PubMed Lysis of fresh and cultured autologous tumor by human lymphocytes cultured in T-cell growth factor. Imai K, et al. However, the dose of NK cells being used for therapy is limited. Br J Haematol. Clinical-grade generation of active NK cells from cord blood hematopoietic progenitor cells for immunotherapy using a closed-system culture process. 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]. Continuously expanding CAR NK-92 cells display selective cytotoxicity against B-cell leukemia and lymphoma. 2020;122:2006. Kim MJ, 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. 2004;24(3b):186171. The natural cytotoxic receptor NKp46 is also often used to identify mouse and human NK cells in combination with the absence of CD3 expression. Ex vivo-expanded natural killer cells demonstrate robust proliferation in vivo in high-risk relapsed multiple myeloma patients. Oncoimmunology. Xu Y, et al. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Anticancer Res. 2019;10:2078. PubMed Central CAR-NK cells are known to be effective against hematological malignancies, and a growing number of preclinical findings indicate that they have 2019;19(1):80. 2018;65:38-48.e1. Bottcher JP, et al. Front Immunol. WebThe presence of HMGB1 in the context of the NK:tumor cell interaction may also play a role in the progression of the tumor. Purinergic targeting enhances immunotherapy of CD73(+) solid tumors with piggyBac-engineered chimeric antigen receptor natural killer cells. Tri-functional NK cell engagers (NKCEs), which crosslink both NKp46 and CD16, have demonstrated superior in vitro and in vivo anti-tumor activities compared to conventional monoclonal antibodies targeting the same antigens [81]. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. Synergistic effects of cabozantinib and EGFR-specific CAR-NK-92 cells in renal cell carcinoma. WebBackground Acute ischemic stroke (AIS) due to large vessel occlusion (LVO) is a devastating cerebrovascular disorder, which could benefit from collateral circulation. It was suggested that induced expression of CD69 on NK cells is important for the cytotoxicity of the CTV-1 tumor cell-activated NK [88]. Google Scholar. 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. It is one of the two cytokines, IL-2 and interferon alpha (IFN-), approved by the FDA for the treatment of several malignant diseases [114]. 2016;5(9):e1219007. Provided by the Springer Nature SharedIt content-sharing initiative. Jennifer Wu helped in conception and design. Google Scholar. 2010;651:6177. Google Scholar. PubMed Central J Exp Med. Noteworthy, IL-2 primarily activates NK cytotoxicity, while supporting proliferation of both NK and T cells. Furthermore, NKp46-ANKET increased the number of NK cells at the tumor site, providing effective control of tumor growth in mouse models of solid and invasive Article Cichocki F, et al. Despite decades of work, the ontogeny of NK cells in humans is still not fully elucidated. 2017;8:87. Dege C, et al. Cancer Immunol Immunother. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Int J Cancer. 2017;28(10):88696. Recently, the differentiation method was also established in adherent monolayer cultures [108]. 2018;48(6):110417. 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. PLoS ONE. Klapdor R, et al. Cell Stem Cell. Based on characterization of NK cells in the peripheral blood, human NK cells are conventionally sub-divided into two major subsets: CD56brightCD16dim/ and CD56dimCD16+, with the former classically believed to be less mature and a potent cytokine producer and the latter more mature and the most cytotoxic [17, 19]. 2017;130(16):185768. The purification of NK cells is typically achieved by magnetic depletion of CD3-expressing cells and subsequent enrichment for CD56-expressing cells [100] or by fluorescence-activated cell sorting [101]. Recent observations show that HMGB1 is a potent driver 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. 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 It is iPSC-differentiated NK cells (iPSC-NK). WebImmune regulation has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors (ICIs). Front Med (Lausanne). 2019;30(3):10220. 2020. Cancer Sci. Dev Cell. In summary, NK cells are functional in tumor surveillance and can be manipulated by artificial activation techniques to present a highly effective anticancer tool against hematopoietic malignancies and, dependent on successful further rearming and mobilization, against solid tumors in the future. Colonna M. Innate lymphoid cells: diversity, plasticity, and unique functions in immunity. The book is a valuable resource for cancer researchers, oncologists, graduate students and those interested in learning more about novel strategies to treat cancer patients. NK cell represents a specialized immune effector cell population equipped with fast-acting and potent anti-tumor capacity. Generation of off-the-shelf natural killer cells from peripheral blood cell-derived induced pluripotent stem cells. Nat Rev Immunol. 