

NK-92: an ‘off-the-shelf therapeutic’ for adoptive natural killer cell-based cancer immunotherapy

  • Symposium-in-writing paper
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Natural killer (NK) cells are increasingly considered as immunotherapeutic agents in particular in the fight against cancers. NK cell therapies are potentially broadly applicable and, different from their T cell counterparts, do not cause graft-versus-host disease. Efficacy and clinical in vitro or in vivo expansion of primary NK cells will however always remain variable due to individual differences of donors or patients. Long-term storage of clinical NK cell lots to allow repeated clinical applications remains an additional challenge. In contrast, the established and well-characterized cell line NK-92 can be easily and reproducibly expanded from a good manufacturing practice (GMP)-compliant cryopreserved master cell bank. Moreover, no cost-intensive cell purification methods are required. To date, NK-92 has been intensively studied. The cells displayed superior cytotoxicity against a number of tumor types tested, which was confirmed in preclinical mouse studies. Subsequent clinical testing demonstrated safety of NK-92 infusions even at high doses. Despite the phase I nature of the trials conducted so far, some efficacy was noted, particularly against lung tumors. Furthermore, to overcome tumor resistance and for specific targeting, NK-92 has been engineered to express a number of different chimeric antigen receptors (CARs), including targeting, for example, CD19 or CD20 (anti-B cell malignancies), CD38 (anti-myeloma) or human epidermal growth factor receptor 2 (HER2; ErbB2; anti-epithelial cancers). The concept of an NK cell line as an allogeneic cell therapeutic produced ‘off-the-shelf’ on demand holds great promise for the development of effective treatments.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

ADCC:

Antibody-dependent cell-mediated cytotoxicity

ALL:

Acute lymphoblastic leukemia

BIKE or TRIKE:

Bi-specific or tri-specific killer engager

CAR:

Chimeric antigen receptor

CLL:

Chronic lymphocytic leukemia

EBV:

Epstein–Barr virus

EPCAM:

Epithelial cell adhesion molecule

E:T:

Effector:target

Fc:

Fragment crystallizable region

GMP:

Good manufacturing practice

GvHD:

Graft-versus-host disease

HER2; ErbB2:

Human epidermal growth factor receptor 2

HLA:

Human leukocyte antigen

IgG:

Immunoglobulin G

IL:

Interleukin

KIR:

Killer cell immunoglobulin-like receptor

LIR-1:

Leukocyte immunoglobulin-like receptor

MICA:

MHC class I chain-related gene A

MICB:

MHC class I chain-related gene B

NK:

Natural killer

NKG:

Natural killer group

PBMC:

Peripheral blood mononuclear cell

RCC:

Renal cell carcinoma

RECIST:

Response Evaluation Criteria in Solid Tumors

scFv:

Single-chain variable fragment

SCID:

Severe combined immunodeficiency

References

  1. Klingemann HG, Martinson J (2004) Ex vivo expansion of natural killer cells for clinical applications. Cytotherapy 6:15–22

    Article  PubMed  Google Scholar 

  2. Suck G, Koh MB (2010) Emerging natural killer cell immunotherapies: large-scale ex vivo production of highly potent anticancer effectors. Hematol Oncol Stem Cell Ther 3:135–142

    Article  CAS  PubMed  Google Scholar 

  3. Childs RW, Berg M (2013) Bringing natural killer cells to the clinic: ex vivo manipulation. Hematol Am Soc Hematol Educ Progr 2013:234–246

    Article  Google Scholar 

  4. Gong JH, Maki G, Klingemann HG (1994) Characterization of a human cell line (nk-92) with phenotypical and functional characteristics of activated natural killer cells. Leukemia 8:652–658

    CAS  PubMed  Google Scholar 

  5. Tam YK, Martinson JA, Doligosa K, Klingemann HG (2003) 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 5:259–272

    Article  CAS  PubMed  Google Scholar 

  6. Tonn T, Becker S, Esser R, Schwabe D, Seifried E (2001) Cellular immunotherapy of malignancies using the clonal natural killer cell line NK-92. J Hematother Stem Cell Res 10:535–544

    Article  CAS  PubMed  Google Scholar 

  7. Maki G, Klingemann HG, Martinson JA, Tam YK (2001) Factors regulating the cytotoxic activity of the human natural killer cell line, nk-92. J Hematother Stem Cell Res 10:369–383

