NK-92

The NK-92 cell line is an immortal cell line that has the features and characteristics of a type of immune cell found in human blood called ’natural killer’ (NK) cells. Blood NK cells and NK-92 cells recognize and attack cancer cells as well as cells that have been infected with a virus, bacteria or fungus.[1] These unique NK cells were originally isolated in 1992 in the laboratory of Hans Klingemann at the British Columbia Cancer Agency in Vancouver, Canada, from a patient who had a rare NK cell lymphoma[2] and were subsequently transformed in culture into a continuously growing NK cell line and characterized for the first time. NK-92 cells are distinguished by their suitability for expansion to large numbers, ability to consistently kill cancer cells and testing in clinical trials. When NK-92 cells recognize a cancerous or infected cell, they secrete perforin that, punches holes into the diseased cells and releases granzymes that kill the target cells. NK-92 cells are also capable of producing cytokines such as cancer cell-killing tumor necrosis alpha factor (TNF-a) and interferon, gamma (IFN-y),[3] which stimulates proliferation and activation of other immune cells.

In clinical trials

Several phase I clinical trials, conducted by experts in adoptive immunotherapy of cancer, have yielded very favorable results. Hans Klingemann and Sally Arai completed the US trial at Rush University Medical Center (Chicago) in renal cell and melanoma patients,[4] and Torsten Tonn, MD and Oliver Ottmann, MD completed the European trial at the University of Frankfurt in patients with various solid and hematological malignancies.[5] Armand Keating at Princess Margaret Hospital in Toronto conducted a trial wherein NK-92 cells were given to patients who had relapsed after autologous bone marrow transplants for leukemia or lymphoma.[6] In all clinical trials so far, NK-92 cells were administered as a simple intravenous infusion, dosed two or three times per treatment course and given in the outpatient setting.

Most importantly, there were no grade ≥ 2 side-effects during or after the short infusion of NK-92 cells in any of the clinical studies. The maximum dose given to patients in any of these studies was 10e10 cells/M2 per infusion, each 48 hours apart. About one third of the treated patients had a clinically meaning response with some of them becoming long term survivors.

Genetic engineering

NK-92 cells have been genetically engineered to recognize and kill specific human cancers. Chimeric Antigen Receptor-engineered T-lymphocytes (CAR-T) have already garnered attention in immuno-oncology because infusion of CAR-T cells has been shown to induce remissions in some patients with acute and chronic leukemia and lymphoma. Unfortunately, CAR-T cells can cause a ‘cytokine release syndrome’ (CRS) which can be quite deleterious for the patient. CAR-engineered potentially cell-killing (cytotoxic) NK cells from either peripheral or cord blood have not proved to be as feasible for use to treat diseases because they are difficult to expand to get sufficient numbers, and the yields can be variable and/or too low. Also, genetic transduction to introduce the CAR into blood NK cells requires lentiviral or retroviral vectors, which are only moderately efficient.

NK-92 cells, in contrast, have predictable expansion kinetics and can be grown in bioreactors that produce billions of cells within a couple of weeks.[7] Further, NK-92 cells can easily be transduced by physical methods. Even mRNA can be shuttled into NK-92 cells with high efficiency. CAR-expressing NK-92 have been generated to target a number of cancer surface receptors[8] such as PD-L1 (programmed death domain ligand 1), CD19 (a type of B cell receptor),[9][10] HER2/ErbB2 human epidermal growth factor receptor 2 and EGFR (epiderminal growth factor receptor, aka HER1); and many of these engineered NK-92 cells are currently in clinical trials for the treatment of cancer.[11]

NK-92 cells, which require interleukin-2 (IL-2) for growth, have also been genetically altered with an IL-2 gene to allow them to grow in culture without the addition of IL-2.[12] They have also been engineered to express a high-affinity Fc-receptor which is the main receptor for monoclonal antibodies to bind to NK-92 and use their cytotoxic load to kill cancer cells.[13][14] During the course of development, NK-92 cells were renamed activated NK cells (aNK) and the different variants have been designated as follows:

