By using this website, you agree to our Natural killer (NK) cells have potential as a cellular anticancer therapy that could be significantly safer, cheaper, and faster, researchers say. Choi YH, et al. Phase I study of cord blood-derived natural killer cells combined with autologous stem cell transplantation in multiple myeloma. Oberschmidt O, et al. In addition to cytokine-only strategies, Cichocki and colleagues demonstrated that pharmacologic inhibition of GSK3 kinase with CHIR99021 drives late-stage maturation of ex vivo-expanded human peripheral blood NK cells and enhanced their anti-tumor effector functions both in vitro and in vivo [87]. Tumor boron neutron capture therapy (BNCT) subcutaneousC26 tumor-bearing BALB/c mice were intrave- nously injected PEG-b-P(Glu-SS-BSH)respectively 100mg/kg BSHbasis, when Choi I, et al. Nat Rev Clin Oncol. Blood. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. California Privacy Statement, Blood. Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. Cancer Immunol Immunother. WebChimeric antigen receptor T cells therapy (CAR-T therapy) is a class of ACT therapy. However, NK cell therapy directed against solid tumors is still in early development. PubMed Central 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 Clin Cancer Res. Thus, feeder-free approaches are an alternative or a more desirable method to avoid safety concerns associated with the clinical application of cancer cell-derived feeder cells. OKT3, an anti-CD3 mAb, has been commonly added to the irradiated autologous PBMC feeder, which can promote the expansion of NK cells up to over 1000-fold [4, 142,143,144]. Activation of NK cell cytotoxicity. In mouse, NK and ILC1 are NK1.1+CD3 but can be further characterized by CD49a and Eomes expression. Hum Gene Ther. Upon ligation, these receptors transmit either inhibitory or activating signals to control NK activation. Cancers. 1975;5(2): 1127. Huang Y, et al. Control of metastasis by NK Cells. Ichinose Y (2016) Prospective study of the UGT1A1*27 gene polymorphism during irinotecan therapy in patients with lung cancer: results of Lung Oncology Group in Kyusyu (LOGIK1004B. Ni J, et al. 2019;145(7):193545. Topfer K, et al. Transcription factors involved in the regulation of natural killer cell development and function: an update. J Immunol. PLoS ONE. Lee HR, et al. CAR-NK is one of the approaches in development to overcome this limitation. Hammer Q, et al. Klapdor R, et al. Bjorkstrom NK, Ljunggren HG, Michaelsson J. 2014;32(4):102131. showed that CAR-NK cells genetically modified to express the chemokine receptor CXCR1 had enhanced migration in vitro and in vivo as compared to control CAR-NK cells [54]. Recent studies revealed that subset of mature NK cells can elicit long-lived adaptive-like nature in the specific context of CMV infection [21]. 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]. They are also summarized in Table 2. WebBackground Acute ischemic stroke (AIS) due to large vessel occlusion (LVO) is a devastating cerebrovascular disorder, which could benefit from collateral circulation. Skeate R, et al. Natural killer (NK) cells are an essential part of tumor immunosurveillance, evidenced by higher cancer susceptibility and metastasis in association with diminished NK activity in mouse models and clinical studies [1,2,3]. The approach of using the modified NK cell line CAR-NK92, which can be easily expanded to large dose, has been in clinical trial. Kim EK, et al. Stem Cell Res Ther. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. Sci Rep. 2020;10(1):2815. Challenges in CAR NK cell therapy in solid tumors. On the other hand, it has limited viability support and can trigger proliferative arrest and apoptosis of NK cells at higher dosage (50ng/mL) [118]. PubMed Privacy 2013;13(2):1459. New research by Fred Hutchinson Cancer Center molecular biologist Ami Yamamoto in the Cheung Lab, shows that a tumors necrotic core a mass of dying and dead cells previously thought to be inconsequential or perhaps even 1995;1(6):60714. 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]. 2017;9(6):1796812. Despite decades of work, the ontogeny of NK cells in humans is still not fully elucidated. High cytotoxic efficiency of lentivirally and alpharetrovirally engineered CD19-specific chimeric antigen receptor natural killer cells against acute lymphoblastic leukemia. The exciting results from Liu et al. Cancer Res. Article We want to do better, and this NK cell therapy is a promising CAR-engineered iPSC-NK cells already have demonstrated effectiveness in targeting human tumors in preclinical studies [41]. For instance, the enhancement of the Wnt signaling pathway with GSK3b inhibitor induces definitive hematopoiesis [112, 113] NK cells developed in such conditions had more pronounced inflammatory cytokine production phenotype, whereas Wnt independent NK subsets, similar to primary fetal NK cells, formed a bias for increased cytotoxicity [110]. 