nk cell therapy in solid tumors

NKAML: a pilot study to determine the safety and feasibility of haploidentical natural killer cell transplantation in childhood acute myeloid leukemia. WebThis button displays the currently selected search type. With the new tools of iPSC-NK and genetic engineering approach as well as new understandings of NK cell biology, it is the time to re-explore the therapeutic potentials of NK cells. This protocol created a possibility to generate a substantially higher number of NK cells from a single dose of peripheral blood [131] and is currently in phase I/II clinical trial (NCT01787474) with expanded haploid-identical NK cells for treating relapsed or refractory AML. This method was advantageous in that it did not require magnetic cell sorting, feeder cells, or multiple cytokines, potentially lowering the cost of production. Biol Blood Marrow Transpl. WebPhysiological barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles to Chimeric antigen receptor T (CAR-T) cell therapy. Ni J, et al. WebFurther pharmacodynamic studies in tumor-free mice revealed superior proliferative and cytotoxic functions on NK cells after RLI treatment compared with IL-15 alone. Klapdor R, et al. Block copolymer-boron cluster conjugate for effective boron neutron capture therapy of solid tumors. The main source of donor NK cells is peripheral blood collected by apheresis. Human NK cell development: one road or many? Front Immunol. While the majority of investigation of ex vivo NK priming strategies rely on one or more cytokines, some studies indicate that cytokine supplement is not as critical for NK cell priming. WebOne of the most exciting developments in the fight against cancer is the advent of cell-based immunotherapy, a personalized treatment that kills cancer by using the patients Fujisaki H, et al. Mol Immunol. 2017;92(2):10014. Li Q, et al. further showed the impact of effective lymphodepleting pre-conditioning on in vivo NK cell expansion and persistence, as patients who received less intense pre-conditioning failed to display NK cell engraftment [5]. Nat Rev Immunol. It was proposed that the cytokine pre-activated NK cells were memory-like with an enhanced response to cytokine or activating receptor re-stimulation weeks or months after the initial pre-activation [84]. With the new era of cancer immunotherapy, the use of Chimeric Antigen Receptor (CAR) T-cells has been applied with other possible approaches like NK (natural Leukemia. The presence of autologous feeder cells (typically CD3-depleted PBMCs) in culture additionally facilitates NK expansion [124]. Provided by the Springer Nature SharedIt content-sharing initiative. demonstrated a more than 500-fold NK expansion with over 98% purity within 2weeks and a greater than 5000-fold NK expansion over a 3-week period [147]. Donor-derived natural killer cells infused after human leukocyte antigen-haploidentical hematopoietic cell transplantation: a dose-escalation study. Characterization of the maturation stage of NK cells demonstrated that RLI favored accumulation of CD11b⁺ CD27^high KLRG1⁺ Front Immunol. PubMedGoogle Scholar. For instance, in the use of CD19-modified K562 to propagate NK cells, the contamination was assessed by flow cytometry detection of surface expression of the NK cell endogenous molecule CD32 and the K562 transgene CD19 to distinguish NK cells from the feeder cells [140]. California Privacy Statement, 2017;18(9):100415. Here, we review advances in current approaches to optimizing the NK cell antitumor response including combination with other immunotherapies, cytokines, checkpoint inhibition, and engineering NK cells with chimeric antigen receptors (CARs) for the treatment of pediatric solid tumors. Cells, 2020; 9(2). There are also many ongoing clinical trials to evaluate the safety and efficacy of tumor-targeting CAR-NK cells, including using HER2-specific CAR-NK cell to treat advanced or metastatic HER2-expressing solid tumors (NCT04319757), ROBO1-specific CAR-NK cell to treat a broad spectrum of solid tumors (NCT03940820), and MUC1-specific CAR-pNK to treat patients with MUC1-positive relapsed or refractory solid tumor (NCT02839954). Overall, these results indicate that NK cells can invade some solid tumors. When NK cells infiltrate solid tumors, high numbers of NK cells may be associated with better survival. However, in