Abstract
The development of chimeric antigen receptor (CAR) T cell therapy has introduced a new and effective strategy to guide and promote the immune response against tumors in the clinic. More recently, in an attempt to enhance its utility, this method has been expanded to novel cell types. One of the more successful variants has proven to be the expression of CARs in Natural Killer (NK) cells (CAR-NK). Gene engineering NK cells to express an exogenous CAR receptor allows the innate anti-tumor ability of NK cells to be harnessed and directed against a target tumor antigen. In addition, the biology of NK cells allows the development of an allogeneic cell therapeutic product useable with most or all patient haplotypes. NK cells cause little or no graft versus host disease (GvHD) and are therefore suitable for development of an “off the shelf” therapeutic product. Initial trials have also shown that CAR-NK cells rarely cause cytokine release syndrome. However, despite their potential NK cells have proven to be difficult to engineer, with high sensitivity to apoptosis and low levels of gene expression. The creation of optimized methods to introduce genes into NK cells will promote the widespread application of CAR-NK in research laboratories and the clinics.
Highlights
Natural Killer (NK) cells are a subpopulation of lymphocytes central to the innate immune system and the innate response to viruses
The most important stage in the generation of NK-chimeric antigen receptor (CAR) cells is the introduction of the genetic element into the NK cell itself (Figure 1) and the subsequent expansion of the CAR-NK cells
Recent data shows that the performance of lentiviral vectors in generating CAR-NK cells depends on the envelope protein they express
Summary
NK cells are a subpopulation of lymphocytes central to the innate immune system and the innate response to viruses. NK cells are intrinsically unreactive to foreign major histocompatibility (MHC) molecules This has made them an attractive alternative for generation of therapeutic cell products, as their insensitivity to antigens presented by MHC allows them to be used in an allogenic context with minimal risk of graft versus host disease (GvHD). The recognition domain is usually derived from the antigen-binding regions of an antibody. This is presented on the cell surface by a. NK-Based CAR Therapy Gene Transfer so-called hinge or spacer region providing flexibility. This is bound by a transmembrane domain to intracellular signaling domains, usually CD3-zeta. The most important stage in the generation of NK-CAR cells is the introduction of the genetic element into the NK cell itself (Figure 1) and the subsequent expansion of the CAR-NK cells
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