NK cells for cancer immunotherapy

Abstract

Natural killer (NK) cells can swiftly kill multiple adjacent cells if these show surface markers associated with oncogenic transformation. This property, which is unique among immune cells, and their capacity to enhance antibody and T cell responses support a role for NK cells as anticancer agents. Although tumours may develop several mechanisms to resist attacks from endogenous NK cells, ex vivo activation, expansion and genetic modification of NK cells can greatly increase their antitumour activity and equip them to overcome resistance. Some of these methods have been translated into clinical-grade platforms and support clinical trials of NK cell infusions in patients with haematological malignancies or solid tumours, which have yielded encouraging results so far. The next generation of NK cell products will be engineered to enhance activating signals and proliferation, suppress inhibitory signals and promote their homing to tumours. These modifications promise to significantly increase their clinical activity. Finally, there is emerging evidence of increased NK cell-mediated tumour cell killing in the context of molecularly targeted therapies. These observations, in addition to the capacity of NK cells to magnify immune responses, suggest that NK cells are poised to become key components of multipronged therapeutic strategies for cancer.

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Fig. 1: Activating and inhibitory NK receptors and their corresponding ligands.
Fig. 2: Sources and methods for isolation, activation and propagation of allogeneic NK cells.
Fig. 3: Genetic modification approaches to increase the antitumour capacity of NK cells.
Fig. 4: Scenarios for interaction between NK cells and other immune cells in the tumour microenvironment.

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Acknowledgements

The authors thank the National Medical Research Council of Singapore (grant NMRC/STaR/0025/2015), the Goh Foundation and the VIVA Foundation for Children with Cancer for their support.

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All authors researched data for article, substantially contributed to discussion of the content and reviewed and edited the manuscript before submission. D.C. wrote the article.

Correspondence to Dario Campana.

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Competing interests

D.C. has received patent royalties from Juno Therapeutics (a Celgene company), Unum Therapeutics, Nkarta Therapeutics and Medisix Therapeutics; he is a co-founder of, stockholder of and consultant for Unum, Nkarta and Medisix. N.S. and D.C. are co-inventors on patent applications licensed to Nkarta or unlicensed. A.J. has no financial competing interests. None of the authors has non-financial competing interests.

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Glossary

Graft-versus-host disease

(GVHD). A condition resulting from the systemic attack of allogenic T cells on the tissues of an immunosuppressed recipient, which, in its most severe grade, is fatal. It can occur after allogeneic haematopoietic stem cell transplantation or after infusion of allogeneic T cells.

Killer cell immunoglobulin-like receptors

(KIRs). Transmembrane proteins expressed by natural killer (NK) cells that interact with major histocompatibility complex/human leukocyte antigen class I molecules to modulate NK cell cytotoxicity by delivery predominantly inhibitory signals. KIR signalling during NK cell development is important for NK cell functional competency or licensing.

Licensing

A process driven by the interaction between inhibitory receptors on maturing natural killer cells and self-major histocompatibility complex molecules which increases natural killer cell responses to activating receptor signals.

Anergic

A hypofunctional state. In natural killer cells, anergy or hyporesponsiveness to activating signals might be caused by chronic stimulation during maturation through an activating receptor interacting with a self-ligand.

K562 cells

A chronic myelogenous leukaemia cell line that expresses the BCR–ABL1 fusion gene, which lacks major histocompatibility complex/human leukocyte antigen surface expression and is commonly used as a target in natural killer (NK) cell cytotoxicity assays. Contact with K562 activates NK cells, K562 cells modified to express cytokines and stimulatory molecules are used to stimulate NK cell proliferation.

Leukapheresis

A procedure that removes white blood cells from blood,while returning the remainder blood components to circulation. A leukapheresis product is often used as a starting material to obtain peripheral blood natural killer cells.

Lymphokine-activated killer cells

(LAK cells). Lymphocytes obtained from cancer patients, incubated with cytokines, such as IL-2, and then reinfused into patients with therapeutic intent, often in conjunction with IL-2.

Vascular leak syndrome

A serious clinical condition characterized by increased vascular permeability accompanied by the escape of plasma through capillary walls. It is most commonly seen in sepsis, and it is one of the major dose-limiting toxic effects of IL-2.

Minimal residual disease

Leukaemic cells undetectable by conventional morphological techniques but detectable by flow cytometry or molecular methods in peripheral blood or bone marrow. Contemporary minimal residual disease assays can detect one leukaemic cell among 10,000 or more normal cells.

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Shimasaki, N., Jain, A. & Campana, D. NK cells for cancer immunotherapy. Nat Rev Drug Discov (2020). https://doi.org/10.1038/s41573-019-0052-1

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