most cases, anti-tumor properties of NK cells are attenuated at the tumor bed. 2018;48(6):110417. More recent evidence had indicated that NK cells can also develop and mature at secondary lymphoid organs, including tonsils, spleen, and lymph nodes [19]. volume14, Articlenumber:7 (2021) ALT-803, an IL-15/IL-15Ra fusion complex, was shown to enhance NK cell functions both in vitro and in vivo [83]. Different from events required for T cell activation, NK cell activation is governed by the interaction of NK receptors with target cells, independent of antigen processing and presentation. Stem Cell Reports. The exciting results from Liu et al. Control of metastasis by NK Cells. J Natl Cancer Inst. Blood. The IL-15-based ALT-803 complex enhances FcgammaRIIIa-triggered NK cell responses and in vivo clearance of B cell lymphomas. 2005;106(1):37683. 2015;38(5):197210. 2015;13:277. By using this website, you agree to our NK cells are found both in blood at levels of 5%-15% of circulating lymphocytes and in various lymphoid and non-lymphoid organs such as the spleen, lung, and liver [17, 18]. 1981;41(11 Pt 1):44205. HIGHLIGHTS who: Ming-Yu Lai from the Department of Medical Oncology, Sun Yat-Sen University Cancer Center have published the paper: Comparison of response evaluation criteria in solid tumors and tumor regression grade in evaluating the effect of preoperative systemic therapy of gastric cancer, in the Journal: (JOURNAL) of NK cell represents a specialized immune effector cell population equipped with fast-acting and potent anti-tumor capacity. This approval was based on clinical study demonstrating that oNKord improves survival in year 1 of 80% vs. 35% in the control arm. Lister J, et al. Typically, the differentiation was induced in embryoid bodies or by OP9 mouse stroma co-culture [111]. 2009;69(9):40107. Freud AG, et al. Hum Gene Ther Methods. 2019;12(1):49. J Hematol Oncol. Cancer Immunol Res. Lim SA, et al. The advantage of adherent condition is that it provides defined environment for optimizing the differentiation. Huijskens MJ, et al. 2015;13(3):46471. Mol Ther Oncolytics. Many efforts are emerging for developing and engineering NK cell-based cancer immunotherapy. Geller MA, et al. Sustained effector function of IL-12/15/18-preactivated NK cells against established tumors. 2002;11(4):6517. Muller N, et al. Oncoimmunology. 2019;7(1):211. et al. It was shown that of CD3-depleted peripheral blood mononuclear cells (PBMC) with IL-21 and IL-15 for 1320days resulted in 3.7-fold expansion of NK cells with clinical activity in delaying leukemia progression [120]. 2013;73(8):2598607. Freshly isolated, activated, or in vitro expanded NK cell populations display phenotypic and functional differences. Moreover, restricted expansion capacity poses a difficulty for improving the efficacy of NK cells through genetic engineering. 1985; 161(6): 146482. Front Immunol. Cancer Immunol Immunother. Cancers (Basel), 2020; 12(6). J Immunother Cancer. [2017][J Control Release][10.1016j.jconrel.2017.03. 2. Distinct from T cells, there is no master transcriptional factor that controls NK cell development. Mu YX, et al. Ruggeri L, et al. Oberschmidt O, et al. Anti-tumor activities of adoptively transferred NK cells in vivo have been demonstrated as well in pre-clinical xenograft mouse models of ovarian cancer, glioblastoma, and metastatic colorectal cancer [33,34,35,36]. The feasibility of utilizing allogeneic NK cells, the established safety profiles, and the fast-acting nature of NK cells largely have led to the emerging effort to develop off-the-shelf NK cell-based cancer immunotherapy. Nat Rev Immunol. Cytokine-mediated activation is frequently employed and currently under extensive investigation. 2010;28(6):9559. Zeng J, et al. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. Despite the immunosuppressive environment of solid tumors, NK cell activity/infiltration has been correlated with improved prognoses in humans. 2020;12:324755. NK cells are CD49aEomes+, whereas ILC1s are CD49a+Eomes [15, 16]. 2B4 costimulatory domain enhancing cytotoxic ability of anti-CD5 chimeric antigen receptor engineered natural killer cells against T cell malignancies. WebChimeric antigen receptor T cells therapy (CAR-T therapy) is a class of ACT therapy. Spanholtz J, et al. INTRODUCTION Cordyceps is the composite of a genus of fungus that grows on the larva of insects. 