NK-92 = parental cells, later designated aNK

NK-92ci = NK-92 cells transfected with an episomal vector for expression of IL-2

NK-92 mi = NK-92 cells transfected with an MFG vector for expression of IL-2

haNK = NK-92 (aNK) transfected with a plasmid expressing high affinity CD16 FcR and erIL-2

taNK =  NK-92 (aNK) transfected with either a plasmid or lentiviral vector expressing a CAR

t-haNK = NK-92 (aNK) transfected with a plasmid expressing a CAR and CD16 FcR erIL-2

qt-haNK = NK-92 (aNK) transfected with a plasmid expressing a 4th gene in addition to a CAR, the CD16 FcR, and erIL-2: examples: homing receptor of the CXCR family or immune-active cytokines

The high affinity Fc-receptor-expressing NK (haNK) cells were administered to patients with advanced Merkel cell carcinoma (MCC) and there were some notable responses. Currently, a HER2-targeted aNK (taNK) line and various t-haNK (CAR and Fc-receptor expressing) cell lines are in clinical trials in patients with various cancers.

Ownership and Licenses

Global rights to the NK-92 cell line were assigned to ImmunityBio Inc. (formerly NantKwest, Inc.). ImmunityBio’s only authorized NK-92 distributor is Brink Biologics, Inc. (San Diego), which makes NK-92 cells and certain genetically modified CD16+ variants available to third parties for non-clinical research under a limited use license agreement.

References
  1. Mody, H., et al.  (2019). "Microbial killing by NK cells". Journal of Leukocyte Biology; 105 (6): 1285–1296. doi:10.1002/jlb.mr0718-298r.
  2. Gong, J., Maki, G., and Klingemann, H-G. (1994). “Characterization of a human cell line (NK-92) with phenotypical and functional characteristics of activated natural killer cells”. Leukemia; 8: 652-58.
  3. Paul, S. and Lal, G. (2017). "The Molecular Mechanism of Natural Killer Cells Function and Its Importance in Cancer Immunotherapy". Frontiers in Immunology.;  8. doi:10.3389/fimmu.2017.01124/full. ISSN 1664-3224.
  4. Arai, S., et al. (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 - 32.
  5. Tonn, T. et al. (2013). “Treatment of patients with advanced cancer with the natural killer cell line NK-92.” Cytotherapy;15(12):1563-70. doi: 10.1016/j.jcyt.2013.06.017.
  6. Williams, B.A., et al. (2017). “A phase I trial of NK-92 cells for refractory hematological malignancies relapsing after autologous hematopoietic cell transplantation shows safety and evidence of efficacy.”  Oncotarget;  51:89256-68.
  7. Klingemann, H.; Boissel, L.; and Toneguzzo, F. (20166). “Natural Killer Cells for Immunotherapy – Advantages of the NK-92 Cell Line over Blood NK Cells.” Frontiers in Immunology; 7: 91. doi: 10.3389/fimmu.2016.00091
  8. Kilingemann, H. (2014). “Are natural killer cells superior CAR drivers?” Oncoimmunology; 3: e28147. doi: 10.4161/onci.28147
  9. Romanski, A. et al. (2013). “CD19‐CAR engineered NK‐92 cells are sufficient to overcome NK cell resistance in B‐cell malignancies.” Journal of Cellular and Molecular Medicine; 20(7): 1287–1294
  10. Boissel, L. et al. (2013) “ Retargeting NK-92 cells by means of CD19- and CD20-specific chimeric antigen receptors compares favorably with antibody-dependent cellular cytotoxicity” Oncoimmunology; 2(10)
  11. Fabian, K.P. and Hodge, J.W. (2021).”The emerging role of off-the-shelf engineered natural kill cells in targeted cancer immunotherapy.” Molecular Therapy Oncolytics; 23:267-276.
  12. Tam, Y.K. et al. (1999). “Characterization of genetically altered, interleukin 2 independent natural killer cell lines suitable for adoptive cellular immunotherapy.” Human Gene Therapy; 10: 1359 – 73.
  13. Jochems, C.; Hodge, J.W.; Fantini, M. et al.  (2016) “A NK cell line (haNK) expressing high levels of granzyme and engineered to express the high affinity CD16 allele.” Oncotarget; 7: 86359-73.
  14. Solocinski, K. et al. (2020). “Overcoming hypoxia-induced functional suppression of NK cells”. Journal for Immunotherapy of Cancer; 8:e000246. doi:10.1136/ jitc-2019-000246
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