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Exploring the NK cell platform for cancer immunotherapy


Natural killer (NK) cells are cytotoxic lymphocytes of the innate immune system that are capable of killing virally infected and/or cancerous cells. Nearly 20 years ago, NK cell-mediated immunotherapy emerged as a safe and effective treatment approach for patients with advanced-stage leukaemia. Subsequently, the field of NK cell-based cancer therapy has grown exponentially and currently constitutes a major area of immunotherapy innovation. In general, the development of NK cell-directed therapies has two main focal points: optimizing the source of therapeutic NK cells for adoptive transfer and enhancing NK cell cytotoxicity and persistence in vivo. A wide variety of sources of therapeutic NK cells are currently being tested clinically, including haploidentical NK cells, umbilical cord blood NK cells, stem cell-derived NK cells, NK cell lines, adaptive NK cells, cytokine-induced memory-like NK cells and chimeric antigen receptor NK cells. A plethora of methods to augment the cytotoxicity and longevity of NK cells are also under clinical investigation, including cytokine-based agents, NK cell-engager molecules and immune-checkpoint inhibitors. In this Review, we highlight the variety of ways in which diverse NK cell products and their auxiliary therapeutics are being leveraged to target human cancers. We also identify future avenues for NK cell therapy research.

Key points

  • Natural killer (NK) cell-based therapies are emerging as safe and efficacious treatments for some cancers.

  • Generally, the two main considerations relating to NK cell therapies are the choice of NK cell source and the method of in vivo enhancement of NK cell function; determining approaches to optimize both of these aspects is of high clinical interest.

  • Therapeutic NK cells include haploidentical NK cells, chimeric antigen receptor NK cells, stem cell-derived NK cells, umbilical cord blood NK cells, NK cell lines, adaptive NK cells and cytokine-induced memory-like NK cells.

  • Auxiliary methods for enhancing the therapeutic activity of NK cells in vivo include cytokine-based agents, NK cell-engager molecules (such as TriKEs, ROCK engagers, NKCEs and TriNKETs) and immune-checkpoint inhibitors.

  • Potential advantages that NK cell therapies have over T cell therapies include more manageable safety profiles and fewer graft restrictions (for example, no requirement for autologous cells, providing opportunities for off-the-shelf products).

  • NK cell therapies remain subject to important immunosuppressive barriers in the tumour microenvironment; the future success of these therapies will require a better understanding of how these suppressive factors operate and how they can be overcome.

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Fig. 1: NK cells respond to virally infected and transformed cells via balancing signals.
Fig. 2: Summary of the various approaches to enhancing NK cell effector function.


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J.A.M. researched data for the article and was the primary author. J.S.M. made substantial contributions to writing and revising the article.

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Correspondence to Jeffrey S. Miller.

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J.S.M. consults for and holds stock in Fate Therapeutics and GT Biopharma. These competing interests have been reviewed and managed by the University of Minnesota in accordance with its conflict of interest policy. J.A.M. declares no competing interests.

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Myers, J.A., Miller, J.S. Exploring the NK cell platform for cancer immunotherapy. Nat Rev Clin Oncol 18, 85–100 (2021).

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