Genetic Manipulation of NK Cells for Cancer Immunotherapy: Techniques and Clinical Implications

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.

Keywords: NK cells; cancer immunotherapy; electroporation; genetic manipulation; viral transduction.

Figure 1

Schematic overview of how genetic manipulation can be can be used to improve the efficacy of NK cell-based cancer immunotherapy in the clinic. Genetic engineering of NK cells to promote persistence and expansion by autocrine cytokine stimulation, migration to the tumor tissue via introduction of receptors involved in cellular homing (i.e., chemokine receptors and adhesion molecules), as well as bolstering their anti-tumor cytotoxicity via introduction of CARs or activating NK cell receptors (aNKRs) or via silencing of inhibitory NK cell receptors (iNKRs), protection from suppressive cytokines in the tumor environment, and boosted function via autocrine cytokine stimulation.