PubMed I. 2016;18(5):65363. 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]. Felices M, et al. The exhausted T cells or NK cells in the tumor microenvironment exhibit imbalanced Engineering NK cells modified with an EGFRvIII-specific chimeric antigen receptor to overexpress CXCR4 improves immunotherapy of CXCL12/SDF-1alpha-secreting glioblastoma. 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 Innate lymphoid cells: a proposal for uniform nomenclature. 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. Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. Methods Mol Biol. Stem Cell Res Ther. Barrow AD, Martin CJ, Colonna M. The natural cytotoxicity receptors in health and disease. NKp44-NKp44 ligand interactions in the regulation of natural killer cells and other innate lymphoid cells in humans. The relative proportion of CD56bright and CD56dim NK cells in tissues can be very different from that observed in the peripheral blood [17]. Natural killer cells stimulated with PM21 particles expand and biodistribute in vivo: clinical implications for cancer treatment. 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]. 2015;23(2):3308. Spanholtz J, et al. 2013;73(6):177786. 2013;15(10):1297306. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. CAR-engineered NK cells targeting wild-type EGFR and EGFRvIII enhance killing of glioblastoma and patient-derived glioblastoma stem cells. It is widely used as an agent to combat solid tumors including lung, colorectal, gastric, gynecologic, and other types of cancer. Fehniger TA, et al. Terms and Conditions, Google Scholar. Pinz KG, et al. Front Immunol. Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. reported that a CD16/IL-15/CD33 TriKE not only enhances NK-mediated immunity against CD33+ targets, but also promotes the in vivo persistence, activation, and survival of NK cells by delivering IL-15 [80]. J Immunol. 2015;13(3):46471. Zhang C., et al. Oncoimmunology. 2016; 8(357): p. 357ra123. 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 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]. Google Scholar. 2019;30(3):10220. observed in CAR NK cell therapy in liquid tumors have not yet been seen in 2012;16(3):56981. Anticancer Res. Despite decades of work, the ontogeny of NK cells in humans is still not fully elucidated. Huang Y, et al. Ex vivo activation and expansion of natural killer cells from patients with advanced cancer with feeder cells from healthy volunteers. J 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]. Br J Haematol. Leukemia. Multi-dose Treatment Cohorts Initiated in FT576 Phase 1 Study for Multiple Myeloma; Interim Google Scholar. Clinical-grade generation of active NK cells from cord blood hematopoietic progenitor cells for immunotherapy using a closed-system culture process. Webgeneration NK cell therapies. 2015;2:93. 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]. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. 2016;22(3):596608. It is believed that membrane-bound interleukins are able to stimulate the expansion of NK cells more effectively than the soluble form. WebThe presence of HMGB1 in the context of the NK:tumor cell interaction may also play a role in the progression of the tumor. Cancer Sci. 2017;28(10):88696. Ex vivo expansion of natural killer cells from human peripheral blood mononuclear cells co-stimulated with anti-CD3 and anti-CD52 monoclonal antibodies. Methods Mol Biol. Noteworthy, IL-2 primarily activates NK cytotoxicity, while supporting proliferation of both NK and T cells. In mouse, the lack of CD3 and the presence of NK1.1 are canonical criterion for distinguishing NK cells. There are great numbers of clinical trials on NK cell immunotherapy to treat solid tumors. Activation of NK cell cytotoxicity. PubMed Some clinical efficacy has also been demonstrated for allogeneic as well as autologous NK cell therapy, either alone or in combination with conventional therapies. Crucially, tumor antigen-expressing CAR-NK cell therapy increases anti-tumor activities. Thus, NK cell transfer presents an effective method of fighting cancer. Gao Y, et al. Masuyama J, et al. J Immunol Res. Nat Immunol. Masuyama et al. 2017;9(6):1796812. Human NK cell development: one road or many? Distinctly different from T cell receptors, NK cell receptors are germline-encoded and hard-wired receptors without a requirement for V(D)J recombination. CXCL16 positively correlated with M2-macrophage infiltration, enhanced angiogenesis, and poor prognosis in thyroid cancer. Mehta RS, Shpall EJ, Rezvani K. Cord blood as a source of natural killer cells. 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 Wang J, et al. Li Y, et al. Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation. Part of Autologous natural killer cell therapy for human recurrent malignant glioma. 2008;28(4):57180. 2016;16(5):31020. Lancet. 