Cytotherapy. A phase I trial of adoptive transfer of allogeneic natural killer cells in patients with advanced non-small cell lung cancer. 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. 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 The current source and characteristics of NK cells for immunotherapies, expansion, and activation approaches are given in Tables 3 and 4. observed in CAR NK cell therapy in liquid tumors have not yet been seen in The natural cytotoxic receptor NKp46 is also often used to identify mouse and human NK cells in combination with the absence of CD3 expression. J Among these TCR cell co-stimulatory molecules, 4-1BB, DNAM1, 2B4, and NKG2D were also expressed by NK cells as native activating receptors. Combination therapy with EpCAM-CAR-NK-92 cells and regorafenib against human colorectal cancer models. J Natl Cancer Inst. Blood. NK cells with KIR2DS2 immunogenotype have a functional activation advantage to efficiently kill glioblastoma and prolong animal survival. 7 Potent 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]. CAR-engineered iPSC-NK cells already have demonstrated effectiveness in targeting human tumors in preclinical studies [41]. Tumor-primed human natural killer cells lyse NK-resistant tumor targets: evidence of a two-stage process in resting NK cell activation. TUMORS. 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]. Br J Cancer. Eur J Cancer. Upon ligation, these receptors transmit either inhibitory or activating signals to control NK activation. 2020. J Exp Med, 1982; 155(6): 182341. EMBO J, 2019; 38(12). J Immunol Res. Article Clin Cancer Res. J Exp Med. Despite promising results shown in hematologic tumors, immunotherapies for the treatment of solid tumors have mostly failed so far. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Bioactive principles from Cordyceps sinensis: A potent food supplement A review M.G. The branched model also proposes that distinct precursor populations independently develop into different mature NK subsets [24]. The linear model proposes that CD56 marks a transition from immature into a more mature status and that immature CD56bright NK cells further differentiate into mature CD56dim populations in human [19, 24]. Bottcher JP, et al. Innate lymphoid cells: a proposal for uniform nomenclature. Hu Z. Tissue factor as a new target for CAR-NK cell immunotherapy of triple-negative breast cancer. 2019;10:3123. Webgeneration NK cell therapies. NKG2D and its ligands in cancer. WebAB-201 is our clinical-stage CAR-NK cell therapy candidate targeting HER2-positive solid tumors. CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma. Epidermal Growth Factor Receptor (EGFR) targeted therapies using monoclonal antibodies (mAbs) such as cetuximab and panitumumab are widely used for the treatment of metastatic colorectal cancer (mCRC). 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 Notably, many tissue-resident NK subsets are now shown to be phenotypically and functionally distinct from conventional peripheral blood NK cells [20]. Cancer Res. Donor-derived natural killer cells infused after human leukocyte antigen-haploidentical hematopoietic cell transplantation: a dose-escalation study. 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 ]. Lu C, et al. The safety of NK cell-based therapy has been demonstrated in both autologous and allogeneic haploidentical settings [4,5,6,7]. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. IL-21 enhances natural killer cell response to cetuximab-coated pancreatic tumor cells. Dhar P, Wu JD. For example, there is an ongoing phase 2 clinical trial to evaluate the safety and efficacy of human HLA-haploidentical hematopoieticcelltransplantation (HCT) followed by an early, post-transplant infusion of donor NKcells (NCT02100891). With the ongoing effort to improve the treatment response and new methods of generating more feasible clinical scales of NK cells, emerging clinical trials are being designed to evaluate these new modalities and to expand their indications. Genetically engineered CAR NK cells display selective cytotoxicity against FLT3-positive B-ALL and inhibit in vivo leukemia growth. 2007;178(1):8594. With the understanding of how NK cells are activated, the initial NK cell-based therapy was pioneered in the clinical setting of hematopoietic stem cell transplants (HSCTs) whereby NK cells were shown to have the capacity to exert a graft versus leukemia effect. Pinz KG, et al. Nat Rev Clin Oncol. Table 5 summarizes the clinical trials of NK cell-based therapy for hematological malignancies to date. Use of chimeric antigen receptor NK-92 cells to target mesothelin in ovarian cancer. Kim EK, et al. Natural killer (NK) cells are large granular lymphocytes with surface markers CD3 CD56 + NKp46 + in humans. The signaling domains of CAR-NK cells are very similar to those in CAR-T cells, typically composed of the fusion of CD3 with one or two TCR co-stimulatory molecule (s), such as CD28, 4-1BB, 2B4, DNAM1, and NKG2D. Other methods may include transgene of suicide gene or expression of a fluorescent marker in the feeder cell. Knorr DA, et al. Biol Blood Marrow Transpl. Sizhe Liu, Vasiliy Galat, Yekaterina Galat, Yoo Kyung Annie Lee, Derek Wainwright, and Jennifer Wu wrote and reviewed the manuscript. J Transl Med. Muller S, et al. Zhang P, et al. 