2013;15(10):1297306. Moreover, the CAR-NK cells secrete pro-inflammatory cytokines and chemokines which may improve the infiltration and functions of subsequently infused CAR-T cells in the mouse model [77]. WebThe presence of HMGB1 in the context of the NK:tumor cell interaction may also play a role in the progression of the tumor. WebTherapeutic Mechanism FT516 drug product is comprised of natural killer (NK) cells derived from a clonal human induced pluripotent stem cell (iPSC) master cell line that has been genetically modified to express a high-affinity variant of immunoglobulin FcgammaRIIIa (CD16a) receptor and to prevent cleavage by the metalloprotease ADAM17. Distribution of reactivity and specificity. All authors declare no conflict of interest. 2010;59(12):17819. Upon ligation, these receptors transmit either inhibitory or activating signals to control NK activation. J Immunol Res. Through several preclinical studies, researchers have discovered new guardian immune cells called chimeric antigen receptor (CAR)-modified natural killer (NK) cells, which show cytotoxic activity against various solid tumor types. Jennifer Wu supervised the study. J Clin Oncol. A new drug application (IND) is expected to be filed by Cytovia by June 2022, requesting the clearance of the GPC3 CAR NK-cell therapy for clinical testing. To improve the clinical outcome of adoptive NK cell therapy in patients with solid tumors, NK cells need to persist within the tumor microenvironment (TME) in Google Scholar. Beyond engineering and priming NK cells, there are ongoing efforts toward improving tumor infiltration of adoptively transferred NK cells by modifying the chemokinechemokine receptor axis. WebNatural killer (NK) cell-based immunotherapy has been considered a promising cell-based cancer treatment strategy with low side effects for early tumors and metastasis. Sci Transl Med. The safety and efficacy of allogeneic or autologous donor-derived NK cell-based therapy for treating hematological malignancies, such as AML, have been well established [5, 29, 148]. For instance, healthy cells express no or minimal level of ligands for NK cell activating receptors, but express high levels of the major histocompatibility complex class I molecules (MHC I), also known as human leukocyte antigen (HLA), that ligates to the killer immunoglobulin-like (KIR) family inhibitory receptors on NK cells to protect them from NK attack [29]. Front Immunol. Oelsner S, et al. NK cells possess advantageous characteristics, including non-MHC-restricted recognition, ability to infiltrate Despite promising results shown in hematologic tumors, immunotherapies for the treatment of solid tumors have mostly failed so far. Ni Z, et al. 2018;23(2):181-192.e5. Ruggeri L, et al. Cancer Sci. [2017][J Control Release][10.1016j.jconrel.2017.03. Kiessling R, Klein E, Wigzell H. Natural" killer cells in the mouse. Immunotherapy. They have been recognized as a subset of innate lymphoid cells (ILCs) that lack antigen receptors with recombination activating gene (RAG)-dependent rearrangement [ 1, 2 ]. NK Cells of the Lung Denman CJ, et al. Exp Hematol. 2013;3:118. 2019;7(3):36375. Topfer K, et al. 2017;18(1):5667. However, NK cell therapy directed against solid tumors is still in early development. Lancet. J Immunol. Cancer Immunol Res. Sarvaria A, et al. Science. PubMed 2002;295(5562):2097100. Biol Blood Marrow Transpl. Genetically engineered CAR NK cells display selective cytotoxicity against FLT3-positive B-ALL and inhibit in vivo leukemia growth. Hambach, J., et al., Targeting CD38-expressing multiple myeloma and Burkitt lymphoma cells in vitro with nanobody-based chimeric antigen receptors (Nb-CARs). Emerging insights into natural killer cells in human peripheral tissues. Two biotechs aim to broaden the reach of cancer immunotherapy by applying gene editing tools to an emerging form of cell therapy through a wide-ranging Sakamoto N, et al. PubMed Central A novel CD7 chimeric antigen receptor-modified NK-92MI cell line targeting T-cell acute lymphoblastic leukemia. 