Abstract
Given their rapid and efficient capacity to recognize and kill tumor cells, natural killer (NK) cells represent a unique immune cell to genetically reprogram in an effort to improve the outcome of cell-based cancer immunotherapy. However, technical and biological challenges associated with gene delivery into NK cells have significantly tempered this approach. Recent advances in viral transduction and electroporation have now allowed detailed characterization of genetically modified NK cells and provided a better understanding for how these cells can be utilized in the clinic to optimize their capacity to induce tumor regression in vivo. Improving NK cell persistence in vivo via autocrine IL-2 and IL-15 stimulation, enhancing tumor targeting by silencing inhibitory NK cell receptors such as NKG2A, and redirecting tumor killing via chimeric antigen receptors, all represent approaches that hold promise in preclinical studies. This review focuses on available methods for genetic reprograming of NK cells and the advantages and challenges associated with each method. It also gives an overview of strategies for genetic reprograming of NK cells that have been evaluated to date and an outlook on how these strategies may be best utilized in clinical protocols. With the recent advances in our understanding of the complex biological networks that regulate the ability of NK cells to target and kill tumors in vivo, we foresee genetic engineering as an obligatory pathway required to exploit the full potential of NK-cell based immunotherapy in the clinic.
Highlights
Natural killer (NK) cells are immune cells primarily found in the blood, liver, spleen, bone marrow, and to a lesser extent, in lymph nodes [1]
The introduction of chimeric antigen receptors (CARs) and the down-regulation of inhibitory natural killer (NK) cell receptors such as NKG2A are additional examples of specific genetic manipulations that can be utilized to improve the outcome of adoptive NK cell immunotherapy. Given their rapid and efficient method of recognizing tumor cells, NK cells represent a unique immune cell to genetically reprogram in an effort to improve the outcome of cell-based cancer immunotherapy
Anti-tumor antibodies and CAR T cells have established immunotherapy as a viable treatment option for patients with cancer
Summary
Natural killer (NK) cells are immune cells primarily found in the blood, liver, spleen, bone marrow, and to a lesser extent, in lymph nodes [1]. Genetic manipulation of NK cells to improve their persistence, cytotoxicity, tumor targeting capacity, and ability to home to disease sites in vivo holds potential to advance the efficacy of NK cell-based cancer immunotherapy. One example of how this technique can be utilized is to introduce genes into NK cells coding for gamma-cytokines (IL-2 and IL-15) to induce independence from the obligate need of exogenous cytokines for proper in vivo persistence and expansion post infusion This and similar strategies may further improve the efficacy of NK cell-based immunotherapy, as tumor regression following adoptive NK cell infusions in AML patients has been reported to be dependent on their ability to expand in vivo [6], while being limited by regulatory T cells mobilized following exogenous cytokine administration [12, 13]. Box 1 | Pros and Cons for Methods of Genetic Modification of NK Cells
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