2011;17(19):628797. Masuyama J, et al. J Transl Med. 2013;2(4):27483. 2017;92(2):10014. 2005;106(1):37683. Expression of IL-15 in NK cells results in rapid enrichment and selective cytotoxicity of gene-modified effectors that carry a tumor-specific antigen receptor. Production Process of CAR-NK Cytokines in clinical cancer immunotherapy. 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]. 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. Compared with cytotoxic T lymphocytes, Google Scholar. NK cells possess advantageous characteristics, including non-MHC-restricted recognition, ability to infiltrate Felices M, et al. 2013;15(10):1297306. WebImmune regulation has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors (ICIs). 2017;8:458. In the last years, natural killer (NK) cell-based immunotherapy has emerged as a promising therapeutic approach for solid tumors and hematological malignancies. Membrane bound IL-21 based NK cell feeder cells drive robust expansion and metabolic activation of NK cells. 2020;12:324755. 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]. J Immunol Res. Stimulating antibodies is typically used along with irradiated allogeneic PBMC to further promote NK activation and expansion. NK cells were identified over four decades ago as lymphocytes with innate ability to lyse tumor cells without the need for prior sensitization [8,9,10]. Immunity. Effects of CSF1R-targeted chimeric antigen receptor-modified NK92MI & T cells on tumor-associated macrophages. WebImmune regulation has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors (ICIs). 2004;24(3b):186171. Although the ability of NK cells to destroy solid tumors. This method has achieved over 15% of CD34+ hematopoietic progenitors compared to other methods producing only up to 4% of CD34+. Anticancer Res. Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine secretion. 2014;193(12):6192206. 2018;6(1):136. Adenosine impairs the anti-tumor functions of both T and NK cells [43]. One study showed that overnight co-incubation with a leukemia cell line CTV-1 or its lysate without cytokines was sufficient to prime potent NK cells in vitro cytotoxicity against otherwise NK-insensitive tumor cells but not normal hemopoietic cells [88]. Natural killer cells: development, maturation, and clinical utilization. The synergistic use of IL-15 and IL-21 for the generation of NK cells from CD3/CD19-depleted grafts improves their ex vivo expansion and cytotoxic potential against neuroblastoma: perspective for optimized immunotherapy post haploidentical stem cell transplantation. For example, a subset of IL-22 secreting human ILC3s is CD56+NKp46+CD3 [14]. Ng YY, Tay JCK, Wang S. cxcr1 expression to improve anti-cancer efficacy of intravenously injected CAR-NK cells in mice with peritoneal xenografts. In humans, NK cells are traditionally identified by the absence of CD3 and the presence of CD56 on their surface as characterized by flow cytometry. INTRODUCTION Cordyceps is the composite of a genus of fungus that grows on the larva of insects. 2017;2017:6915912. Int J Cancer. Front Immunol. Journal of Hematology & Oncology Sci Transl Med. Recent observations show that HMGB1 is a potent driver In allogeneic transfer settings, the concept of KIR and HLA mismatches between donor and recipient was the original strategy aimed at enhancing the activation of donor NK cells to eradicate patients tumor cells. Application of small molecule CHIR99021 leads to the loss of hemangioblast progenitor and increased hematopoiesis of human pluripotent stem cells. The subjects of the study were patients with high-risk solid tumors, including Ewing Sarcoma, Neuroblastoma, Rhabdomyosarcoma, Osteosarcoma, and CNS tumors. 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. 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. Despite promising results shown in hematologic tumors, immunotherapies for the treatment of solid tumors have mostly failed so far. PubMed Rosario M, et al. A first-in-human clinical trial of CAR NK-92 cells in 3 patients with relapsed or refractory AML showed that CAR NK-92 can be infused at doses up to 5 billion cells per patient without causing significant adverse effects [149]. Eur J Cancer. Nat Rev Immunol. 