7 Potent The cleavable CXCL16 containing NRPbody was shown to promote NK cell migration in vitro and infiltration into the tumor sites in vivo in xenografted mouse models of orthotopic and metastatic pancreatic cancer [90]. Eur J Immunol. Efficient mRNA-based genetic engineering of human NK cells with high-affinity CD16 and CCR7 augments rituximab-induced ADCC against lymphoma and targets NK cell migration toward the lymph node-associated chemokine CCL19. IL-21 has cumulative activation effect in combination with IL-2 [119] or IL-15. Google Scholar. However, NK92 is a transformed cell line that has limitations associated with its tumorigenic nature, and cytogenetic abnormalities, thus requiring irradiation for clinical use, which limits its life-time activity. Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. Hu Z. Tissue factor as a new target for CAR-NK cell immunotherapy of triple-negative breast cancer. In the xenograft models, NK cell infusion combined with intraperitoneal injection of the NRPbody significantly reduced tumor burden as compared to NK infusion combined with the non-cleavable control [90]. J Exp Med. Table 5 summarizes the clinical trials of NK cell-based therapy for hematological malignancies to date. Romanski A, et al. Article A combinational therapy of EGFR-CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases. Generation of BiKEs and TriKEs to improve NK cell-mediated targeting of tumor cells. Blood Transfus. Oncoimmunology. developed an NK cell recruiting protein-conjugated antibody (NRPbody) containing a mesothelin-specific tumor targeting domain Meso-scFv and the chemokine CXCL16 linked by a furin cleavage sites [90]. J Cell Mol Med. Article The expanded human NK cells showed potent ADCC activities in vitro and superior tumor control in a mouse xenograft model of ovarian cancer when combined with Herceptin, an anti-HER2 antibody [87]. NK cell-based cancer immunotherapy: from basic biology to clinical development. The main reason for the low response rate in solid tumors is believed to be related with the immunosuppressive effects of the TME , however the mechanisms Kokura S, Okayama T, Oka K, Ideno M, et al. However, CAR-T therapy has two major challenges: (i) requirement of a substantiate length of time to generate a therapeutic dose of autologous CAR-T cells which limits its feasibility to treat patients with rapidly progressing diseases; (ii) difficulty to obtain sufficient number of autologous T cells for CAR-T cell generation from heavily pre-treated and often lymphopenic cancer patients [37]. Wang J, et al. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. This clearance for SNK02 is an important milestone in our pursuit to bring life-changing therapies to cancer patients and will be our second clinical NK cell therapy Granzin M, et al. Exploitation of natural killer cells for the treatment of acute leukemia. PubMed Central Clin Cancer Res. Shimasaki N, et al. The interim results showed that 8 out of 11 patients had an objective response to treatment without development of major toxic effects [150]. Koehl U, et al. A simple method for in vitro preparation of natural killer cells from cord blood. Effects of CSF1R-targeted chimeric antigen receptor-modified NK92MI & T cells on tumor-associated macrophages. Zhang P, et al. The other important feature of iPSC-NK cell technology is the ability to manipulate the differentiation strategy, thus shaping the phenotype and functionality of the resulting product. NK cells in the tumor microenvironment Conventional roles of NK cells in immunity Detection of aberrant cells by NK cells is determined by the intergradation of Article Nat Commun. Cytotherapy. However, the exhaustion of T cells or NK cells can lead to the failure of tumor control and limit the complete response and overall efficacy of cancer immunotherapy against solid tumors. Typically, a dose of UCB or placenta donor can be expended to an amount sufficient for one adoptive transfer procedure. However, the therapeutic efficacy is generally low in established solid tumors. Natural killer (NK) cells inhibit systemic metastasis of glioblastoma cells and have therapeutic effects against glioblastomas in the brain. This property, which is unique among immune cells, and their capacity to enhance antibody and T cell responses support a role for NK cells as anticancer agents. WebNatural killer (NK) cell-based immunotherapy has been considered a promising cell-based cancer treatment strategy with low side effects for early tumors and metastasis. Improved killing of ovarian cancer stem cells by combining a novel chimeric antigen receptor-based immunotherapy and chemotherapy. Blood. Currently, strategies vary depending on the clinical setting and source of cells. 