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  • Review Article
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Therapeutic approaches to enhance natural killer cell cytotoxicity against cancer: the force awakens

Key Points

  • Adoptive infusions of short-term IL-2-activated NK cells have so far provided the best direct evidence for the potential of using NK cells to induce tumour regression in patients with cancer.

  • The cytokine IL-2 has been used as single-agent therapy in multiple clinical settings in an attempt to augment the antitumour reactivity of the immune system, including NK cells, with limited clinical benefits so far. IL-15 is another common γ-chain cytokine that has an immune cell stimulation profile that is distinct compared with IL-2. The antitumour potential of IL-15 is now being studied in the clinic.

  • Monoclonal antibodies are potent agents that can redirect and trigger NK cell tumour killing. Further clinical studies are needed to fully determine the degree to which NK cells contribute to tumour regression following monoclonal antibody therapy. Bispecific or trispecific killer engagers (BiKEs or TriKEs) are engineered antibody-like molecules that have shown great promise in preclinical studies, warranting an investigation of their efficacy in the clinical setting.

  • Preclinical studies indicate that immune-modulatory antibodies, such as programmed cell death protein 1 (PD1)-specific antibodies, have the potential to prompt NK cell-mediated tumour rejection in vivo.

  • Several recently developed strategies to sensitize tumour cells to NK cell killing have shown efficacy in vitro and in preclinical animal models, and are currently being evaluated in the clinical setting.

  • A variety of new methods to expand large numbers of NK cells ex vivo using good manufacturing practice-compliant conditions have recently been established, with several studies now evaluating the antitumour potential of these adoptively infused NK cells in the clinic. The advantage of ex vivo expanded NK cells compared to the infusion of non-expanded cells is that a large number of highly activated NK cells can be infused at one or multiple time points.

  • Advances in techniques to genetically manipulate NK cells provide new means to engineer NK cells to improve their tumour targeting capacity in vivo. Infusion of genetically manipulated NK cells has just reached clinical evaluation and will soon shed light on the potential of this strategy.

  • So far, most studies have focused on methods to improve tumour killing at the NK cell–tumour interface, neglecting the importance of establishing methods to improve NK cell persistence and expansion in vivo as well as methods to promote NK cell migration to the tumour environment.

Abstract

Scientific insights into the human immune system have recently led to unprecedented breakthroughs in immunotherapy. In the twenty-first century, drugs and cell-based therapies developed to bolster humoral and T cell immunity represent an established and growing component of cancer therapeutics. Although natural killer (NK) cells have long been known to have advantages over T cells in terms of their capacity to induce antigen-independent host immune responses against malignancies, their therapeutic potential in the clinic has been largely unexplored. A growing number of scientific discoveries into pathways that both activate and suppress NK cell function, as well as methods to sensitize tumours to NK cell cytotoxicity, have led to the development of numerous pharmacological and genetic methods to enhance NK cell antitumour immunity. These findings, as well as advances in our ability to expand NK cells ex vivo and manipulate their capacity to home to the tumour, have now provided investigators with a variety of new methods and strategies to harness the full potential of NK cell-based cancer immunotherapy in the clinic.

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Figure 1: Schematic overview of drugs that bolster NK cell antitumour immunity and their interaction points.
Figure 2: Development status of drugs designed to augment NK cell antitumour immunity.

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Acknowledgements

The authors acknowledge all the members of the US National Heart, Lung and Blood Institute's Laboratory of Transplantation Immunotherapy and the Dean R. O'Neill Memorial Fellowship for their many contributions and support for the original research described in this Review.

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Correspondence to Richard W. Childs.

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Childs, R., Carlsten, M. Therapeutic approaches to enhance natural killer cell cytotoxicity against cancer: the force awakens. Nat Rev Drug Discov 14, 487–498 (2015). https://doi.org/10.1038/nrd4506

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