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

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.

CAR-Expressing Natural Killer Cells for Cancer Retargeting

“…Thus, it should be noted that activated CAR-modified NK-92 cells must be irradiated with at least 10 Gy before infusion in tumour patients, resulting in a lower cell persistence and a loss of effector-mediated anti-tumour functions [99]. Despite these disadvantages, preclinical results were described for CAR-expressing NK-92 cells targeting a wide range of tumour antigens [100, 101].…”

“…Another unfavourable aspect is the absence of some KIRs, with the exception of KIR2DL4 (CD158d) on the surface of NK-92, which may contribute to a possible stimulation of graft-versus-host disease [12, 97-99]. Thus, it should be noted that activated CAR-modified NK-92 cells must be irradiated with at least 10 Gy before infusion in tumour patients, resulting in a lower cell persistence and a loss of effector-mediated anti-tumour functions [99].…”

Natural Killer Cells for Therapy of Leukemia

“…Optimized culture conditions have been established [62]. After initial cell inoculation of culture bags, no further media additions were required and clinical doses could be yielded within a few days [59,63,64]. A maximal expandable dose of 10 10 cells/m 2 body surface was considered achievable in the established culture system [63].…”

“…Multiplex genome-edited large-scale manufacture of universal T cells may provide a means in overcoming limitations of the current personalized CAR-T-cell therapies thereby broadening applicability [84]. A major advantage for the NK-92 drug remains in its ease of clinical-scale production, allowing keeping operational costs at a minimum [59,64]. Thus, clinical testing of the novel NK-92-CAR products is imperative to estimate their true potential and for decision-making among the alternative treatment options.…”

Natural killer cells, ageing and cancer

“…In this context, Suck et al [7] also review their group's work on the potential for cellular therapy of cancer using the allogeneic natural killer cell line NK-92. The results of preclinical testing of NK-92 in mice indicate that it is well tolerated and lacks toxicity (suitable for clinical application).…”