Evaluation of ex vivo expanded human NK cells on antileukemia activity in SCID-beige mice

Guimarães, Fernando; Guvén, Hayrettin; Donati, Daria; Christensson, Birger; Ljunggren, Hans Gustaf; Bejarano, Maria-Teresa; Dilber, M. Siraç

doi:10.1038/sj.leu.2404147

Cited by 26 publications

(20 citation statements)

References 30 publications

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“…S5C; refs. [40][41][42], transient expression of CAR in exPBNK may not be a significant disadvantage and it does not need a suicide gene to limit the risk of the long-term side effect using retroviral or lentiviral vectors. In our xenograft models, three injections of anti-CD20 CAR mRNA-electroporated exPBNK significantly mediated CD20 þ tumor regression, extended survival ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Targeting CD20+ Aggressive B-cell Non–Hodgkin Lymphoma by Anti-CD20 CAR mRNA-Modified Expanded Natural Killer Cells In Vitro and in NSG Mice

Chu

Hochberg

Yahr

et al. 2015

Cancer Immunology Research

142

109

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Section: Discussionmentioning

confidence: 99%

Targeting CD20+ Aggressive B-cell Non–Hodgkin Lymphoma by Anti-CD20 CAR mRNA-Modified Expanded Natural Killer Cells In Vitro and in NSG Mice

Chu

Hochberg

Yahr

et al. 2015

Cancer Immunology Research

142

109

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“…However, the limitation of this method becomes apparent when long-term expression of the acquired molecule is essential to achieve therapeutic efficacy such as expression of chimeric Ag receptors. Nevertheless, in the context of NK cells, transient persistence of acquired receptors may not be a significant disadvantage, considering that adoptively transferred NK cells may have limited lifespan 49 of ϳ 10-12 days after infusion even with cytokine support. 50 It may be possible to administer multiple infusions of expanded NK cells modified via trogocytosis to overcome the limitations of receptor persistence.…”

Section: Discussionmentioning

confidence: 99%

Engineering lymph node homing of ex vivo–expanded human natural killer cells via trogocytosis of the chemokine receptor CCR7

Somanchi

Cooper

et al. 2012

Blood

104

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Until recently, the main limiting factor to the clinical application and efficacy of NK cells was the difficulty in obtaining sufficient cell numbers for adoptive transfer. Development of novel methods of expanding primary human NK cells ex vivo has renewed interest in NK cells for immunotherapy for cancer. [2][3][4][5][6] Expanded NK cells have enhanced expression of activating receptors, 4,7,8 that in turn improves their antitumor cytotoxicity. Where activating receptors did not sufficiently elicit an antitumor response, researchers augmented the antitumor effect of NK cells by expression of chimeric Ag receptors. 9-11 Ultimately, the success of NK cell adoptive immunotherapy for cancer depends not only on target recognition but also on homing of NK cells to the tumor target in vivo. Thus, the effector cells must express the appropriate chemokine receptors.Cancer cells express a wide array of chemokines and chemokine receptors that are instrumental in tumor survival 12 and metastatic spread. 13 Lymph nodes, particularly the tumor-draining nodes, are the foci of metastatic spread of tumors for a vast number of cancer types. 13,14 The expression of CCR7, a member of the G protein-coupled receptor family, on lymphocytes directs their homing to lymph node, coordinates primary immune responses, and induces peripheral immune tolerance. 15 CCR7 expression on tumor cells has been reported and shown to play a pivotal role in lymph node metastasis of various cancers such as breast, 16 pancreatic, 17 thyroid, 18 and colorectal 19 cancers; oral squamous cell carcinoma 20 ; melanoma 21 ; and lymphoma. 22 Lymph node involvement in these cancers is generally associated with poor prognosis.Peripheral NK cells express a variety of chemokine receptors such as CXCR1, CXCR3, and CXCR4 with subsets expressing CCR1, CCR4, CCR5, CCR6, CCR7, CCR9, CXCR5, and CXCR6. Expression of CCR7 on NK cells can facilitate homing to lymph nodes, which, in the context of adoptive immunotherapy for various cancers, would offer a main advantage in targeting lymph node metastases. However, CD56 bright CD16 Ϫ NK cells, which primarily secrete cytokines, express CCR7, but CD56 dim CD16 ϩ NK cells, which are primarily responsible for cytotoxicity, do not. 23 In a previous study, we reported that expanded NK cells are predominantly of CD56 ϩ CD16 bright phenotype and did not express CCR7. 7 In this study, we sought to express CCR7 on expanded NK cells ex vivo to facilitate lymph node homing on adoptive transfer. Although investigators have used viral vectors to gene modify NK cell lines 10,24 and primary NK cells, 9,25 because of safety concerns over integrating viral vectors there has been a recent shift in emphasis toward nonviral methods of gene transfer, particularly nonintegrating, mRNA-based electroporation approaches. 11 However, electroporation of NK cells has been difficult in that the transfection efficiency and viability of NK cells are low, and high-throughput electroporation methods for gene modifying clinically relevant NK cell numbers are ...

