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  • Review Article
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Natural killer cells in antitumour adoptive cell immunotherapy

Nature Reviews Cancer volume 22, pages 557–575 (2022)Cite this article

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Abstract

Natural killer (NK) cells comprise a unique population of innate lymphoid cells endowed with intrinsic abilities to identify and eliminate virally infected cells and tumour cells. Possessing multiple cytotoxicity mechanisms and the ability to modulate the immune response through cytokine production, NK cells play a pivotal role in anticancer immunity. This role was elucidated nearly two decades ago, when NK cells, used as immunotherapeutic agents, showed safety and efficacy in the treatment of patients with advanced-stage leukaemia. In recent years, following the paradigm-shifting successes of chimeric antigen receptor (CAR)-engineered adoptive T cell therapy and the advancement in technologies that can turn cells into powerful antitumour weapons, the interest in NK cells as a candidate for immunotherapy has grown exponentially. Strategies for the development of NK cell-based therapies focus on enhancing NK cell potency and persistence through co-stimulatory signalling, checkpoint inhibition and cytokine armouring, and aim to redirect NK cell specificity to the tumour through expression of CAR or the use of engager molecules. In the clinic, the first generation of NK cell therapies have delivered promising results, showing encouraging efficacy and remarkable safety, thus driving great enthusiasm for continued innovation. In this Review, we describe the various approaches to augment NK cell cytotoxicity and longevity, evaluate challenges and opportunities, and reflect on how lessons learned from the clinic will guide the design of next-generation NK cell products that will address the unique complexities of each cancer.

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Fig. 1: Advantages and limitations arising from different sources of NK cells.
Fig. 2: Strategies to redirect NK cell specificity.
Fig. 3: Principles and strategies for CAR design.
Fig. 4: Genetic engineering strategies to overcome suppressors of NK cell function.

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Acknowledgements

The authors thank J. S. Moyes for providing editing support during the preparation of this manuscript. A.B. received support from the German Research Foundation as Walter Benjamin Postdoctoral Fellow (464778766). This work was supported, in part, by generous philanthropic contributions to The University of Texas MD Anderson Cancer Center Moon Shots Program, The Sally Cooper Murray endowment, generous support of Ann and Clarence Cazalot, and Lyda Hill Philanthropies; and by grants from CPRIT (RP160693), a Stand Up To Cancer Dream Team Research Grant (Grant number: SU2C-AACR-DT-29-19), grants from the National Institutes of Health (NIH) (1 R01 CA211044-01, 5 P01CA148600-03, and P50CA100632-16), the Specialized Program of Research Excellence (SPORE) in Brain Cancer Grant (P50CA127001) and a grant to MD Anderson Cancer Center from the NIH (CA016672). The SU2C research grant is administered by the American Association for Cancer Research, the scientific partner of SU2C.

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Authors and Affiliations

  1. Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA

    Tamara J. Laskowski, Alexander Biederstädt & Katayoun Rezvani

  2. Department of Medicine III: Hematology and Oncology, School of Medicine, Technical University of Munich, Munich, Germany

    Alexander Biederstädt

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  1. Tamara J. Laskowski
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  2. Alexander Biederstädt
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The authors contributed equally to all aspects of the article.

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Correspondence to Katayoun Rezvani.

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Competing interests

K.R. and The University of Texas MD Anderson Cancer Center have an institutional financial conflict of interest with Takeda Pharmaceutical and Affimed GmbH. K.R. participates on the Scientific Advisory Board for GemoAb, AvengeBio, Virogin Biotech, GSK, Bayer, Navan Technologies and Caribou Biosciences. The remaining authors declare no competing interests.

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Glossary

Autologous chimeric antigen receptor (CAR) T cell therapy

A patient-specific cellular therapy in which the patient’s own T cells are genetically modified to express a chimeric antigen receptor.

Lymphopenic

A lower than normal number of lymphocytes in the blood.

Allogeneic setting

The therapy setting in which adoptive cell therapies are generated from material obtained from a different individual of the same species.

Graft-versus-host disease

(GvHD). A potentially fatal condition that results from the response of allogeneic T cells against the host tissues of recipients who are immunosuppressed, which can occur after adoptive cell therapy or allogeneic haematopoietic stem cell transplantation.

Killer cell immunoglobulin-like receptors

(KIRs). A family of polymorphic activating and inhibitory transmembrane proteins that regulate natural killer cell development and function through interactions with major histocompatibility complex class I molecules.

Induced pluripotent stem cells

(iPSCs). Cells that result from the reprogramming of adult somatic cells into an embryonic-like pluripotent stem cell state, capable of self-renewal and differentiation into tissues originated from the three germ layers (endoderm, mesoderm and ectoderm).

Apheresis

The process that allows for collection of specific components from blood, such as white blood cells, by separating the cellular and soluble fractions, retaining what is of interest and returning the remainder to circulation.

Chimeric antigen receptors

(CARs). Genetically engineered cell surface receptors designed to recognize specific proteins on tumour cells.

Tonic signalling

The constitutive signalling mediated by a chimeric antigen receptor in a ligand-independent manner.

Logic gated

A term derived from electronics that refers to implementation of a Boolean strategy to execute a logical function on one or more input signals to generate a single output signal.

Licensing

A process of education in maturing natural killer (NK) cells that is driven by the interaction of inhibitory receptors and self-major histocompatibility complex class I molecules, which potentiates NK cell responses to activating signals.

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Laskowski, T.J., Biederstädt, A. & Rezvani, K. Natural killer cells in antitumour adoptive cell immunotherapy. Nat Rev Cancer 22, 557–575 (2022). https://doi.org/10.1038/s41568-022-00491-0

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