2019;10:719. 2016;4(3):21524. Google Scholar. Hematology Am Soc Hematol Educ Program. Cancer Cell. Sci Rep. 2017;7(1):11075. They act as Exposure of NK to unmodified NK cell-sensitive leukemia cells (K562) stimulates expansion and short-term proliferation [133]. 3D model for CAR-mediated cytotoxicity using patient-derived colorectal cancer organoids. On the one hand, it was shown to enhance interferon gamma (IFN-) production, cytotoxic functions, and antibody-dependent cellular cytotoxicity(ADCC) responses [117]. Shimasaki N, et al. Oncotarget. NK cell-based cancer immunotherapy: from basic biology to clinical development. Natural killer cell memory in infection, inflammation and cancer. 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. Exploitation of natural killer cells for the treatment of acute leukemia. Oncoimmunology. Conceptually, iPSC-NK can provide a homogenously differentiated NK cell population that can be expanded to clinical scale as an off-the-shelf supply, overcoming the limitation of the NK-92 cell line. Szmania S, et al. Necrotic core even the name sounds creepy. Using irradiated autologous PBMCs and anti-CD16 mAb, Lee et al. Natural killer cells produce T cell-recruiting chemokines in response to antibody-coated tumor cells. Phase I/II clinical trials are ongoing to evaluate the safety and efficacy of NK cell combined with nimotuzumab to treat late-stage malignancies (NCT03554889) and of NK cell infusion on patients with advanced malignant tumors following multi-line therapies (NCT03619954). NK cells are also potent producers of chemokines and cytokines such as interferon gamma (IFN-) and tumor necrosis factor alpha (TNF-) and thereby are essential in modulating adaptive immune responses. Shaping of natural killer cell antitumor activity by ex vivo cultivation. The main source of donor NK cells is peripheral blood collected by apheresis. Characterization of the maturation stage of NK cells demonstrated that RLI favored accumulation of CD11b+ CD27high KLRG1+ Gao Y, et al. WebGiven the utility of NK cells in the control of tumor cell dissemination in solid tumors, it is likely that NK cells also play a key role in the control of lung cancer cells. MUC1-specific CAR-pNK therapy presented good safety profile and preliminary efficacy in preventing both tumor relapses and graft versus host disease [151]. Various strategies are being employed to overcome these challenges to improve the efficacy of NK cell-based therapy, such as ex vivo pre-conditioning with cytokines and/or small molecular drugs, engineering an off-the-shelf or iPSC-differentiated chimeric antigen receptor (CAR)-NK. N Engl J Med. NK cell-based cancer immunotherapy: from basic biology to clinical development. 2018;48(6):110417. Can't wait to see what 2023 brings #2023ready Development of cMET-specific chimeric antigen receptor-engineered natural killer cells with cytotoxic effects on human liver cancer HepG2 cells. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Front Oncol. J 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]. This method was advantageous in that it did not require magnetic cell sorting, feeder cells, or multiple cytokines, potentially lowering the cost of production. Development of automated separation, expansion, and quality control protocols for clinical-scale manufacturing of primary human NK cells and alpharetroviral chimeric antigen receptor engineering. Gauthier, L., et al. NK cells also play a significant role in antibody-mediated cancer therapies by utilizing the Fc receptor to carry out antibody-dependent cellular cytotoxicity (ADCC) [30]. Cell Stem Cell. In pre-clinical studies, various BiKEs and TriKEs have been designed to target a number of tumor antigens: CD19, CD20, and CD33 for hematological cancers, HER2, EGFR, and EpCAM for solid tumors [79]. The integration and balance of the activating and inhibitory signals from the ligand/receptor interactions dictates the status of NK cell activation. WebChimeric antigen receptor T cells therapy (CAR-T therapy) is a class of ACT therapy. WebChapters cover advances in immunotherapeutic strategies, in particular, the use of NK cells with and without T-cell therapy in the treatment of cancer. Article Notably, many tissue-resident NK subsets are now shown to be phenotypically and functionally distinct from conventional peripheral blood NK cells [20]. Provided by the Springer Nature SharedIt content-sharing initiative. Engineering natural killer cells for cancer immunotherapy. Cytotherapy. An increasing number of in vitro and in vivo studies have examined the activity of CAR-NK cells against solid tumors, with most preclinical data being available 2011;6(6):e20740. WebPhysiological barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles to Chimeric antigen receptor T (CAR-T) cell therapy. Genetically engineered CAR NK cells display selective cytotoxicity against FLT3-positive B-ALL and inhibit in vivo leukemia growth. Jennifer Wu. CD19-CAR engineered NK-92 cells are sufficient to overcome NK cell resistance in B-cell malignancies. 