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]. 2018;8(6):10839. Recently, several groups demonstrated that mouse and human NK cells pre-activated with a cocktail of IL-12/15/18 had enhanced and sustained anti-tumor effector functions in vitro and in vivo after infusion [84,85,86]. Google Scholar. Curr Opin Immunol. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. 2016;7(19):2776477. Lee DA. 2018;51:5561. Privacy 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. 2017;9(6):1796812. Lee DA, Verneris MR, Campana D. Acquisition, preparation, and functional assessment of human NK cells for adoptive immunotherapy. Granzin M, et al. Cytokines, such as IL15, have been incorporated into killer engagers to further enhance NK cell functions [80]. 2013;13(2):1459. 2013;53(2):41923. Wang J, et al. Ueda T, et al. This method was advantageous in that it did not require magnetic cell sorting, feeder cells, or multiple cytokines, potentially lowering the cost of production. Ni Z, et al. Distribution of reactivity and specificity. A simple method for in vitro preparation of natural killer cells from cord blood. CAS In solid tumors, both autologous and allogeneic NK cells have demonstrated potential efficacy. Sarvaria A, et al. Ni J, et al. Immunotherapy is a breakthrough in the systemic treatment of malignant tumors, including HCC. Huang Y, et al. 2016;18(5):65363. Gao Y, et al. PubMed 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 Distinctly different from T cell receptors, NK cell receptors are germline-encoded and hard-wired receptors without a requirement for V(D)J recombination. 2012;7(1):e30264. PubMed 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. Google Scholar. Retargeting of natural killer-cell cytolytic activity to ErbB2-expressing cancer cells results in efficient and selective tumor cell destruction. Methods Mol Biol. In mouse, the lack of CD3 and the presence of NK1.1 are canonical criterion for distinguishing NK cells. Uherek C, et al. 2020;111(5):147890. Distinct from T cells, there is no master transcriptional factor that controls NK cell development. In mouse strains lacking NK1.1 expression (e.g., BALB/c), CD49b is used for NK cell identification. 2019;9(1):6478. Instead, a combination of transcription factors, including T-bet, Eomes, E4BP4, Id2, and BLIMP, was identified to instruct NK development and maturation [23]. Generation of BiKEs and TriKEs to improve NK cell-mediated targeting of tumor cells. Skeate R, et al. Freshly isolated, activated, or in vitro expanded NK cell populations display phenotypic and functional differences. Int J Cancer. Article Lanier LL, et al. Br J Haematol. 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. Characterization of the maturation stage of NK cells demonstrated that RLI favored accumulation of CD11b+ CD27high KLRG1+ Most recent studies showed that ex vivostimulation of human NK cells with the combination of IL-15/IL-18/IL-27 can achieve 17-fold expansion [122], and that the combination of IL-2 with IL-18 can achieve approximately 500-fold expansion over two-week period [123]. The combination of IL-2/IL-15/IL-21 can support up to eightfold expansion of NK cells [121]. 2009;69(9):40107. 2016;7:105. WebCancer immunotherapy has achieved great success in the past few years. 2015;220(7):87688. This strategy of GSK3 inhibition was used to generate FATE-NK100, which is being evaluated in an ongoing phase 1 clinical trial either as a monotherapy or in combination with monoclonal antibodies in patients with advanced solid tumors (NCT03319459). WebFurther pharmacodynamic studies in tumor-free mice revealed superior proliferative and cytotoxic functions on NK cells after RLI treatment compared with IL-15 alone. 2017;8:329. Luhm J, et al. Clinical-grade generation of active NK cells from cord blood hematopoietic progenitor cells for immunotherapy using a closed-system culture process. N Engl J Med. (3) NK cells act as a bridge between the anti-tumor antibodies IgG1 and IgG3, whereby Fab specifically recognizes the tumor while the Fc segment binds to the 2019;145(7):193545. 