Generation of “Off-the-Shelf” Natural Killer Cells from Peripheral Blood Cell-Derived Induced Pluripotent Stem Cells

Zeng, Jieming; Tang, Shin Yi; Toh, Lai Ling; Wang, Shu

doi:10.1016/j.stemcr.2017.10.020

Cited by 117 publications

(102 citation statements)

References 33 publications

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“…Another approach is to specifically block CD16A cleavage by expressing a non‐cleavable version of the receptor, such as CD16A‐S197P, in engineered NK cells. Various autologous and allogeneic NK cell platforms could be utilized, including expanded cord blood or peripheral blood NK cells, NK cell lines, and stem cell‐derived NK cells, which offer different advantages . A potential limitation of this approach is that NK cells expressing non‐cleavable CD16A might be less efficient at serial killing of Ab‐coated tumor cells in vivo.…”

Section: Resultsmentioning

confidence: 99%

“…Of importance is that several clinically successful tumor-targeting Abs utilize ADCC as a primary mechanism of action. 3,89 [92][93][94] A potential limitation of this approach is that NK cells expressing non-cleavable CD16A might be less efficient at serial killing of Ab-coated tumor cells in vivo. However, it is also possible that noncleavable CD16A may further stabilize and increase NK cell attachment to tumor cells in the tumor microenvironment for more effective killing of resilient cancer cells.…”

Section: Resultsmentioning

confidence: 99%

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Role of ADAM17 as a regulatory checkpoint of CD16A in NK cells and as a potential target for cancer immunotherapy

Mishra

Walcheck

2019

Journal of Leukocyte Biology

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Human NK cell antitumor activities involve Ab‐dependent cell‐mediated cytotoxicity (ADCC), which is a key mechanism of action for several clinically successful tumor‐targeting therapeutic mAbs. Human NK cells exclusively recognize these Abs by the Fcγ receptor CD16A (FcγRIIIA), one of their most potent activating receptors. Unlike other activating receptors on NK cells, CD16A undergoes a rapid down‐regulation in expression by a proteolytic process following NK cell activation with various stimuli. In this review, the role of a disintegrin and metalloproteinase‐17 (ADAM17) in CD16A cleavage and as a regulatory checkpoint is discussed. Several studies have examined the effects of inhibiting ADAM17 or CD16A cleavage directly during NK cell engagement of Ab‐coated tumor cells, which resulted in strengthened Ab tethering, decreased tumor cell detachment, and enhanced CD16A signaling and cytokine production. However, the effects of either manipulation on ADCC have varied between studies, which may be due to dissimilar assays and the contribution of different killing processes by NK cells. Of importance is that NK cells under various circumstances, including in the tumor microenvironment of patients, down‐regulate CD16A and this appears to impair their function. Considerable progress has been made in the development of ADAM17 inhibitors, including human mAbs that have advantages of high specificity and increased half‐life in vivo. These inhibitors may provide a therapeutic means of increasing ADCC potency and/or antitumor cytokine production by NK cells in an immunosuppressive tumor microenvironment, and if used in combination with tumor‐targeting Abs or NK cell‐based adoptive immunotherapies may improve their efficacy.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Role of ADAM17 as a regulatory checkpoint of CD16A in NK cells and as a potential target for cancer immunotherapy

Mishra

Walcheck

2019

Journal of Leukocyte Biology

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“…However, an effective clinically applicable off-the-shelf allogenic T-cell therapy should meet the following criteria: (i) expandable to a therapeutically relevant number under clinically compliant condition; (ii) do not cause graft-versus-host disease (GvHD); (iii) are able to target an array of cancers in a donor-unrestricted manner; (iv) are not rejected by the recipient's immune system; (v) can be stored under GMP conditions without hampering their function (10). There are reports on ACTs with a potential to be used as an off-the-shelf therapy, including NK-92 (14), primary NK cells (17), and gd T cells (18), due to their HLA-unrestricted antitumor toxicity and low risk of off-tumor toxicity. However, to the best of our knowledge, there has not been a report to show an ACT that can avoid host-versus-graft (HvG) rejection while fulfilling other requirements of off-the-shelf therapy without any genetic modification.…”

Section: Introductionmentioning

confidence: 99%

Developing Allogeneic Double-Negative T Cells as a Novel Off-the-Shelf Adoptive Cellular Therapy for Cancer

