Abstract
Natural killer (NK) cells are potent innate immune system effector lymphocytes armed with multiple mechanisms for killing cancer cells. Given the dynamic roles of NK cells in tumor surveillance, they are fast becoming a next-generation tool for adoptive immunotherapy. Many strategies are being employed to increase their number and improve their ability to overcome cancer resistance and the immunosuppressive tumor microenvironment. These include the use of cytokines and synthetic compounds to bolster propagation and killing capacity, targeting immune-function checkpoints, addition of chimeric antigen receptors (CARs) to provide cancer specificity and genetic ablation of inhibitory molecules. The next generation of NK cell products will ideally be readily available as an “off-the-shelf” product and stem cell derived to enable potentially unlimited supply. However, several considerations regarding NK cell source, genetic modification and scale up first need addressing. Understanding NK cell biology and interaction within specific tumor contexts will help identify necessary NK cell modifications and relevant choice of NK cell source. Further enhancement of manufacturing processes will allow for off-the-shelf NK cell immunotherapies to become key components of multifaceted therapeutic strategies for cancer.
Highlights
Immunotherapies utilizing T cells expressing chimeric antigen receptors (CARs) have shown encouraging clinical success in blood cancers
natural killer (NK) cells are being derived from stem cell sources such as induced pluripotent stem cells which possess limitless self-renewal potential and can be genetically engineered to increase NK cell killing specificity, potency and efficacy in vivo and subsequently in the clinic [3]
In vitro culture of CD3-depleted mononuclear cells, post donor apheresis, with NAM and IL-15 resulted in a 40-fold increase in NK cells after 14–16 days of culture; with the expression of homing receptor CD62L increasing from 2.9% in apheresis to 21% in final product
Summary
Immunotherapies utilizing T cells expressing chimeric antigen receptors (CARs) have shown encouraging clinical success in blood cancers. NK cells naturally express multiple cancer recognition receptors, do not induce graft-versus-host disease (GvHD) and have a reduced potential for inducing adverse life-threatening events such as a cytokine storm in patients [1]. Their clinical translation poses its own challenges including logistical difficulty in obtaining sufficient numbers for treatment, difficulties in genetic engineering to enhance function and their limited persistence in vivo [1,2]. Other ways to increase the effect of NK-based therapy include adjuvant inhibitory checkpoint therapy or application of synthetic compounds to increase the yield and potency of these eff2eocft3o1r cells [5]
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