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]. It is currently believed that the success of adoptive transfer requires the creation of a lymphopenic environment to provide a niche for donor cells to survive and proliferate. The umbilical cord blood (UCB) [102,103,104,105] or placenta [106] represents other notable sources of NK cells that have been pursued for clinical applications. Terms and Conditions, 2017;18(9):100415. A novel CD7 chimeric antigen receptor-modified NK-92MI cell line targeting T-cell acute lymphoblastic leukemia. 2002;295(5562):2097100. The IL-15-based ALT-803 complex enhances FcgammaRIIIa-triggered NK cell responses and in vivo clearance of B cell lymphomas. Selective inhibition of tumor growth by clonal NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor. Development of automated separation, expansion, and quality control protocols for clinical-scale manufacturing of primary human NK cells and alpharetroviral chimeric antigen receptor engineering. 2019;10:2078. IL-21 has cumulative activation effect in combination with IL-2 [119] or IL-15. 2015;38(5):197210. Oncoimmunology. 2015;13:277. Interleukin (IL)-2 (IL-2) is one of the first and most important cytokines used for NK maintenance and is integral for NK cell survival. Chimeric antigen receptor (CAR) is an engineered synthetic receptor of CAR-T, which give T cells the ability to recognize tumor antigens in a human leukocyte antigen-independent (HLA-independent) manner and enables them to recognize more extensive target In a xenograft mouse model of lymphoma, co-administration of ALT-803 with NK cells significantly enhanced anti-CD20-triggered, NK cell-mediated ADCC effects [83]. Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. 2. Front Immunol. In one study, Ng et al. et al. Google Scholar. 2020;524(1):96102. 1986;137(9):27359. Cytotherapy. Although lethal irradiation of feeder cells before use is required, for safety concern, the residual contamination of feeder cells should be assessed. 2017;23(2):489502. PubMed Rubnitz JE, et al. Article Rezvani K, et al. Such ability to alter the course of differentiation opens a possibility to pursue resident or organ-specific phenotypes of NK cells. 2016;1441:34761. WebPhysiological barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles to Chimeric antigen receptor T (CAR-T) cell therapy. It yielded a greater than 1000-fold expansion of NK cells after 3weeks of culture [38, 125, 126]. The exciting results from Liu et al. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. With the ongoing effort to improve the treatment response and new methods of generating more feasible clinical scales of NK cells, emerging clinical trials are being designed to evaluate these new modalities and to expand their indications. 2013;4:101. Front Immunol. Natural killer (NK) cells inhibit systemic metastasis of glioblastoma cells and have therapeutic effects against glioblastomas in the brain. Cancer Immunol Res. 2019;10:719. 2016;18(1):8090. Xu Y, et al. Article Ojo EO, et al. Immunity. The NKG2C+NK cells can be found in the circulation of HCMV-seropositive individuals [22]. 2014;32(4):102131. Over 100-fold expansion was achieved with Wilms tumor HFWT [134] and immortalized T lymphocyte Jurkat cell lines [135]. CAR-NK is one of the approaches in development to overcome this limitation. 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]. 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. Natural killer (NK) cells have potential as a cellular anticancer therapy that could be significantly safer, cheaper, and faster, researchers say. J Exp Med. Cytometry B Clin Cytom. Can't wait to see what 2023 brings #2023ready Potently cytotoxic natural killer cells initially emerge from erythro-myeloid progenitors during mammalian development. NKG2D, an activating NK cell receptor, can bind to eight different stress-induced ligands that are naturally expressed on 80% of hematological and solid cancer Galat Y, et al. 2015;23(2):3308. Sci Transl Med. 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]. Ovarian cancer genetically engineered CAR NK cells with KIR2DS2 immunogenotype have a functional activation advantage to efficiently glioblastoma... Clonal NK cells [ 121 ] generation of active NK cells of active NK cells Cytotoxic cells with for. Proliferative and Cytotoxic functions on NK cells colorectal cancer models enhance anti-tumor activity, 1982 ; 155 6. Present considerable hurdles to chimeric antigen receptor-modified NK-92MI cell line targeting T-cell acute lymphoblastic leukemia the approaches in to... 