Optimising NK cell metabolism to increase the efficacy of cancer immunotherapy

Choi, Chloe; Finlay, David K.

doi:10.1186/s13287-021-02377-8

Cited by 44 publications

(37 citation statements)

References 77 publications

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“…A growing body of work has established the crucial role of rapid metabolic reconfigurations required for NK cells to effectively mount anti-tumor responses [ 72 , 73 ]. Targeting of immune-metabolic pathways, hence, has emerged as an intriguing concept to render NK cells more metabolically robust and preserve their functional capacity.…”

Section: The Next Frontier—multiplexed Genetic Editingmentioning

confidence: 99%

“…Transferring the knowledge acquired to CAR-engineered NK cells, the same group recently reported on the successful application of CD19-CAR-modified memory-like NK cells against a xenograft lymphoma mouse model [ 85 ]. Several groups are now investigating and analyzing the immunometabolic signatures underpinning this distinct memory-like NK phenotype [ 73 ]. Mitochondrial fitness, in particular, has come to the center of attention with growing evidence linking mitochondrial dysfunction to impaired NK cell immune responses, and strategies to promote mitochondrial health to improve NK cell function are already under way [ 34 , 86 , 87 ].…”

Section: The Next Frontier—multiplexed Genetic Editingmentioning

confidence: 99%

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Engineering the next generation of CAR-NK immunotherapies

Biederstädt

Rezvani

2021

Int J Hematol

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Over the past few years, cellular immunotherapy has emerged as a novel treatment option for certain forms of hematologic malignancies with multiple CAR-T therapies now routinely administered in the clinic. The limitations of generating an autologous cell product and the challenges of toxicity with CAR-T cells underscore the need to develop novel cell therapy products that are universal, safe, and potent. Natural killer (NK) cells are part of the innate immune system with unique advantages, including the potential for off-the-shelf therapy. A recent first-in-human trial of CD19-CAR-NK infusion in patients with relapsed/refractory lymphoid malignancies proved safe with promising clinical activity. Building on these encouraging clinical responses, research is now actively exploring ways to further enhance CAR-NK cell potency by prolonging in vivo persistence and overcoming mechanisms of functional exhaustion. Besides these strategies to modulate CAR-NK cell intrinsic properties, there are increasing efforts to translate the successes seen in hematologic malignancies to the solid tumor space. This review will provide an overview on current trends and evolving concepts to genetically engineer the next generation of CAR-NK therapies. Emphasis will be placed on innovative multiplexed engineering approaches including CRISPR/Cas9 to overcome CAR-NK functional exhaustion and reprogram immune cell metabolism for enhanced potency.

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Section: The Next Frontier—multiplexed Genetic Editingmentioning

confidence: 99%

Section: The Next Frontier—multiplexed Genetic Editingmentioning

confidence: 99%

Engineering the next generation of CAR-NK immunotherapies

Biederstädt

Rezvani

2021

Int J Hematol

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“…Beyond broad actions to ameliorate ILCs' function [147,148], interest has emerged on ILC metabolism as a therapeutic target [149,150]. While these enhancements are not specifically directed towards the treatment of MM, CD38 knockout via CRISPR/Cas9 resulted in higher mitochondrial respiratory activity, with improved persistence in ex vivo expanded peripheral blood NK cells directed against MM cells [134].…”

Section: Targeting Ilcs Through Receptorsmentioning

confidence: 99%

Therapeutic Potential of Innate Lymphoid Cells for Multiple Myeloma Therapy

Szudy‐Szczyrek

Ahern

Kozioł

et al. 2021

Cancers

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Innate lymphoid cells (ILCs) are a recently identified family of lymphocyte-like cells lacking a specific antigen receptor. They are part of the innate immune system. They play a key role in tissue homeostasis and also control inflammatory and neoplastic processes. In response to environmental stimuli, ILCs change their phenotype and functions, and influence the activity of other cells in the microenvironment. ILC dysfunction can lead to a wide variety of diseases, including cancer. ILC can be divided into three subgroups: ILC Group 1, comprising NK cells and ILC1; Group 2, including ILC2 alone; and Group 3, containing Lymphoid Tissue inducers (LTi) and ILC3 cells. While Group 1 ILCs mainly exert antitumour activity, Group 2 and Group 3 ILCs are protumorigenic in nature. A growing body of preclinical and clinical data support the role of ILCs in the pathogenesis of multiple myeloma (MM). Therefore, targeting ILCs may be of clinical benefit. In this manuscript, we review the available data on the role of ILCs in MM immunology and therapy.

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“…Indeed, HIF-1 can orchestrate the expression of genes involved in the energy production, favoring the process of glycolysis and inhibiting ox-idative phosphorylation (OXPHOS) [40,41]. At steady state NK cells show relatively low glycolysis and OXPHOS rates, which, however, are significantly increased upon cytokine exposure, to support enhanced cytotoxicity and IFN-γ production [42]. Similarly, adaptive NK cells appear to maintain higher rates of glycolysis and OXPHOS [43].…”

Section: Role Of Hif In the Orchestration Of The Host/tumor Interfacementioning

confidence: 99%

Blocking HIF to Enhance NK Cells: Hints for New Anti-Tumor Therapeutic Strategies?

Vitale

Parodi

2021

Vaccines

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Natural Killer (NK) cells are becoming an ever more promising tool to design new anti-tumor strategies. However, two major issues are still a challenge to obtain versatile and effective NK-based therapies: the way to maximize the persistency of powerful NK effectors in the patient, and the way to overcome the multiple escape mechanisms that keep away or suppress NK cells at the tumor site. In this regard, targeting the hypoxia-inducible factors (HIFs), which is important for both tumor progression and immune suppression, may be an opportunity. Especially, in the context of the ongoing studies focused on more effective NK-based therapeutic products.

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Optimising NK cell metabolism to increase the efficacy of cancer immunotherapy

Cited by 44 publications

References 77 publications

Engineering the next generation of CAR-NK immunotherapies

Engineering the next generation of CAR-NK immunotherapies

Therapeutic Potential of Innate Lymphoid Cells for Multiple Myeloma Therapy

Blocking HIF to Enhance NK Cells: Hints for New Anti-Tumor Therapeutic Strategies?

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