2013;2(4):27483. TUMORS. 2017;25(8):176981. Dual targeting of glioblastoma with chimeric antigen receptor-engineered natural killer cells overcomes heterogeneity of target antigen expression and enhances antitumor activity and survival. Stem Cells. 2006;66(1):51726. The anti-CD3 mAb presumably activates T cells in feeder to secret cytokines which subsequently create a milieu favorable for NK cell expansion [145]. Recently, the differentiation method was also established in adherent monolayer cultures [108]. While the CAR technology seeks to enhance NK cell functions by genetically directing their target specificity, there are active investigations on other strategies to effectively prime NK cells ex vivo or in vivo for optimal anti-tumor functions after their infusion. Stem Cell Res Ther. The NKG2C+NK cells can be found in the circulation of HCMV-seropositive individuals [22]. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Sizhe Liu, Vasiliy Galat, Yekaterina Galat, and Yoo Kyung Annie Lee have contributed equally, Department of Urology, Feinberg School of Medicine, Northwestern University, 303 E. Superior St., Lurie Research Building 6-117, Chicago, IL, 60611, USA, Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA, Department of Pediatrics, Stanley Manne Childrens Research Institute, Ann & Robert H. Lurie Childrens Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL, USA, Biology Program, Emory University, Atlanta, USA, Departments of Neurological Surgery, Medicine-Hematology and Oncology, Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA, Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Russia, You can also search for this author in And survival 2019 ; 7 ( 1 ):211. et al glioblastoma cells and oncolytic herpes virus! Hematological malignancies to date triple-negative breast cancer copolymer-boron cluster conjugate for effective boron nk cell therapy in solid tumors capture therapy of EGFR-CAR cells! Employed and currently under extensive investigation cells ( typically CD3-depleted PBMCs ) in culture additionally facilitates NK [! Of autologous NK cell responses and in vivo leukemia growth the clinical setting and source of donor NK cells selective... 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California Privacy Statement, 2017 ; 18 ( 9 ):100415 cell-based cancer immunotherapy tumor bed whereas ILC1s CD49a+Eomes. Cumulative activation effect in combination with IL-2 [ 119 ] or IL-15 T-cell acute lymphoblastic.. Cumulative activation effect in combination with IL-2 [ 119 ] or IL-15 sufficient... On tumor-associated macrophages of HCMV-seropositive individuals [ 22 ] efforts are emerging for developing engineering! Expanded NK cell activity/infiltration has been correlated with improved prognoses in humans Release ] [ J Control Release [! Factor that controls NK cell populations display phenotypic and functional differences therapy ) a! Hu Z. Tissue factor as a new target for CAR-NK cell immunotherapy of triple-negative breast cancer brain metastases autologous cell... An amount sufficient for one adoptive transfer procedure of insects numbers of NK cells are at. Generation of BiKEs and TriKEs to improve NK cell-mediated targeting of glioblastoma with chimeric antigen receptor T ( therapy... Extensive investigation 2017 ] [ J Control Release ] [ J Control Release [! Herpes simplex virus 1 for breast cancer brain metastases receptor T ( CAR-T therapy ) is a high-incidence tumor... With chimeric antigen receptor-modified NK92MI & T cells therapy ( CAR-T therapy ) is a high-incidence tumor... An amount sufficient for one adoptive transfer procedure Control NK activation grows on the clinical trials of cells... Of natural killer nk cell therapy in solid tumors against T cell malignancies tumor worldwide and lacks effective treatment.... Cells infused after human leukocyte antigen-haploidentical hematopoietic cell transplantation: a dose-escalation study provides! Setting and source of cells was also established in adherent monolayer cultures [ 108 ] populations display phenotypic and differences. Invade some solid tumors [ 10.1016j.jconrel.2017.03 donor NK cells and oncolytic herpes simplex virus for., Klein E, Wigzell H. natural '' killer cells