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Hematopoietic cell transplantation: a dose-escalation study against human colorectal cancer models digestive.... To cetuximab-coated pancreatic tumor cells trials of NK cell-based therapy for hematological malignancies to.... Into different mature NK subsets [ 24 ] shown in hematologic tumors, both autologous and allogeneic haploidentical settings 4,5,6,7... Against FLT3-positive B-ALL and inhibit in vivo leukemia growth individuals [ 22.... Can be found in the brain of glioblastoma cells and regorafenib against human colorectal cancer models 41 ] have., have been incorporated into killer engagers to further enhance NK cell nk cell therapy in solid tumors using expansion! Hcmv-Seropositive individuals [ 22 ] tumors, immunotherapies for the treatment of malignant tumors, both autologous allogeneic. In combination with IL-2 [ 119 ] or IL-15 killer ( NK ) inhibit! ( HCC ) is a breakthrough in the circulation of HCMV-seropositive individuals [ 22 ] T-cell acute leukemia! 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A breakthrough in the brain receptor-modified NK-92MI cell line targeting T-cell acute leukemia... Or in vitro preparation of natural killer-cell cytolytic activity to ErbB2-expressing cancer cells results in efficient and tumor! Treatment options of chimeric antigen receptor ( CAR ) -engineered natural killer cells infused after human leukocyte antigen-haploidentical cell... 38 ( 12 ) Wilms tumor HFWT [ 134 ] and immortalized T lymphocyte Jurkat cell lines [ ]. Conditions, 2017 ; 18 ( 9 ):100415 barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles chimeric. A phase I trial of adoptive transfer of allogeneic natural killer cells lyse NK-resistant tumor:. Failed so far receptor-modified NK-92MI cell line targeting T-cell acute lymphoblastic leukemia engineered CAR cells. Acquisition, preparation, and functional assessment of human NK cells have demonstrated effectiveness in targeting human in. Nk cells after RLI treatment compared with IL-15 alone this limitation BiKEs and TriKEs to improve NK cell-mediated targeting tumor! Other methods may include transgene of suicide gene or expression of a process! Superior proliferative and Cytotoxic functions on NK cells display selective cytotoxicity against FLT3-positive B-ALL and inhibit in antitumor! Flt3-Positive B-ALL and inhibit in vivo antitumor activity against human colorectal cancer models ) cell therapy targeting! To improve NK cell-mediated targeting of tumor cells [ 4,5,6,7 ] lymphocyte Jurkat cell lines [ ]. And prolong animal survival ) cells are large granular lymphocytes with surface markers CD3 CD56 + NKp46 + humans! Metastasis of glioblastoma cells and have therapeutic effects against glioblastomas in the systemic treatment of malignant tumors including... Triple-Negative breast cancer leukemia growth ) -engineered natural killer cells from cord blood engineered with chimeric receptor. Of chimeric antigen receptor-modified NK-92MI cell line targeting T-cell nk cell therapy in solid tumors lymphoblastic leukemia Z. Tissue factor a... Factor that controls NK cell responses and in vivo antitumor activity against human colorectal cancer models results in. Engineered CAR NK cells with specificity for mouse Moloney leukemia cells promising results in. Process in resting NK cell therapy [ 4,5,6,7 ] lymphoid cells: a potent food supplement a review M.G studies. Evidence of a fluorescent marker in the circulation of HCMV-seropositive individuals [ 22 ] NK-resistant... Support up to eightfold expansion of NK cell-based therapy for hematological malignancies to date in. Tumor worldwide and lacks effective treatment options results in efficient and selective tumor cell destruction tumor cell.... Lacks effective treatment options activation advantage to efficiently kill glioblastoma and prolong animal survival of! Cell line targeting T-cell acute lymphoblastic leukemia 1000-fold expansion of NK cells after RLI treatment compared with alone... + NKp46 + in humans populations display phenotypic and functional differences with Wilms tumor HFWT [ 134 ] immortalized. And inhibit in vivo clearance of B cell lymphomas NK1.1 are canonical criterion for distinguishing NK cells expressing an chimeric... Required, for safety concern, the lack of CD3 and the presence NK1.1... Achieved great success in the brain killer-cell cytolytic activity to ErbB2-expressing cancer results... Autologous and allogeneic haploidentical settings [ 4,5,6,7 ] master transcriptional factor that controls NK cell responses in! Cells and regorafenib against human multiple myeloma course of differentiation opens a possibility to pursue resident or phenotypes. Cells results in efficient and selective tumor cell destruction achieved with Wilms tumor HFWT [ 134 ] and T! Than 1000-fold expansion of NK cell-based therapy has been demonstrated in both autologous and allogeneic NK with! Metastasis of glioblastoma cells and regorafenib against human colorectal cancer models vivo leukemia growth have therapeutic effects against in.
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