NK-92

NK-92 is an immortal cell line that has features and characteristics of natural killer (NK) cells that every person has circulating in the blood. Blood NK cells and NK-92 cells recognize invaders such as viruses and fungi. NK-92 cells, like blood NK cells, can attack cancer cells if the tumor has not grown out of control. NK-92 cells were isolated and characterized by the laboratory of Hans Klingemann at the British Columbia Cancer Agency in Vancouver, Canada. The cells came from a patient who had a NK cell lymphoma, a rare lymphoma type. Although several other NK cell lines have been cloned, only NK-92 cells can be expanded to larger numbers and consistently kill tumor cells. When NK-92 cells bind to a cancer or infected cell, they secrete perforin, which punches holes in target cells, followed by granzymes, which induce apoptosis in the target cells. NK-92 cells also attack cancer cells through the Fas-Fas ligand system and are capable of producing cytokines that by themselves can kill cancer cells (such as TNF-alpha) or stimulate and expand other immune cells such as interferon.

Licensing

The cell line has been licensed to NantKwest, Inc. and is currently being developed in the clinic for intravenous therapy in hematological malignancies and solid tumors, for local intra-tumor injection, as effector cells for antibody-mediated killing via CD16 modified cells and as effector cells for chimeric antigen receptor (CAR) specific killing. The cell line has been licensed for non-clinical applications to Brink Biologics and for veterinary applications to Coneksis.

NantKwest's authorized distributor is Brink Biologics, which makes NK-92 cells and certain genetically modified variants available for laboratory assays and in vivo research, including ADCC assays that quantify the contribution of ADCC in the therapeutic effect of monoclonal antibodies (Brink Biologics' Neukopanel) and for other non-clinical assay applications.

In clinical trials

Three phase I clinical trials, led by experts in adoptive immunotherapy of cancer, have so far yielded excellent results. Hans Klingemann and Sally Arai completed the US trial at Rush University Medical Center (Chicago) in renal cell and melanoma patients,[1] 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.[2] Armand Keating is completing the last cohort of patients in the Canadian trial at Princess Margaret Hospital in Toronto in lymphoma patients after autologous bone marrow transplants. In all three programs, 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. The maximum dose given in the Frankfurt trial was 10e10 cells/me2 x 2 infusions, each 48 hours apart. The Chicago study infused NK-92 cells at a maximum of 5 x 10e cells/me2 x 3 infusions, each 48 hours apart. This was not the MTD but rather the number of cells that could be expanded in culture bags over a three-week culture period. Alternative cell expansion technologies (bioreactors) will make it possible to further expand the numbers of NK-92 cells on a smaller 'footprint'. Anecdotal reports of antitumor activity in the two completed phase I studies have been observed in 6/11 patients with renal cancer, 3/4 patients with lung cancer, and 1/1 patient with melanoma, all with very advanced disease. In addition to disease stabilization and regression of metastases in lung and lymph nodes, the severe pain associated with tumor metastases in several patients, which had been refractory to standard chemotherapy, was remarkably lessened. The ongoing trial in Toronto treats patients with lymphoma who have relapsed after an autologous stem cell transplant. Preliminary results suggest a significant benefit in several patients.

Genetic engineering

NK-92 cells can be genetically engineered to recognize and kill human cancer cells. Chimeric Antigen Receptor (CAR) engineered T-lymphocytes are popular in immuno-oncology, having shown that infusion of those engineered cells can achieve remissions in some patients with acute and chronic leukemia.[3] In contrast, NK cells (either from peripheral blood or cord blood) have not generated sufficient interest as CAR‑engineered cytotoxic effector cells because the extent of NK cell expansion can be dependent on the donor and because transfection efficiency, even with lentiviral or retroviral vectors, is only moderately efficient. NK-92 cells, on the other hand, have predictable expansion kinetics and can be grown in bioreactors to billions of cells within a couple of weeks. They can easily be transfected either with viral supernatant or physical methods. Even mRNA can be shuttled into the cells with high efficiency. Since no integration of mRNA into the genome occurs, this transfection is less risky.

NK-92 cells have also been transfected with a high affinity Fc Receptor (NK-92Fc) which is the main receptor for monoclonal antibodies to execute antibody dependent cellular cytotoxicty (ADCC), including rituximab and ofatumumab. Based on this variant, an assay called Neukopanel has been developed to quantify the ADCC of monoclonal antibodies,[4] a technology that has caught the attention of a number of biotech and pharmaceutical companies that use Neukopanel to determine the contribution of ADCC of their monoclonal antibodies.

References
  1. Arai S, Meagher R, Swearingen M, et al. Infusion of the allogeneic cell line NK-92 in patients with advanced renal cell cancer or melanoma: a phase I trial. Cytotherapy 2008;10:625-32
  2. Tonn T, Becker S, Esser R, Schwabe D, Seifried E. Cellular immunotherapy of malignancies using the clonal natural killer cell line NK-92. J Hematother Stem Cell Res 2001;10:535-44.
  3. Porter DL, Levine BL, Kalos M, Bagg A, June CH (August 2011). "Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia". N. Engl. J. Med. 365 (8): 725–33. doi:10.1056/NEJMoa1103849. PMC 3387277. PMID 21830940.
  4. Weitzman J, Betancur M, Boissel L, Rabinowitz AP, Klein A, Klingemann H (August 2009). "Variable contribution of monoclonal antibodies to ADCC in patients with chronic lymphocytic leukemia". Leuk. Lymphoma. 50 (8): 1361–8. doi:10.1080/10428190903026500. PMID 19562616.
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