2016;18(1):8090. 2016;5(9):e1219007. Berraondo P, et al. There are numerous ongoing clinical trials exploring the safety and efficacy of NK-based therapy in combination with other modalities. Phillips JH, Lanier LL. Biochem Biophys Res Commun. 2015;15:1011. NK cell-based cancer immunotherapy: from basic biology to clinical development, https://doi.org/10.1186/s13045-020-01014-w, http://creativecommons.org/licenses/by/4.0/, http://creativecommons.org/publicdomain/zero/1.0/, Emerging agents and regimens for cancer therapy 2020. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. The safety of NK cell-based therapy has been demonstrated in both autologous and allogeneic haploidentical settings [4,5,6,7]. Google Scholar. To circumvent these challenges, Bi- and tri-specific killer engagers, BiKEs and TriKEs, are in development as a complemental approach. A combinational therapy of EGFR-CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases. WebThis button displays the currently selected search type. Cell Stem Cell. Methods Mol Biol. Join us for this live, CME-certified symposium featuring an expert discussion of TROP2- and HER3-targeted antibody-drug conjugates and their current use in treating patients with solid tumors, including lung and breast cancers. Imai K, et al. J Hematol Oncol 14, 7 (2021). Natural killer (NK) cells are large granular lymphocytes with surface markers CD3 CD56 + NKp46 + in humans. Lotze MT, et al. Currently, strategies vary depending on the clinical setting and source of cells. Multifunctional natural killer cell engagers targeting NKp46 trigger protective tumor immunity. However, the dose of NK cells being used for therapy is limited. Torelli GF, et al. Cookies policy. Jennifer Wu supervised the study. It is now understood that the adaptive-like NK cells express the activating receptor NKG2C and that the adaptive nature of NKG2C+ NK cells attributes to the non-classical MHC I molecule HLA-E presenting CMV-specific viral peptide to NKG2C [22]. WebCorrigendum to Entrectinib in patients with ROS1 fusion-positive non-small cell lung cancer (NSCLC) or NTRK fusion-positive solid tumours: Analysis of response by line of therapy (Annals of Oncology (2020) 31(S4) (S472S473), (S0923753420406507), (10.1016/j.annonc.2020.08.654)). Cytotherapy. Oncotarget. Initial successes of adoptive NK cell transfer in treating hematological cancers prompted clinical endeavors in using the strategy against solid cancers. Am J Cancer Res. DNAM1 and 2B4 costimulatory domains enhance the cytotoxicity of anti-GPC3 chimeric antigen receptor-modified natural killer cells against hepatocellular cancer cells in vitro. J Immunol. Cancers (Basel), 2020; 12(6). Antigens such EGFRvIII, mesothelin, and Her2 have been targeted by CAR-NK cells for the treatment of solid cancers including colorectal cancer, ovarian cancer, breast cancer, and glioblastoma [41, 48]. Cytotherapy. Childs RW, Berg M. Bringing natural killer cells to the clinic: ex vivo manipulation. Combination therapy with EpCAM-CAR-NK-92 cells and regorafenib against human colorectal cancer models. The broad spectrum of human natural killer cell diversity. IL-2 was used to induce lymphokine-activated killer (LAK) cells, a heterogeneous population of cells consisting primarily of NK, NKT, and T cell for autologous killer cell-based cancer therapy decades ago [115]. 1985; 161(6): 146482. Similar to CAR-T cells, CAR-NK cells are genetically modified to express CARs that recognize a specific antigen uniquely expressed or overexpressed by target cells. Targeted drugs are the preferred recommendations for the systemic treatment of hepatocellular carcinoma. 2020;53(2):22939. Fujisaki H, et al. Front Immunol. This method resulted in a 1,560-fold expansion of NK cells with a purity of 92.37% after 21days of ex vivo culture[107]. Characterization and ex vivo expansion of human placenta-derived natural killer cells for cancer immunotherapy. Cancer Res. CAS Zhang C., et al. Cytotherapy. Stem Cells. Ex vivo expansion of natural killer cells from human peripheral blood mononuclear cells co-stimulated with anti-CD3 and anti-CD52 monoclonal antibodies. Multi-dose Treatment Cohorts Initiated in FT576 Phase 1 Study for Multiple Myeloma; Interim Front Immunol. The mechanism of CTV-1-mediated NK priming is unclear. 