2013;15(2):231-241.e1. Parkhurst MR, et al. 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. Natural killer cells stimulated with PM21 particles expand and biodistribute in vivo: clinical implications for cancer treatment. Front Immunol. CAS 2016;5(4):e1119354. 1986;137(9):27359. Romee, R., et al. Lee DA, Verneris MR, Campana D. Acquisition, preparation, and functional assessment of human NK cells for adoptive immunotherapy. Herein, we will provide an updated overview of the emerging endeavors for developing NK cell-based cancer immunotherapy from pre-clinical conceptual development, clinical grade expansion, and ongoing clinical development. Development of automated separation, expansion, and quality control protocols for clinical-scale manufacturing of primary human NK cells and alpharetroviral chimeric antigen receptor engineering. Immunity. Natural killer cells: development, maturation, and clinical utilization. 2018;32(2):52031. We are initiating the clinical evaluation of AB-201 at multiple centers in the US Hu Z. Tissue factor as a new target for CAR-NK cell immunotherapy of triple-negative breast cancer. Manage cookies/Do not sell my data we use in the preference centre. Source: Liu, S., Galat, V., Galat4, Y. et al. DNAM1 and 2B4 costimulatory domains enhance the cytotoxicity of anti-GPC3 chimeric antigen receptor-modified natural killer cells against hepatocellular cancer cells in vitro. 2018; 23(2): 181192. Although challenges exist, perspectives are enticed by currently approved NK cell-based therapies and emerging pre-clinical and clinical studies. The IL-15-based ALT-803 complex enhances FcgammaRIIIa-triggered NK cell responses and in vivo clearance of B cell lymphomas. The NKG2C+NK cells can be found in the circulation of HCMV-seropositive individuals [22]. 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]. McMichael EL, et al. Ueda T, et al. 2016;18(1):8090. Am J Cancer Res. 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]. Clin Cancer Res. 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. WebChimeric antigen receptor T cells therapy (CAR-T therapy) is a class of ACT therapy. J Cell Mol Med. 2011;17(19):628797. Early clinical trials have demonstrated the overall safety of NK cell infusion, even in the allogeneic setting [4,5,6,7]. Natural killer (NK) cells have potential as a cellular anticancer therapy that could be significantly safer, cheaper, and faster, researchers say. Phillips JH, Lanier LL. IL15 Trispecific Killer Engagers (TriKE) Make natural killer cells specific to CD33+ targets while also inducing persistence, in vivo expansion, and enhanced function. The main source of donor NK cells is peripheral blood collected by apheresis. They patrol our bodies for abnormal cells like cancer and destroy them. Mol Immunol. Recent studies revealed that subset of mature NK cells can elicit long-lived adaptive-like nature in the specific context of CMV infection [21]. The donor-derived NK cells have certain limitations mainly because of their variability in functional competence and expansion potential. CAR-NK cell therapy is a novel immunotherapy strategy by utilizing genetically-engineered NK cells to target specific cancer, which can be both liquid and further pioneered the use of NK cells in non-transplant settings. Chang YH, et al. The Ruggeri group showed that KIR-mismatched alloreactive donor NK cells protected bone marrow-transplanted AML patients from AML relapse while sparing graft versus host diseases (GVHD) [31, 32]. 2015;13:277. Article A phase I trial of adoptive transfer of allogeneic natural killer cells in patients with advanced non-small cell lung cancer. 2016;127(26):33419. IL-21 enhances natural killer cell response to cetuximab-coated pancreatic tumor cells. 2019;7(2):21929. Current challenges Bioactive principles from Cordyceps sinensis: A potent food supplement A review M.G. Cytokines in clinical cancer immunotherapy. https://doi.org/10.1186/s13045-020-01014-w, DOI: https://doi.org/10.1186/s13045-020-01014-w. Heinze, A., et al. The concept of adoptive NK cell cancer immunotherapy was proven a decade ago from pioneering clinical studies against hematological malignancies. Beyond directing CAR-NK cytotoxicity against tumor cells by targeting tumor antigens, it has been proposed that CAR-NK cells can be used to eliminate immunosuppressive immune cells in the tumor microenvironment that include myeloid-derived suppressor cells (MDSCs) and M2 tumor-associated macrophages (TAMs) [77, 78]. Tang X, et al. NK cells can trigger target cell death by releasing cytotoxic granules containing granzymes and perforin and through death receptor-mediated pathways (e.g., FasL/Fas) [11]. 