2013;15(2):231-241.e1. WebExperienced R&D leader in pharmaceutical industry focusing on biologics and cell therapy drug discovery for immuno-oncology. N Engl J Med. In one study, Ng et al. Cells, 2020; 9(2). Cancer Res. Lopez-Soto A, et al. To date, more than 350 Cordyceps-related species have been found worldwide based on fungus and/or insect host. Oyer JL, et al. 2018;19(5):45363. Tanaka Y, et al. Article 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 J Exp Med. J Immunother. Cytotherapy. Non-clinical efficacy, safety and stable clinical cell processing of induced pluripotent stem cell-derived anti-glypican-3 chimeric antigen receptor-expressing natural killer/innate lymphoid cells. 2017;8:458. 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. Chapter 5 Cordyceps as an Herbal Drug Bao-qin Lin and Shao-ping Li. 2017;177(3):45766. Google Scholar. Privacy Anti-tumor activities of adoptively transferred NK cells in vivo have been demonstrated as well in pre-clinical xenograft mouse models of ovarian cancer, et al. Typically, the differentiation was induced in embryoid bodies or by OP9 mouse stroma co-culture [111]. Production Process of CAR-NK Shah N, et al. 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. Mol Ther Oncolytics. 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]. Jennifer Wu helped in conception and design. 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]. 2007;178(1):8594. Front Oncol. Kiessling R, Klein E, Wigzell H. Natural" killer cells in the mouse. PubMed Nat Rev Immunol. A novel source of NK cells has emerged to circumvent many of the challenges associated with NK cell therapy. PubMed Central Front Immunol. NK cells, which were discovered almost 50 years ago, can defend against tumors in most tissues without requiring detection of specific tumor antigens. 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]. Many efforts are emerging for developing and engineering NK cell-based cancer immunotherapy. We are initiating the clinical evaluation of AB-201 at multiple centers in the US Killer (NK) cell activity against solid tumors. Natural killer cells: definition of a cell type rather than a function. 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. Jennifer Wu. Geller MA, et al. Sustained effector function of IL-12/15/18-preactivated NK cells against established tumors. Current challenges T cells equipped with CARs have been shown to provide clinical benefit for patients with select liquid cancers. WebImmune regulation has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors (ICIs). 2018; 23(2): 181192. 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]. Springer Nature. Article A phase 1 trial of CNDO-109-activated natural killer cells in patients with high-risk acute myeloid leukemia. 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]. Oncoimmunology. 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]. The expansion of NK cells using IL-2 alone is relatively modest and typically results in only several cell divisions in medium containing 1000 U/mL of IL-2 [100]. Dual targeting of glioblastoma with chimeric antigen receptor-engineered natural killer cells overcomes heterogeneity of target antigen expression and enhances antitumor activity and survival. NK cell dysfunction via altered activating receptor expression or tumor downregulation of NK cell receptor ligands is a common method of tumor immune escape. For example, the absence of NKG2D and other NCR ligands on leukemic blasts allows them to escape NK cell surveillance [86, 87]. 2015;13:277. 2014;193(12):6192206. 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]. The interim results showed that 8 out of 11 patients had an objective response to treatment without development of major toxic effects [150]. Imai C, Iwamoto S, Campana D. Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells. Myers JA, Miller JS. 2016;7(19):2776477. 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. Wang W, et al. 2020. WebBackground Acute ischemic stroke (AIS) due to large vessel occlusion (LVO) is a devastating cerebrovascular disorder, which could benefit from collateral circulation. Exploitation of natural killer cells for the treatment of acute leukemia. 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]. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. PubMed Central [2017][J Control Release][10.1016j.jconrel.2017.03. Application of small molecule CHIR99021 leads to the loss of hemangioblast progenitor and increased hematopoiesis of human pluripotent stem cells. The adoptive transfer of natural killer (NK) cells is an emerging therapy in the field of immuno-oncology. 2020;53(2):22939. A wide range of tumor antigens have been targeted by CAR-NK cells in pre-clinical studies for hematological malignancies and solid tumors [38, 39, 41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76]. In the clinical setting, each batch requires validation, which results in additional lag time before a patient receives infusion. 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. CAS Mol Ther. 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. Vallera et al. 2018;48(6):110417. Cancer Res. All authors read and approved the final manuscript. 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