Lee

Kang

Fang

et al. 2019

Clinical Cancer Research

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Purpose: To expand clinical-grade healthy donor-derived double-negative T cells (DNT) to a therapeutically relevant number and characterize their potential to be used as an "offthe-shelf" adoptive cellular therapy (ACT) against cancers.Experimental Design: We developed methods to expand DNTs under GMP conditions and characterized their surface molecule expression pattern using flow cytometry-based high-throughput screening. We investigated the off-the-shelf potential of clinical-grade DNTs by assessing their cytotoxicity against various cancer types and their off-tumor toxicity in vitro and in xenograft models and determining the effect of cryopreservation under GMP conditions on cell viability and cytotoxicity. Further, we determined the susceptibility of DNTs to conventional allogeneic T cells in vitro and in vivo.Results: Clinical-grade DNTs expanded 1,558 AE 795.5-fold in 17 days with >90% purity. Expanded DNTs showed potent in vitro cytotoxic activity against various cancer types in a donor-unrestricted manner. DNTs enhanced the survival of mice infused with a lethal dose of EBV-LCL and significantly reduced leukemia engraftment in xenograft models. Expanded DNTs cryopreserved using GMP-compliant reagents maintained viability and anticancer functions for at least 600 days. Live allogeneic DNTs did not induce cytotoxicity of alloreactive CD8 þ T cells in vitro, and coinfusion of DNTs with peripheral blood mononuclear cells (PBMC) from a different donor into mice resulted in coengraftment of DNTs and PBMC-derived allogeneic conventional T cells in the absence of cytotoxicity toward DNTs, suggesting the lack of hostversus-graft reaction.Conclusions: We have established a method to generate therapeutic numbers of clinical-grade DNTs that fulfill the requirements of an off-the-shelf ACT.

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“…Genetically modifying peripheral blood NK cells by retroviral or lentiviral transduction at this point has been challenging (36). Embryonic stem cells and iPSCs can be differentiated into cytolytic NK cells in vitro (28–31, 37), and these cells are highly amendable to genetic engineering (14, 30, 38, 39). Undifferentiated iPSCs were transduced to express CD64/16A using a sleeping beauty transposon plasmid for nonrandom gene insertion and stable expression.…”

Section: Resultsmentioning

confidence: 99%

“…We showed that fusion proteins containing a human IgG Fc region, such as L-selectin/Fc, can also be captured by CD64/16A and this may provide further options for directing the tissue and tumor antigen targeting of engineered NK cells. Advantages of the NK92 and iNK cell platforms for adoptive cell therapies is that they can be readily gene modified on a clonal level and expanded into clinical-scalable cell numbers to produce engineered NK cells with improved effector activities as an off-the-shelf therapeutic for cancer immunotherapy (37, 38, 40, 41, 47).…”

Section: Discussionmentioning

confidence: 99%

Expression of a recombinant high affinity IgG Fc receptor by engineered NK cells as a docking platform for therapeutic mAbs to target cancer cells

Snyder

Hullsiek

Mishra

et al. 2018

Preprint

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22Anti-tumor mAbs are the most widely used and characterized cancer immunotherapy agents. 23 Despite having a significant impact on some malignancies, most cancer patients respond poorly 24 or develop resistance to this therapy. A known mechanism of action of these therapeutic mAbs is 25 antibody-dependent cell-mediated cytotoxicity (ADCC), which is a primarily effector function of 26 NK cells. CD16A on human NK cells has an exclusive role in binding to tumor-bound IgG 27antibodies. Though CD16A is a potent activating receptor, it is a low affinity FcγR and its cell 28 surface levels can be rapidly downregulated by a proteolytic process involving ADAM17 upon 29 NK cell activation, which are likely to limit the efficacy of tumor-targeting therapeutic mAbs in 30 the tumor environment. We sought to enhance NK cell binding to anti-tumor mAbs by 31 engineering these cells with a recombinant FcγR consisting of the extracellular region of CD64, 32 the highest affinity IgG Fc receptor expressed by leukocytes, and the transmembrane and 33 cytoplasmic regions of CD16A. This novel recombinant FcγR (CD64/16A) was expressed in the 34 human NK cell line NK92 and in induced pluripotent stem cells from which primary NK cells 35were derived. CD64/16A also lacked the ADAM17 cleavage region in CD16A and it was not 36 rapidly downregulated in expression following NK cell activation during ADCC.

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Generation of “Off-the-Shelf” Natural Killer Cells from Peripheral Blood Cell-Derived Induced Pluripotent Stem Cells

Cited by 117 publications

References 33 publications

Role of ADAM17 as a regulatory checkpoint of CD16A in NK cells and as a potential target for cancer immunotherapy

Role of ADAM17 as a regulatory checkpoint of CD16A in NK cells and as a potential target for cancer immunotherapy

Developing Allogeneic Double-Negative T Cells as a Novel Off-the-Shelf Adoptive Cellular Therapy for Cancer

Expression of a recombinant high affinity IgG Fc receptor by engineered NK cells as a docking platform for therapeutic mAbs to target cancer cells

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