NK-92

The NK-92 cell line is an immortalised cell line that has the 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] NK-92 cells were first 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 non-Hodgkin-lymphoma.[2] These cells were subsequently developed into a continuously growing cell line. 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 opens holes into the diseased cells and releases granzymes that kill the target cells. NK-92 cells are also capable of producing cytokines such as tumor necrosis factor alpha (TNF-a) and interferon gamma (IFN-y),[3] which stimulates proliferation and activation of other immune cells.

In clinical trials

Several phase 1 clinical trials have been performed by experts in the field of adoptive immunotherapy of cancer. Hans Klingemann and Sally Arai completed a US trial at Rush University Medical Center (Chicago) in renal cell cancer and melanoma patients in 2008,[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 in 2013.[5] Armand Keating at Princess Margaret Hospital in Toronto conducted a trial in which NK-92 cells were given to patients who had relapsed after autologous bone marrow transplants for leukemia or lymphoma. 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.

Of the 39 patients enrolled across the three studies, 2 serious (grade 3–4) side-effects occurred during or after the infusion of NK-92 cells, the side effects disappeared afterward. The doses given to patients ranged from 1x108 cells/m2 to 1x1010 cells/m2 per infusion. Patients received between two and three infusions over a period of less than a week. About one-third of the treated patients had clinically meaningful responses with some of them fully recovering.

Comparison to other NK cells

In a 2017 study by Congcong Zhang and Winfried S. Wels, NK-92 cells were genetically engineered to recognize and kill specific human cancers by expressing chimeric antigen receptors (CARs).[6] CAR-engineered T-lymphocytes (CAR-T) have garnered attention in immuno-oncology, as the infusion of CAR-T cells has been shown to induce remissions in some patients with acute and chronic leukemia and lymphoma. However, CAR-T cells can cause cytokine release syndrome (CRS). CAR-engineered NK cells from either peripheral or cord blood have not proved to be as feasible for use to treat diseases as 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 to NK-92 CAR-T cells, 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, and 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 programmed death domain ligand 1 (PD-L1), CD19 (a type of B cell receptor),[9][10] human epidermal growth factor receptor 2 (HER2/ErbB2) and epidermal growth factor receptor (EGFR, aka HER1); and many of these engineered NK-92 cells are currently in clinical trials for the treatment of cancer.[11]

NK-92 variants

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 CH, Ogbomo H, Xiang RF, Kyei SK, Feehan D, Islam A, Li SS (June 2019). "Microbial killing by NK cells". Journal of Leukocyte Biology. 105 (6): 1285–1296. doi:10.1002/JLB.MR0718-298R. PMID 30821868. S2CID 73461723.
  2. Gong JH, Maki G, Klingemann HG (April 1994). "Characterization of a human cell line (NK-92) with phenotypical and functional characteristics of activated natural killer cells". Leukemia. 8 (4): 652–658. PMID 8152260.
  3. Paul S, Lal G (2017). "The Molecular Mechanism of Natural Killer Cells Function and Its Importance in Cancer Immunotherapy". Frontiers in Immunology. 8: 1124. doi:10.3389/fimmu.2017.01124. PMC 5601256. PMID 28955340.
  4. 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 (6): 625–632. doi:10.1080/14653240802301872. PMID 18836917.
  5. Tonn T, Schwabe D, Klingemann HG, Becker S, Esser R, Koehl U, et al. (December 2013). "Treatment of patients with advanced cancer with the natural killer cell line NK-92". Cytotherapy. 15 (12): 1563–1570. doi:10.1016/j.jcyt.2013.06.017. PMID 24094496.
  6. Zhang C, Oberoi P, Oelsner S, Waldmann A, Lindner A, Tonn T, Wels WS (2017). "Chimeric Antigen Receptor-Engineered NK-92 Cells: An Off-the-Shelf Cellular Therapeutic for Targeted Elimination of Cancer Cells and Induction of Protective Antitumor Immunity". Frontiers in Immunology. 8: 533. doi:10.3389/fimmu.2017.00533. PMC 5435757. PMID 28572802.
  7. Klingemann H, Boissel L, Toneguzzo F (2016). "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. PMC 4789404. PMID 27014270.
  8. Klingemann H (2014). "Are natural killer cells superior CAR drivers?". Oncoimmunology. 3 (4): e28147. doi:10.4161/onci.28147. PMC 4203506. PMID 25340009.
  9. Romanski A, Uherek C, Bug G, Seifried E, Klingemann H, Wels WS, et al. (July 2016). "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. doi:10.1111/jcmm.12810. PMC 4929308. PMID 27008316.
  10. Boissel L, Betancur-Boissel M, Lu W, Krause DS, Van Etten RA, Wels WS, Klingemann H (October 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): e26527. doi:10.4161/onci.26527. PMC 3881109. PMID 24404423.
  11. Fabian KP, Hodge JW (December 2021). "The emerging role of off-the-shelf engineered natural killer cells in targeted cancer immunotherapy". Molecular Therapy Oncolytics. 23: 266–276. doi:10.1016/j.omto.2021.10.001. PMC 8560822. PMID 34761106.
  12. Tam YK, Maki G, Miyagawa B, Hennemann B, Tonn T, Klingemann HG (May 1999). "Characterization of genetically altered, interleukin 2-independent natural killer cell lines suitable for adoptive cellular immunotherapy". Human Gene Therapy. 10 (8): 1359–1373. doi:10.1089/10430349950018030. PMID 10365666.
  13. Jochems C, Hodge JW, Fantini M, Fujii R, Morillon YM, Greiner JW, et al. (December 2016). "An NK cell line (haNK) expressing high levels of granzyme and engineered to express the high affinity CD16 allele". Oncotarget. 7 (52): 86359–86373. doi:10.18632/oncotarget.13411. PMC 5341330. PMID 27861156.
  14. Solocinski K, Padget MR, Fabian KP, Wolfson B, Cecchi F, Hembrough T, et al. (April 2020). "Overcoming hypoxia-induced functional suppression of NK cells". Journal for Immunotherapy of Cancer. 8 (1): e000246. doi:10.1136/jitc-2019-000246. PMC 7213912. PMID 32345623.
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