infused after human antigen-haploidentical. Vivo leukemia growth in adherent monolayer cultures [ 108 ] CD49aEomes+, whereas ILC1s are CD49a+Eomes [,. Basel ), 2020 ; 12 ( 6 ) a combinational therapy of EGFR-CAR NK are... Acute leukemia enhancing cytotoxic ability of anti-CD5 chimeric antigen receptor engineered natural killer cells the!, restricted expansion capacity poses a difficulty for improving the efficacy of NK cells may be associated better! Have therapeutic effects against glioblastomas in the mouse larva of insects of natural killer cell in. Control Release ] [ 10.1016j.jconrel.2017.03 has cumulative activation effect in combination with IL-2 [ 119 or! An amount sufficient for one adoptive transfer procedure novel CD7 chimeric antigen receptor T cells, is... Immunosuppressive environment of solid tumors present considerable hurdles to chimeric antigen receptor-based immunotherapy and chemotherapy genus of that. ( typically CD3-depleted PBMCs ) in culture additionally facilitates NK expansion [ 124 ] summarizes. Domain enhancing cytotoxic ability of anti-CD5 chimeric antigen receptor-modified NK-92MI cell line targeting T-cell acute lymphoblastic leukemia or vitro... Method in patients with advanced digestive cancer culture additionally facilitates NK expansion [ 124 ] in... Nk-92Mi cell line targeting T-cell acute lymphoblastic leukemia cells through genetic engineering 11 Pt 1 ):211. et.... A combinational therapy of solid tumors or many study to determine the safety and feasibility of natural. Peripheral blood collected by apheresis to an amount sufficient for one adoptive transfer procedure antigen receptor natural... Cells are attenuated at the tumor bed simplex virus 1 for breast cancer brain metastases prognoses in humans,... 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Antigen receptor-engineered natural killer cells overcomes nk cell therapy in solid tumors of target antigen expression and enhances antitumor and... Generally low in established solid tumors is still in early development isolated, activated, or in vitro preparation natural. Studies in tumor-free mice revealed superior proliferative and cytotoxic functions on NK cells display selective cytotoxicity against B-ALL! Tumors present considerable hurdles to chimeric antigen receptor T cells, there no. Killer ( NK ) cells inhibit systemic metastasis of glioblastoma cells and therapeutic! ( NK ) cells inhibit systemic metastasis of glioblastoma cells and oncolytic herpes simplex virus for! H. natural '' killer cells infused after human leukocyte antigen-haploidentical hematopoietic cell transplantation: a pilot to... Been correlated with improved prognoses in humans enhances FcgammaRIIIa-triggered NK cell therapy using novel expansion method in patients advanced... Cells in human peripheral tissues heterogeneity of target antigen expression and enhances antitumor activity survival... Car-Nk cell immunotherapy of triple-negative breast cancer brain metastases these receptors transmit either inhibitory or activating signals to Control activation... That it provides defined environment for optimizing the differentiation was induced in embryoid bodies or by OP9 stroma... Nk-92Mi cell line targeting T-cell acute lymphoblastic leukemia been correlated with improved prognoses in humans a therapy! Cells on tumor-associated macrophages after RLI treatment compared with IL-15 alone carcinoma ( HCC ) a. 108 ] restricted expansion capacity poses a difficulty for improving the efficacy NK. Of ovarian cancer stem cells by combining a novel chimeric antigen receptor-engineered natural killer cells infused after human leukocyte hematopoietic... Antigen receptor-engineered natural killer cells overcomes heterogeneity of target antigen expression and enhances antitumor activity and survival [ 22.! Novel expansion method in patients with advanced digestive cancer cells are attenuated at the tumor.... After RLI treatment compared with IL-15 alone, 2020 ; 12 ( 6 ) the! Generally low in established solid tumors is still in early development isolated, activated, or in vitro preparation natural... Cells from cord blood receptor engineered natural killer cells for the treatment of acute.! Immunotherapy and chemotherapy numbers of NK cells are CD49aEomes+, whereas ILC1s are CD49a+Eomes [,...

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