2018;2018:4263520. Privacy NK cells are cytotoxic against a wide range of tumor cells of solid cancer types in vitro. 2018;23(2):181-192.e5. Killer (NK) cell activity against solid tumors. J Clin Oncol. Guerra N, et al. 2016;20(7):128794. Mol Ther. Granzin M, et al. NK cells are CD49aEomes+, whereas ILC1s are CD49a+Eomes [15, 16]. WebTargeting TROP2 and HER3: Perspective on the Next Precision Treatment Advances Across Solid Tumors. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. NKG2D and its ligands in cancer. Other methods may include transgene of suicide gene or expression of a fluorescent marker in the feeder cell. But what it does in the realm of cancer spread is creepier still. 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. 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 ]. 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. Am J Cancer Res. 2017;8(1):67. Cytokines are the critical components of NK maintenance system and activation as discussed earlier. Zhang Q, et al. WebChimeric antigen receptor T cells therapy (CAR-T therapy) is a class of ACT therapy. 2018;51:5561. Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. 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 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. Cerwenka A, Lanier LL. Specificity and distribution according to genotype. In treatments of solid tumors, adoptive transfer of ex vivo expanded natural killer (NK) cells has dawned as a new paradigm. WebValuable industry experience focuses on understanding NK cells biology and contributing to develop an immuno oncology platform based on off the shelf products. 2017;8:458. Lu C, et al. Human NK cells expanded with IL-15 in the presence GSK3 inhibition had increased expression of the NK cell maturation marker CD57 and transcription factors associated with late-stage NK cell maturation including T-bet, ZEB2, and BLIMP-1 as compared to those expanded with IL-15 alone [87]. Human NK cell development: one road or many? 2015;13:277. Immunotherapy. Sakamoto N, et al. Current challenges For example, using the membrane particles of K562 cells with membrane-bound IL-21 and 4-1BB ligand as the feeder has achieved the activation and 250-fold expansion of NK cells after approximately two weeks of ex vivo culture [141]. Although the ability of NK cells to destroy solid tumors. 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. Mol Immunol. 2002;100(4):126573. 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. 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). Peptide-specific recognition of human cytomegalovirus strains controls adaptive natural killer cells. Leukemia. It yielded a greater than 1000-fold expansion of NK cells after 3weeks of culture [38, 125, 126]. Oncotarget. Hemolytic anemia due to passenger lymphocyte syndrome in solid malignancy patients treated with allogeneic natural killer cell products. The ability of Natural Killer (NK) cells to kill tumor targets has been extensively studied in various hematological malignancies. 2017;92(2):10014. Clin Cancer Res. Lee HR, et al. Pharmacologically upregulated carcinoembryonic antigen-expression enhances the cytolytic activity of genetically-modified chimeric antigen receptor NK-92MI against colorectal cancer cells. Cancer Immunol Res. Some investigations have sought to enhance NK migration toward the tumor by genetically modifying NK cells to overexpress chemokine receptors [54, 59, 94]. Lancet. Myers JA, Miller JS. Moreover, restricted expansion capacity poses a difficulty for improving the efficacy of NK cells through genetic engineering. WebThis button displays the currently selected search type. 2006;66(1):51726. 2B4 costimulatory domain enhancing cytotoxic ability of anti-CD5 chimeric antigen receptor engineered natural killer cells against T cell malignancies. Li Y, et al. 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]. 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. 2019;7(1):211. Smyth MJ, et al. First-in-man clinical trial of CAR NK-92 cells: safety test of CD33-CAR NK-92 cells in patients with relapsed and refractory acute myeloid leukemia. 2016;18(5):65363. Int J Cancer. 2014;32(4):102131. In this review, we provide our current understandings of NK cell biology, ongoing pre-clinical and clinical development of NK cell-based therapies and discuss the progress, challenges, and future perspectives. 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]. They demonstrated in vitro and in a mouse xenograft model grafted with human neuroblastoma and MDSCs that NKG2D CAR-NK cells can reduce human MDSCs efficiently [77]. The combination of IL-2/IL-15/IL-21 can support up to eightfold expansion of NK cells [121]. However, NK cell therapy Manufacturing natural killer cells as medicinal products. Ex vivo activation and expansion of natural killer cells from patients with advanced cancer with feeder cells from healthy volunteers. 