    Article  CAS  PubMed  Google Scholar 

  8. Luetke-Eversloh M, Killig M, Romagnani C (2013) Signatures of human nk cell development and terminal differentiation. Front Immunol 4:499

    Article  PubMed  PubMed Central  Google Scholar 

  9. Matsuo Y, Drexler HG (2003) Immunoprofiling of cell lines derived from natural killer-cell and natural killer-like t-cell leukemia-lymphoma. Leuk Res 27:935–945

    Article  CAS  PubMed  Google Scholar 

  10. Cooley S, Xiao F, Pitt M, Gleason M, McCullar V, Bergemann TL, McQueen KL, Guethlein LA, Parham P, Miller JS (2007) A subpopulation of human peripheral blood nk cells that lacks inhibitory receptors for self-mhc is developmentally immature. Blood 110:578–586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Faure M, Long EO (2002) Kir2dl4 (cd158d), an nk cell-activating receptor with inhibitory potential. J Immunol 168:6208–6214

    Article  CAS  PubMed  Google Scholar 

  12. Pazmany L, Mandelboim O, Vales-Gomez M, Davis DM, Reyburn HT, Strominger JL (1996) Protection from natural killer cell-mediated lysis by hla-g expression on target cells. Science 274:792–795

    Article  CAS  PubMed  Google Scholar 

  13. Romanski A, Bug G, Becker S, Kampfmann M, Seifried E, Hoelzer D, Ottmann OG, Tonn T (2005) Mechanisms of resistance to natural killer cell-mediated cytotoxicity in acute lymphoblastic leukemia. Exp Hematol 33:344–352

    Article  CAS  PubMed  Google Scholar 

  14. Burshtyn DN, Scharenberg AM, Wagtmann N, Rajagopalan S, Berrada K, Yi T, Kinet JP, Long EO (1996) Recruitment of tyrosine phosphatase hcp by the killer cell inhibitor receptor. Immunity 4:77–85

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Heidenreich S, ZuEulenburg C, Hildebrandt Y, Stubig T, Sierich H, Badbaran A, Eiermann TH, Binder TM, Kroger N (2012) Impact of the nk cell receptor lir-1 (ilt-2/cd85j/lilrb1) on cytotoxicity against multiple myeloma. Clin Dev immunol. 2012:652130

    Article  PubMed  PubMed Central  Google Scholar 

  16. Suck G, Branch DR, Smyth MJ, Miller RG, Vergidis J, Fahim S, Keating A (2005) Khyg-1, a model for the study of enhanced natural killer cell cytotoxicity. Exp Hematol 33:1160–1171

    Article  CAS  PubMed  Google Scholar 

  17. Gong JH, Maki G, Klingemann HG (1994) Characterization of a human cell line (nk-92) with phenotypical and functional characteristics of activated natural killer cells. Leukemia 8:652–658

    CAS  PubMed  Google Scholar 

  18. Klingemann HG, Wong E, Maki G (1996) A cytotoxic nk-cell line (nk-92) for ex vivo purging of leukemia from blood. Biol Blood Marrow Transplant Biol Blood Marrow Transplant 2:68–75

    CAS  PubMed  Google Scholar 

  19. Yan Y, Steinherz P, Klingemann HG, Dennig D, Childs BH, McGuirk J, O’Reilly RJ (1998) Antileukemia activity of a natural killer cell line against human leukemias. Clin Cancer Res 4:2859–2868

    CAS  PubMed  Google Scholar 

  20. Lowdell MW, Theocharous P (1997) “Less is more”: the role of purging in hematopoietic stem cell transplantation. Oncologist 2:268–274

    PubMed  Google Scholar 

  21. Yahng SA, Yoon JH, Shin SH, Lee SE, Cho BS, Eom KS, Kim YJ, Lee S, Kim HJ, Min CK, Kim DW, Lee JW, Min WS, Park CW, Kim Y, Cho SG (2014) Influence of ex vivo purging with clinimacs cd34(+) selection on outcome after autologous stem cell transplantation in non-Hodgkin lymphoma. Br J Haematol 164:555–564

    Article  CAS  PubMed  Google Scholar 

  22. Bais S, Bartee E, Rahman MM, McFadden G, Cogle CR (2012) Oncolytic virotherapy for hematological malignancies. Adv Virol 2012:186512

