Innovative Strategies to Improve the Clinical Application of NK Cell-Based Immunotherapy

Abstract

Natural killer cells constitute a part of the innate immune system that mediates an effective immune response towards virus-infected and malignant cells. In recent years, research has focused on exploring and advancing NK cells as an active immunotherapy platform. Despite major advances, there are several key challenges that need to be addressed for the effective translation of NK cell research to clinical applications. This review highlights some of these challenges and the innovative strategies being developed to overcome them, including in vitro expansion, in vivo persistence, infiltration to the tumor site, and prevention of exhaustion.

Keywords: NK cell exhaustion; immunotherapy; in vitro expansion; natural Killer (NK) cell; tumor infiltrating cell.

Figure 1

Overview of NK cell isolation, expansion, and in vivo persistence. NK cells can be isolated and/or generated from peripheral blood (PB), cord blood (CB), or human induced pluripotent stem cell (iPSC) sources. They are expanded ex vivo using various strategies including cytokine combinations, feeder cells, lipid membranes or biomaterials that carry surface markers to provide biochemical cues. In vivo persistence of NK cells can be accomplished using cytokines like IL-15 and/or cytokine-induced memory-like (CIML) NK cells that have shown long term persistence in an immune compatible environment. Illustration created using BioRender.com.

Figure 2

Strategies involved to improve the tumor infiltration of NK cells, overcome tumor escape and exhaustion. NK cells can be engineered to express CAR and specific chemokine receptors to increase their infiltration in solid tumors. Upon entry into the TME, NK cells can be impaired by its immune suppressive features. Blockade of inhibitory receptors (TIM-3, NKG2A, KIR) on NK cells can increase their antitumor cytotoxicity. Further, inhibition of immune-modulatory molecules (TGF-β) can prevent exhaustion in NK cells and maintain their cytotoxic features. Illustration created using BioRender.com.