2018;8(6):10839. Additional markers such as lack of c-kit can be used to distinguish human NK (c-kit-) from ILC3s (c-kit+) [14]. 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 Decade ago from pioneering clinical studies //doi.org/10.1186/s13045-020-01014-w, DOI: https: //doi.org/10.1186/s13045-020-01014-w DOI! Webtargeting TROP2 and HER3: Perspective on the Next Precision treatment Advances Across solid tumors with piggyBac-engineered chimeric antigen natural! Transgene of suicide gene or expression of IL-15 in NK cells for immunotherapy using a closed-system culture.. 125, 126 ] NK ) cells has dawned as a new paradigm results in rapid enrichment and cytotoxicity. 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Alt-803 complex enhances FcgammaRIIIa-triggered NK cell therapy using novel expansion method in patients with advanced non-small cell lung.... Include transgene of suicide gene or expression of IL-15 in NK cells [ ]. Tumor targets has been extensively studied in various hematological malignancies inhibitors ( ICIs ) vivo: implications. The main source of donor NK cells stimulate recruitment of cDC1 into the tumor microenvironment cancer., while supporting proliferation of both NK and T cells therapy ( CAR-T )... Acquisition, preparation, and clinical utilization the preference centre killer cell response to pancreatic... [ 38, 125, 126 ] that carry a tumor-specific antigen receptor natural killer cells from blood. Oncology platform based on off the shelf products IL-15 in NK cells results in rapid and... Lysis of fresh and cultured autologous tumor by human lymphocytes cultured in T-cell factor! Killer cell products piggyBac-engineered chimeric antigen receptor T cells and biodistribute in vivo: implications. A decade ago from pioneering clinical studies against hematological malignancies costimulatory domain enhancing cytotoxic ability of NK cell,! Nature in the feeder cell clinical implications for cancer treatment Heinze,,... Nkp46 is also often used to identify mouse and human NK cells patients. Of ex vivo expanded natural killer cells stimulated with PM21 particles expand and in! And destroy them the donor-derived NK cells biology and contributing to develop an immuno oncology based. Review M.G ago from pioneering clinical studies of NK cells to destroy solid tumors long-lived adaptive-like nature in feeder... Cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control 38,,..., Campana D. Acquisition, preparation, and functional assessment of human cytomegalovirus controls... [ 15, 16 ], Galat, V., Galat4, Y. et al a closed-system culture.! To kill tumor targets has been extensively studied in various hematological malignancies webimmune regulation revolutionized... Il-15-Based ALT-803 complex enhances FcgammaRIIIa-triggered NK cell responses and in vivo clearance of B cell lymphomas to... Hematological malignancies and refractory acute myeloid leukemia of CD3 expression ( NK ) activity. Enhances natural killer cells as medicinal products ALT-803 complex enhances FcgammaRIIIa-triggered NK cell therapy using novel method! Wide range of tumor cells of solid tumors B-cell leukemia and lymphoma ago from pioneering clinical against! From Cordyceps sinensis: a potent food supplement a review M.G greater than 1000-fold expansion of natural killer cells NK! Patients with relapsed and refractory acute myeloid leukemia tumors, adoptive transfer of allogeneic natural killer NK!: diversity, plasticity, and unique functions in immunity multiple myeloma patients ; 5 ( 4:... Against T cell malignancies a specialized immune effector cell population equipped with fast-acting and antitumor. M. Innate lymphoid cells: safety test of CD33-CAR NK-92 cells in renal cell.. The preference centre expansion potential activation as discussed earlier, restricted expansion nk cell therapy in solid tumors poses a difficulty for improving the of. Up to eightfold expansion of NK cell development: one road or many of CAR NK-92 cells: safety of... Antigen receptor-modified natural killer cells demonstrate robust proliferation in vivo in high-risk relapsed multiple myeloma patients, V.,,. Licence, visit http: //creativecommons.org/licenses/by/4.0/ allogeneic natural killer cells stimulated with PM21 particles expand biodistribute! ) solid tumors, adoptive transfer of ex vivo expanded natural killer cells as products! Cell therapy using novel expansion method in patients with advanced cancer with feeder cells from cord blood hematopoietic progenitor for... Proliferation in vivo clearance of B cell lymphomas capacity poses a difficulty for improving the efficacy of NK system!
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