    Article  PubMed  PubMed Central  Google Scholar 

  23. Maki G, Tam YK, Berkahn L, Klingemann HG (2003) Ex vivo purging with nk-92 prior to autografting for chronic myelogenous leukemia. Bone Marrow Transplant 31:1119–1125

    Article  CAS  PubMed  Google Scholar 

  24. Maki G (2001) Ex vivo purging of stem cell autografts using cytotoxic cells. J Hematother Stem Cell Res 10:545–551

    Article  CAS  PubMed  Google Scholar 

  25. Klingemann HG (2013) Cellular therapy of cancer with natural killer cells-where do we stand? Cytotherapy 15:1185–1194

    Article  CAS  PubMed  Google Scholar 

  26. Tonn T, Seifried E (2006) Natural killer cells for the treatment of malignancies. Transfus Med Hemother 33:144–149

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  29. Tam YK, Miyagawa B, Ho VC, Klingemann HG (1999) Immunotherapy of malignant melanoma in a scid mouse model using the highly cytotoxic natural killer cell line nk-92. J Hematother 8:281–290

    Article  CAS  PubMed  Google Scholar 

  30. Whiteside TL, Griffin DL, Stanson J, Gooding W, McKenna D, Sumstad D, Kadidlo D, Gee A, Durett A, Lindblad R, Wood D, Styers D (2011) Shipping of therapeutic somatic cell products. Cytotherapy 13:201–213

    Article  PubMed  Google Scholar 

  31. Koepsell SA, Kadidlo DM, Fautsch S, McCullough J, Klingemann H, Wagner JE, Miller JS, McKenna DH Jr (2013) Successful “in-flight” activation of natural killer cells during long-distance shipping. Transfusion 53:398–403

    Article  CAS  PubMed  Google Scholar 

  32. Suck G, Branch DR, Aravena P, Mathieson M, Helke S, Keating A (2006) Constitutively polarized granules prime khyg-1 nk cells. Int Immunol 18:1347–1354

    Article  CAS  PubMed  Google Scholar 

  33. Suck G, Branch DR, Keating A (2006) Irradiated khyg-1 retains cytotoxicity: Potential for adoptive immunotherapy with a natural killer cell line. Int J Radiat Biol 82:355–361

    Article  CAS  PubMed  Google Scholar 

  34. Suck G, Tan SM, Chu S, Niam M, Vararattanavech A, Lim TJ, Koh MB (2011) Khyg-1 and nk-92 represent different subtypes of lfa-1-mediated nk cell adhesiveness. Front Biosci 3:166–178

    Article  Google Scholar 

  35. Mallett CL, McFadden C, Chen Y, Foster PJ (2012) Migration of iron-labeled khyg-1 natural killer cells to subcutaneous tumors in nude mice, as detected by magnetic resonance imaging. Cytotherapy 14:743–751

    Article  CAS  PubMed  Google Scholar 

  36. Swift BE, Williams BA, Kosaka Y, Wang XH, Medin JA, Viswanathan S, Martinez-Lopez J, Keating A (2012) Natural killer cell lines preferentially kill clonogenic multiple myeloma cells and decrease myeloma engraftment in a bioluminescent xenograft mouse model. Haematologica 97:1020–1028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yagita M, Huang CL, Umehara H, Matsuo Y, Tabata R, Miyake M, Konaka Y, Takatsuki K (2000) A novel natural killer cell line (khyg-1) from a patient with aggressive natural killer cell leukemia carrying a p53 point mutation. Leukemia 14:922–930

    Article  CAS  PubMed  Google Scholar 

  38. Porter DL, Levine BL, Kalos M, Bagg A, June CH (2011) Chimeric antigen receptor-modified t cells in chronic lymphoid leukemia. N Engl J Med 365:725–733

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wieczorek A, Uharek L (2013) Genetically modified t cells for the treatment of malignant disease. Transfus Med Hemother 40:388–402

    Article  PubMed  PubMed Central  Google Scholar 

  40. Bhat R, Watzl C (2007) Serial killing of tumor cells by human natural killer cells–enhancement by therapeutic antibodies. PLoS ONE 2:e326

    Article  PubMed  PubMed Central  Google Scholar 

  41. Choi PJ, Mitchison TJ (2013) Imaging burst kinetics and spatial coordination during serial killing by single natural killer cells. Proc Natl Acad Sci USA 110:6488–6493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Boissel L, Betancur M, Lu W, Wels WS, Marino T, Van Etten RA, Klingemann H (2012) Comparison of mRNA and lentiviral based transfection of natural killer cells with chimeric antigen receptors recognizing lymphoid antigens. Leuk Lymphoma 53:958–965

