Natural killer cells in antitumour adoptive cell immunotherapy

Laskowski, Tamara; Biederstädt, Alexander; Rezvani, Katayoun

doi:10.1038/s41568-022-00491-0

Cited by 380 publications

(251 citation statements)

References 247 publications

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“…Novel combination approaches are also reaching the clinical stage, such as NK cell engagers, migration enhancers, immunomodulators targeting the suppressive tumor microenvironment, and agents aiming to reverse tumor immune escape. A comprehensive summary of the next-generation NK cell product design has been recently published by Laskowski and colleagues [ 285 ].…”

Section: Discussionmentioning

confidence: 99%

Natural killer cells in clinical development as non-engineered, engineered, and combination therapies

Lamers-Kok¹,

Panella²,

Georgoudaki³

et al. 2022

J Hematol Oncol

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Natural killer (NK) cells are unique immune effectors able to kill cancer cells by direct recognition of surface ligands, without prior sensitization. Allogeneic NK transfer is a highly valuable treatment option for cancer and has recently emerged with hundreds of clinical trials paving the way to finally achieve market authorization. Advantages of NK cell therapies include the use of allogenic cell sources, off-the-shelf availability, and no risk of graft-versus-host disease (GvHD). Allogeneic NK cell therapies have reached the clinical stage as ex vivo expanded and differentiated non-engineered cells, as chimeric antigen receptor (CAR)-engineered or CD16-engineered products, or as combination therapies with antibodies, priming agents, and other drugs. This review summarizes the recent clinical status of allogeneic NK cell-based therapies for the treatment of hematological and solid tumors, discussing the main characteristics of the different cell sources used for NK product development, their use in cell manufacturing processes, the engineering methods and strategies adopted for genetically modified products, and the chosen approaches for combination therapies. A comparative analysis between NK-based non-engineered, engineered, and combination therapies is presented, examining the choices made by product developers regarding the NK cell source and the targeted tumor indications, for both solid and hematological cancers. Clinical trial outcomes are discussed and, when available, assessed in comparison with preclinical data. Regulatory challenges for product approval are reviewed, highlighting the lack of specificity of requirements and standardization between products. Additionally, the competitive landscape and business field is presented. This review offers a comprehensive overview of the effort driven by biotech and pharmaceutical companies and by academic centers to bring NK cell therapies to pivotal clinical trial stages and to market authorization.

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Section: Discussionmentioning

confidence: 99%

Natural killer cells in clinical development as non-engineered, engineered, and combination therapies

Lamers-Kok¹,

Panella²,

Georgoudaki³

et al. 2022

J Hematol Oncol

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“…While NK cells are attracting considerable interest as potential anticancer therapeutics and encouraging data have been documented in patients with hematological malignancies, the use of NK cells for the treatment of solid tumors remains hindered by a number of obstacles, as amply discussed herein [229][230][231]. Indeed, while numerous strategies aimed at improving the recruitment of NK cells to the TME as well as their persistence and activation have been proven effective in preclinical tumor models (see above), some of these approaches are complex to translate into clinically viable procedures (e.g., systemic infusion of NK cell-activating cytokines).…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

NK cells and solid tumors: therapeutic potential and persisting obstacles

et al. 2022

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Natural killer (NK) cells, which are innate lymphocytes endowed with potent cytotoxic activity, have recently attracted attention as potential anticancer therapeutics. While NK cells mediate encouraging responses in patients with leukemia, the therapeutic effects of NK cell infusion in patients with solid tumors are limited. Preclinical and clinical data suggest that the efficacy of NK cell infusion against solid malignancies is hampered by several factors including inadequate tumor infiltration and persistence/activation in the tumor microenvironment (TME). A number of metabolic features of the TME including hypoxia as well as elevated levels of adenosine, reactive oxygen species, and prostaglandins negatively affect NK cell activity. Moreover, cancer-associated fibroblasts, tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells actively suppress NK cell-dependent anticancer immunity. Here, we review the metabolic and cellular barriers that inhibit NK cells in solid neoplasms as we discuss potential strategies to circumvent such obstacles towards superior therapeutic activity.

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“…42, 43 In prior work, the addition of just a single PEG molecule to GM-CSF or interferon alfa-2b was found to be sufficient to confer prolonged circulation and tissue-drug exposure that in-turn improves therapeutic index. 44 Here, we likewise anticipate that prolonged circulation from IL-12-cCy-PEG relative to rIL-12 may enable it to more effectively elicit antitumor immune responses both alone and in combination with T cell bispecifics, immune checkpoint inhibitors, chimeric antigen receptor (CAR) T cells, and autologous gamma delta T cell 45 or NK cell 46, 47 therapies in the future where it may potentiate improved treatment outcomes.…”

Section: Discussionmentioning

confidence: 99%

Multicolor Light-Induced Immune Activation via Polymer Photocaged Cytokines

Birnbaum

Sullivan

et al. 2022

Preprint

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Cytokines act as potent, extracellular signals of the human immune system and can elicit striking treatment responses in patients with autoimmune disease, tissue damage, and cancer. Yet despite their therapeutic potential, recombinant cytokine-mediated immune responses remain difficult to control as their administration is often systemic whereas their intended sites of action are localized. To address the challenge of spatially and temporally constraining cytokine signals, we recently devised a strategy whereby recombinant cytokines are reversibly inactivated via chemical modification with photo-labile polymers that respond to visible LED light. Extending this approach to enable both in vivo and multicolor immune activation, here we describe a strategy whereby cytokines appended with heptamethine cyanine-polyethylene glycol are selectively re-activated ex vivo using tissue-penetrating near-infrared (NIR) light. We show that NIR LED light illumination of caged, pro-inflammatory cytokines restores cognate receptor signaling and potentiates the activity of T cell-engager cancer immunotherapies ex vivo. Using combinations of visible- and NIR- responsive cytokines, we further demonstrate multi-wavelength optical control of T cell cytolysis ex vivo, as well as the ability to perform Boolean logic using multicolored light and orthogonally photocaged cytokine pairs as inputs, and T cell activity as outputs. Together, this work demonstrates a novel approach to control extracellular immune cell signals using light, a strategy that in the future may improve our understanding of and ability to treat cancer and other diseases.

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Natural killer cells in antitumour adoptive cell immunotherapy

Cited by 380 publications

References 247 publications

Natural killer cells in clinical development as non-engineered, engineered, and combination therapies

Natural killer cells in clinical development as non-engineered, engineered, and combination therapies

NK cells and solid tumors: therapeutic potential and persisting obstacles

Multicolor Light-Induced Immune Activation via Polymer Photocaged Cytokines

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