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“…8,26,27,46 To enhance the therapeutic effects of donor NK cells, it is critical to identify functional receptors essential for the interaction of malignant tumor cells and effector NK cells. We have demonstrated that engagement of a novel NK-cell receptor Tim-3 positively regulates IFN-␥-producing NK cells, which have a central role in tumor immunosurvelliance.…”

Section: Discussionmentioning

confidence: 99%

“…8,26,27 Initial studies were based on the KIR-ligand incompatibility model in which transplantation across the HLA class I barriers triggers alloreactive NK-cell responses. 8,26,27 More recently, specific donor NK-cell receptor repertoires have been associated with less relapse and improved survival for patients receiving unrelated donor transplants for both HLA-matched and HLA-mismatched settings. 28,29 Therefore, to enhance the therapeutic effects of NK cells, a better understanding of the mechanisms that underlie target cell recognition is needed.…”

Section: Introductionmentioning

confidence: 99%

“…[21][22][23][24][25] The potential of NK cells to control human hematologic malignancies has been increasingly recognized in recent years. 8,26,27 Initial studies were based on the KIR-ligand incompatibility model in which transplantation across the HLA class I barriers triggers alloreactive NK-cell responses. 8,26,27 More recently, specific donor NK-cell receptor repertoires have been associated with less relapse and improved survival for patients receiving unrelated donor transplants for both HLA-matched and HLA-mismatched settings.…”

mentioning

confidence: 99%

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Tim-3 is an inducible human natural killer cell receptor that enhances interferon gamma production in response to galectin-9

Gleason¹,

Lenvik²,

McCullar³

et al. 2012

Blood

311

288

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NK-cell function is regulated by the integration of signals received from activating and inhibitory receptors. Here we show that a novel immune receptor, T-cell Ig and mucin-containing domain-3 (Tim-3), is expressed on resting human NK cells and is up-regulated on activation. The NK92 NK-cell line engineered to overexpress Tim-3 showed a marked increase in IFN-␥ production in the presence of soluble rhGal-9 or Raji tumor cells engineered to express Gal-9. The Tim-3 ؉ population of low-dose IL-12/IL-18-activated primary NK cells significantly increased IFN-␥ production in response to soluble rhGal-9, Gal-9 presented by cell lines, and primary acute myelogenous leukemia (AML) targets that endogenously express Gal-9. This effect is highly specific as Tim-3 Ab blockade significantly decreased IFN-␥ production, and Tim-3 cross-linking induced ERK activation and degradation of IB␣. Exposure to Gal-9-expressing target cells had little effect on CD107a degranulation. Reconstituted NK cells obtained from patients after hematopoietic cell transplantation had diminished expression of Tim-3 compared with paired donors. This observation correlates with the known IFN-␥ defect seen early posttransplantation. In conclusion, we show that Tim-3 functions as a human NK-cell coreceptor to enhance IFN-␥ production, which has important implications for control of infectious disease and cancer. (Blood. 2012;119(13): 3064-3072) IntroductionHuman NK cells are lymphocytes that develop from hematopoietic progenitor cells in the BM and secondary lymphoid tissues. 1 Peripheral blood (PB) NK cells are phenotypically defined as expressing the surface receptor CD56 (neural cell adhesion molecule [NCAM]) and lacking expression of CD3. 2 They mediate their function through the exocytosis of lytic granules that contain perforin and granzymes, 3 the expression of death receptor ligands, 4 the expression of FcR␥III, which mediates Ab-dependent cellmediated cytotoxicity, 5 and the secretion of cytokines and chemokines. 6 As a result, NK cells take part in both the innate and adaptive immune systems and play important roles in the control of viral infections, pregnancy, tumor immunosurveillance, and hematopoietic cell transplantation (HCT). 7,8 The ability of NK cells to differentiate normal healthy cells (self) from virally infected or malignantly transformed cells (nonself) is regulated by a sophisticated repertoire of cell-surface receptors that control their activation, proliferation, and effector functions. [9][10][11] Recently, a novel receptor, T-cell Ig and mucincontaining domain-3 (Tim-3), has been described to have various roles in immune regulation and is highly expressed on NK cells in mice and humans. [12][13][14][15][16][17] Tim-3 is a type I membrane glycoprotein that was first identified as a cell marker of terminally differentiated CD4 ϩ Th1 cells. 18 Galectin-9 (Gal-9), a 40-kDa S-type ␤-galactoside binding lectin, is a known ligand for Tim-3 and is highly expressed in tissues of the immune system, such as the BM, lymph nodes, thymu...

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Evaluation of ex vivo expanded human NK cells on antileukemia activity in SCID-beige mice

Cited by 26 publications

References 30 publications

Targeting CD20+ Aggressive B-cell Non–Hodgkin Lymphoma by Anti-CD20 CAR mRNA-Modified Expanded Natural Killer Cells In Vitro and in NSG Mice

Targeting CD20+ Aggressive B-cell Non–Hodgkin Lymphoma by Anti-CD20 CAR mRNA-Modified Expanded Natural Killer Cells In Vitro and in NSG Mice

Engineering lymph node homing of ex vivo–expanded human natural killer cells via trogocytosis of the chemokine receptor CCR7

Tim-3 is an inducible human natural killer cell receptor that enhances interferon gamma production in response to galectin-9

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