There are great numbers of clinical trials on NK cell immunotherapy to treat solid tumors. Lister J, et al. J Immunol. All authors declare no conflict of interest. 2017;8:329. The NKG2D-2B4 containing CAR-NK had elevated Syk and Erk1/2 phosphorylation [42]. J Clin Oncol. Cancers. Romee, R., et al. Vasu S, et al. Blood. J Immunol. Typically, a dose of UCB or placenta donor can be expended to an amount sufficient for one adoptive transfer procedure. 2014;193(12):6192206. Dege C, et al. 2. Sci Rep. 2020;10(1):2815. 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. NK cells originate from CD34+ hematopoietic stem cells. DAP12-based activating chimeric antigen receptor for NK cell tumor immunotherapy. 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]. Clinical application of CAR-NK cell therapy in solid tumors. Oncoimmunology. Targeted drugs are the preferred recommendations for the systemic treatment of hepatocellular carcinoma. Clinical-grade generation of active NK cells from cord blood hematopoietic progenitor cells for immunotherapy using a closed-system culture process. 2016;7:13050. An antibody designed to improve adoptive NK-cell therapy inhibits pancreatic cancer progression in a murine model. 2010;651:6177. Despite the immunosuppressive environment of solid tumors, NK cell activity/infiltration has been correlated with improved prognoses in humans. Int J Cancer. Natural killer (NK) cell is a specialized immune effector cell type that plays a critical role in immune activation against abnormal 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. To circumvent these challenges, Bi- and tri-specific killer engagers, BiKEs and TriKEs, are in development as a complemental approach. Cytotherapy. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Mol Immunol. 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. 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]. Oncoimmunology. PubMed 2009;373(9674):155061. Front Immunol. In the clinical setting, each batch requires validation, which results in additional lag time before a patient receives infusion. Masuyama J, et al. Typically, the differentiation was induced in embryoid bodies or by OP9 mouse stroma co-culture [111]. Cancer Res. Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. Oelsner S, et al. Front Med (Lausanne). Zingoni A, et al. 2016;16(5):31020. Immunobiology. https://doi.org/10.1186/s13045-020-01014-w, DOI: https://doi.org/10.1186/s13045-020-01014-w. The following section summarizes the current pre-clinical efforts to enhance the efficacy of NK cell-based therapy. Wang W, et al. CAS NK cells are cytotoxic against a wide range of tumor cells of solid cancer types in vitro. Hambach, J., et al., Targeting CD38-expressing multiple myeloma and Burkitt lymphoma cells in vitro with nanobody-based chimeric antigen receptors (Nb-CARs). statement and Oelsner S, et al. It was shown that the hMesothelin-CAR-NK cells containing the shared native NK cell signaling molecule, such as NKG2D-2B4, exhibited superior in vitro and in vivo anti-tumor activities in comparison with which contains CD28-CD137 [42]. Google Scholar. Siegler U, et al. Sakamoto 2014;32(4):102131. Ni J, et al. 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 Muller S, et al. Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. Both UCB and placenta-derived cells contain some proportion of NK cell progenitors that have the capacity to differentiate into NK cells during maturation and expansion stages. Lim SA, et al. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. It is iPSC-differentiated NK cells (iPSC-NK). 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]. Blood. Part of 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]. Clin Cancer Res. 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. For example, uterine NK cells, which constitute the majority of lymphocyte in the uterus during the first trimester, are CD56super bright and play important roles in pregnancies by regulating placental vascular remodeling [17, 20]. Recent observations show that HMGB1 is a potent driver Potently cytotoxic natural killer cells initially emerge from erythro-myeloid progenitors during mammalian development. Liu, S., Galat, V., Galat4, Y. et al. Cytotherapy. Lee HR, et al. Nat Rev Immunol. Miller JS, et al. 2015;15:1011. Using allogeneic NKs for adoptive transfer without expansion after a short overnight incubation with cytokines was shown to be sufficient to activate NK cells and enhance their cell cytotoxicity against tumor targets [86]. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Targeting immunosuppressive components in the TME to re-invigorate NK functions is also under investigation. 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 Lysis of fresh and cultured autologous tumor by human lymphocytes cultured in T-cell growth factor. 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 Effective against blood cancers, natural killer cells also may be effective against solid tumors. Iliopoulou EG, et al. Colonna M. Innate lymphoid cells: diversity, plasticity, and unique functions in immunity. T cells equipped with CARs have been shown to provide clinical benefit for patients with select liquid cancers. Natural killer cells: definition of a cell type rather than a function. WebThis page lists cancer drugs approved by the Food and Drug Administration (FDA) for the treatment of solid tumors based on their genetic and molecular features and not on Zeng J, et al. California Privacy Statement, J Cell Mol Med. Immunotherapy is a breakthrough in the systemic treatment of malignant tumors, including HCC. 2013;13(2):1459. Sci Rep. 2019;9(1):14916. 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]. PLoS ONE. In one study, Ng et al. Mol Ther Oncolytics. WebHappy New Year to you! CAS However, NK cell therapy Continuously expanding CAR NK-92 cells display selective cytotoxicity against B-cell leukemia and lymphoma. Ditadi A, Sturgeon CM, Keller G. A view of human haematopoietic development from the Petri dish. Natural killer cells: development, maturation, and clinical utilization. North J, et al. IL-21 has various effects on human NK cells. Esser R, et al. It has been shown that freshly isolated, resting NK cells are generally less lytic as compared to NK cells primed via various strategies [82]. Retargeting of natural killer-cell cytolytic activity to ErbB2-expressing cancer cells results in efficient and selective tumor cell destruction. NKG2D and its ligands in cancer. It remains to be determined how NRPbody will interact with a more complex and realistic immune contexture in the TME which consists of more than NK cells, as CXCL16 was shown in other tumor models to correlate with the infiltration of monocytes and M2-macrophages as well [92, 93]. Ni Z, et al. Article Autologous natural killer cell therapy for human recurrent malignant glioma. WebMy interests are based on basic science methodologies to improve the advanced science techniques which improve the cancer immunotherapy effects. This method has achieved over 15% of CD34+ hematopoietic progenitors compared to other methods producing only up to 4% of CD34+. It has been proposed that CAR-NK cells may be able to be combined with T cell-based therapies for solid tumors [77]. Lee DA, Verneris MR, Campana D. Acquisition, preparation, and functional assessment of human NK cells for adoptive immunotherapy. It is believed that membrane-bound interleukins are able to stimulate the expansion of NK cells more effectively than the soluble form. 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). 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. Cells, 2020; 9(2). The interim results showed that 8 out of 11 patients had an objective response to treatment without development of major toxic effects [150]. WebImmune regulation has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors (ICIs). Tumor-primed human natural killer cells lyse NK-resistant tumor targets: evidence of a two-stage process in resting NK cell activation. reported an approximately 1500-fold expansion of NK cells after PBMC stimulation with a combination of anti-CD3 and anti-CD56 mAbs [146]. Adoptive transfer of autologous natural killer cells leads to high levels of circulating natural killer cells but does not mediate tumor regression. BMC Biotechnol. The subjects of the study were patients with high-risk solid tumors, including Ewing Sarcoma, Neuroblastoma, Rhabdomyosarcoma, Osteosarcoma, and CNS tumors. Specialized immune effector cell type that plays a critical role in immune activation against abnormal cells ):14916 of. Rather than a function PBMC stimulation with a combination of anti-CD3 and mAbs. 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