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Suck G (2006) Novel approaches using natural killer cells in cancer therapy. Semin Cancer Biol 16:412–418

    Article  CAS  PubMed  Google Scholar 

  44. Boissel L, Betancur M, Wels WS, Tuncer H, Klingemann H (2009) Transfection with mrna for cd19 specific chimeric antigen receptor restores nk cell mediated killing of cll cells. Leuk Res 33:1255–1259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Muller T, Uherek C, Maki G, Chow KU, Schimpf A, Klingemann HG, Tonn T, Wels WS (2008) 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 57:411–423

    Article  PubMed  Google Scholar 

  46. Boissel L, Betancur-Boissel M, Lu W, Krause DS, Van Etten RA, Wels WS, Klingemann H (2013) Retargeting nk-92 cells by means of cd19- and cd20-specific chimeric antigen receptors compares favorably with antibody-dependent cellular cytotoxicity. Oncoimmunology 2:e26527

    Article  PubMed  PubMed Central  Google Scholar 

  47. Miller JS (2013) Therapeutic applications: Natural killer cells in the clinic. Hematol Am Soc Hematol Educ Progr 2013:247–253

    Article  Google Scholar 

  48. Uherek C, Tonn T, Uherek B, Becker S, Schnierle B, Klingemann HG, Wels W (2002) Retargeting of natural killer-cell cytolytic activity to erbb2-expressing cancer cells results in efficient and selective tumor cell destruction. Blood 100:1265–1273

    CAS  PubMed  Google Scholar 

  49. Daldrup-Link HE, Meier R, Rudelius M, Piontek G, Piert M, Metz S, Settles M, Uherek C, Wels W, Schlegel J, Rummeny EJ (2005) In vivo tracking of genetically engineered, anti-her2/neu directed natural killer cells to her2/neu positive mammary tumors with magnetic resonance imaging. Eur Radiol 15:4–13

    Article  PubMed  Google Scholar 

  50. Meier R, Piert M, Piontek G, Rudelius M, Oostendorp RA, Senekowitsch-Schmidtke R, Henning TD, Wels WS, Uherek C, Rummeny EJ, Daldrup-Link HE (2008) Tracking of [18f]fdg-labeled natural killer cells to her2/neu-positive tumors. Nucl Med Biol 35:579–588

    Article  CAS  PubMed  Google Scholar 

  51. Schönfeld K, Sahm C, Zhang C, Naundorf S, Brendel C, Odendahl M, Nowakowska P, Bönig H, Köhl U, Kloess S, Köhler S, Holtgreve-Grez H, Jauch A, Schmidt M, Schubert R, Kühlcke K, Seifried E, Klingemann HG, Rieger MA, Tonn T, Grez M, Wels WS (2015) Selective inhibition of tumor growth by NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor. Mol Ther 23:330–338

    Article  PubMed  PubMed Central  Google Scholar 

  52. Tam YK, Maki G, Miyagawa B, Hennemann B, Tonn T, Klingemann HG (1999) Characterization of genetically altered, interleukin 2-independent natural killer cell lines suitable for adoptive cellular immunotherapy. Hum Gene Ther 10:1359–1373

    Article  CAS  PubMed  Google Scholar 

  53. Reid GS, Bharya S, Klingemann HG, Schultz KR (2002) Differential killing of pre-b acute lymphoblastic leukaemia cells by activated nk cells and the nk-92 ci cell line. Clin Exp Immunol 129:265–271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Sahm C, Schonfeld K, Wels WS (2012) 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 61:1451–1461

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Torsten Tonn.

Ethics declarations

Conflict of interest

Dr. H. G. Klingemann is affiliated with NantKwest Inc, CA, USA (formerly known as Conkwest, Inc.). All other authors declare no conflicts of interest.

Additional information

This article is part of the Symposium-in-Writing "Natural killer cells, ageing and cancer," a series of papers published in Cancer Immunology, Immunotherapy.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Suck, G., Odendahl, M., Nowakowska, P. et al. NK-92: an ‘off-the-shelf therapeutic’ for adoptive natural killer cell-based cancer immunotherapy. Cancer Immunol Immunother 65, 485–492 (2016). https://doi.org/10.1007/s00262-015-1761-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-015-1761-x

Keywords

Navigation