Natural Killer Cells and the Battle Against Cancer
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The human immune system constitutes a complex network of biological processes and cells working in unison to keep the body healthy and stable. Our immune system is generally separated into two major components, the innate- and the adaptive immune system. Cells of the adaptive immune system are often referred to as having memory, thus being able to learn and adapt their response to the invasion of certain pathogens. On the contrary, the innate immune cells are responsible for the general upkeep of the body’s cells and are also responsible for the swift reaction to invasive microorganisms and tumor cells. One major classification subset of lymphocytes of the innate immune system is the natural killer (NK) cells. This class of immune cells is responsible for mediating anti-microbial and anti-tumor activity . In the 70’s, when NK cells were first discovered, scientists struggled to figure out how exactly activation and inhibition of the different cell types were regulated. However, from studying the selective activity, it became apparent that NK cells were not regulated by a master receptor but instead, by a wide repertoire of receptors. Activation is controlled by activating receptors mainly stimulated by cytokines and surface molecules on target cells. Inhibition of NK cells is regulated by the cells’ ability to recognize the presence of the major histocompatibility complex I (MHC-I) on cells, as well as various other inhibitory receptors [2, 3]. As MHC-I is expressed by all regular cells in the body, this mechanism can effectively regulate which cells will be targeted by the natural killer cells. Ligands relevant for the activation of NK cells are often found on the surface of tumor cells, making NK cells great at killing cancerous cells . However, while NK cells are effective cancer killers, cancerous mutations are tricky subjects, and not all tumors and cancers are alike. Some tumors may mutate in a way that makes NK cells unable to recognize them and thus evade elimination, for instance by downregulation of NK-activating surface ligands .
Nevertheless, the inherent anti-tumoral activity of natural killer cells has led a lot of companies to engage in developing NK cell based therapies. While NK-cells have inherent limitations as discussed above, they are also known to be able to destroy solid-tumors, likely due to a better tolerance of the inhibitory tumor microenvironment associated with many cancers, a feature that has evaded alternative cell-based immunotherapies so far. Cellular engineering with Chimeric antigen receptors (CARs) has most often been associated with T-cells, but so far, this modality has not seen any success in effectively eliminating solid tumors, instead achieving favourable outcomes in haematological cancers. However, several NK-cell focused companies are now developing CAR-engineered NK cells, combining the inherent functionality of NK cells with the specificity of CARs. CAR-NK focused companies like Nkarta Therapeutics and ONK Therapeutics are developing novel NK based therapies for solid- and haematological cancers, targeting a variety of surface-molecules such as CD70, CD19, CD38 and MUC-1 .
However, the emergence of CAR-engineered NK cells does not constitute the only variation of the NK cell technology that companies are working on. Other companies are working on deriving engineered NK cells from induced pluripotent stem cells (iPSC). Among these are Fate Therapeutics, Century Therapeutics and Cytovia Therapeutics, who use their proprietary iPSC platforms to develop and mass produce off-the-shelf engineered NK cell therapeutics .
Other NK cell focused companies are looking further into genetically engineering the NK cells, using technologies such as CRISPR or TALENs. For instance, Nkarta Therapeutics has established a collaboration with rapidly growing gene editing company, CRISPR Therapeutics for the development of gene edited NK cells [7,8]. ONK Therapeutics and Fate Therapeutics uses CRISPR to induce knock-outs of the genes encoding proteins such as CISH and CD38, possibly enhancing in vivo persistence and durability of the therapies.
The utilization of natural killer cells may constitute a powerful platform for developing therapeutics against both infectious diseases and cancers, and the high level of plasticity within the technology is attracting many companies and much new capital to the field. Gaining a relevant competitive advantage in the field is important to come out ahead or catch up to a highly paced segment like NK cell therapeutics, and it can be costly to keep up.
At Stargazing Bio Research, we have compiled the most comprehensive and highly specific, commercially available database of natural killer cell based companies in the industry. In this database we have catalogued every NK cell company that is currently operational and developing NK cell based preclinical- or clinical assets. If you are interested in learning more about the database it can be accessed here.
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The Stargazing Bio Research team