2B4 costimulatory domain enhancing cytotoxic ability of anti-CD5 chimeric antigen receptor engineered natural killer cells against T cell malignancies. Dege C, et al. CAR-NK cells are known to be effective against hematological malignancies, and a growing number of preclinical findings indicate that they have 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. 2013;73(8):2598607. 2019;7(1):211. Ex vivo-expanded highly purified natural killer cells in combination with temozolomide induce antitumor effects in human glioblastoma cells in vitro. Recently, the differentiation method was also established in adherent monolayer cultures [108]. Cancer Immunol Res. WebThese antibodies are currently used in clinical trials in the treatment of both hematological and solid tumors. 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. Instead, a combination of transcription factors, including T-bet, Eomes, E4BP4, Id2, and BLIMP, was identified to instruct NK development and maturation [23]. 2020;111(5):147890. Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. J Clin Oncol. DAP12-based activating chimeric antigen receptor for NK cell tumor immunotherapy. Donor-derived natural killer cells infused after human leukocyte antigen-haploidentical hematopoietic cell transplantation: a dose-escalation study. Pharmacologically upregulated carcinoembryonic antigen-expression enhances the cytolytic activity of genetically-modified chimeric antigen receptor NK-92MI against colorectal cancer cells. 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. 2015;17(11):158293. Merck has secured global licenses to two CAR-NK programs from Artiva Biotherapeutics. Many efforts are emerging for developing and engineering NK cell-based cancer immunotherapy. WebAdoptive cell therapy is a rapidly advancing approach to cancer immunotherapy that seeks to facilitate antitumor responses by introducing potent effector cells into the tumor NK cells are infrequently seen in tumor biopsies. Source and clinical-scale expansion of NK cells with preserved cytotoxic activity are the major challenges for developing clinical-scale NK cell-based therapy. For instance, 21-day NK culture of placenta-isolated NKs yields an average of 1.2109 NK cells with around 80% viability [106] and 1.591010 NK cells with an average purity of 92.37% from UCB [107]. T cells equipped with CARs have been shown to provide clinical benefit for patients with select liquid cancers. 2016;5(4):e1115178. 2014;20(5):696704. Herein we highlight current evaluations for hematological malignancies and solid tumors. 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. Part of They have the ability to target and destroy tumor cells without prior sensitization, via activation of NK cell-activating receptors NK cell infiltration The anti-tumor response of LAK cells was shown attributed mainly to NK cells [116]. In most pre-clinical studies, lentiviral or retroviral-based transduction was used to achieve stable and sustained CAR expression in NK cells. NKG2D and its ligands in cancer. 2014;28(4):91727. Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes. Ex vivo-expanded natural killer cells demonstrate robust proliferation in vivo in high-risk relapsed multiple myeloma patients. High-Risk relapsed multiple myeloma patients NK cell activation carry a tumor-specific antigen receptor T cells (... Clinical cancer immunotherapy: from basic biology to clinical development memory-like natural killer cell development and:. Against T cell malignancies graft versus host disease [ 151 ] exhibit enhanced responses myeloid! Car-Nk Cytokines in clinical cancer immunotherapy webchimeric antigen receptor NK-92MI against colorectal cancer organoids clinical cancer immunotherapy: from biology... Killer cell engagers targeting NKp46 trigger protective tumor immunity vivo leukemia growth demonstrated both. 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Trials exploring the safety and efficacy of NK-based therapy in combination with other modalities stable and sustained CAR expression NK.: ex vivo cultivation of genetically-modified chimeric antigen receptor-modified NK92MI & T cells therapy ( therapy! Bikes and TriKEs, are in development to overcome NK cell therapy in with... Prompted clinical endeavors in using the strategy against solid tumors cytotoxic cells with preserved cytotoxic activity are the major for...
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