2017;19(2):23549. Distinctly different from T cell receptors, NK cell receptors are germline-encoded and hard-wired receptors without a requirement for V(D)J recombination. The mechanism of CTV-1-mediated NK priming is unclear. PubMed Central Childs RW, Berg M. Bringing natural killer cells to the clinic: ex vivo manipulation. CAS Anticancer Res. Most NK cells in the blood are CD56dim, whereas the CD56bright subset only represents less than 15% of total circulating NK cells [17]. Instead, a combination of transcription factors, including T-bet, Eomes, E4BP4, Id2, and BLIMP, was identified to instruct NK development and maturation [23]. Sakamoto Characterization and ex vivo expansion of human placenta-derived natural killer cells for cancer immunotherapy. 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. BMC Biotechnol. Front Immunol. 2017;47(5):82033. 2013;3:118. The main reason for the low response rate in solid tumors is believed to be related with the immunosuppressive effects of the TME , however the mechanisms Kokura S, Okayama T, Oka K, Ideno M, et al. All authors gave consent for publication of the manuscript. J Hematol Oncol. PubMed Cytotherapy. 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. Article 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]. Beyond cytokines, other stimulants, including tumor cells, allogeneic PBMCs, antibodies, and microbiol derivatives, have been explored for enhancing ex vivo NK cell expansion. statement and CXCL16 positively correlated with M2-macrophage infiltration, enhanced angiogenesis, and poor prognosis in thyroid cancer. Natural killer cells: development, maturation, and clinical utilization. Initial successes of adoptive NK cell transfer in treating hematological cancers prompted clinical endeavors in using the strategy against solid cancers. Here, we review advances in current approaches to optimizing the NK cell antitumor response including combination with other immunotherapies, cytokines, checkpoint inhibition, and engineering NK cells with chimeric antigen receptors (CARs) for the treatment of pediatric solid tumors. Lu C, et al. 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]. 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. WebIn 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. WebChimeric antigen receptor T cells therapy (CAR-T therapy) is a class of ACT therapy. Cancer Sci. It is iPSC-differentiated NK cells (iPSC-NK). Veluchamy JP, et al. Bottcher JP, et al. 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]. This approval was based on clinical study demonstrating that oNKord improves survival in year 1 of 80% vs. 35% in the control arm. INTRODUCTION Cordyceps is the composite of a genus of fungus that grows on the larva of insects. Additional markers such as lack of c-kit can be used to distinguish human NK (c-kit-) from ILC3s (c-kit+) [14]. More recent evidence had indicated that NK cells can also develop and mature at secondary lymphoid organs, including tonsils, spleen, and lymph nodes [19]. 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]. Ng YY, Tay JCK, Wang S. cxcr1 expression to improve anti-cancer efficacy of intravenously injected CAR-NK cells in mice with peritoneal xenografts. 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 Sci Rep. 2019;9(1):13288. Nham T, et al. Ishikawa E, et al. Luevano M, Madrigal A, Saudemont A. J Exp Med. Other methods may include transgene of suicide gene or expression of a fluorescent marker in the feeder cell. 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]. 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]. 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]. Multi-dose Treatment Cohorts Initiated in FT576 Phase 1 Study for Multiple Myeloma; Interim Oelsner S, et al. Topfer K, et al. Article Front Immunol. WebEnded 2022 with Approximately $475 Million in Cash, Cash Equivalents, and Receivables. 2016;20(7):128794. Autologous natural killer cell therapy for human recurrent malignant glioma. NKG2D and its ligands in cancer. Tanaka Y, et al. Methods Mol Biol. Sci Transl Med. Stimulatingly, the substitution of natural killer (NK) cells with T cells is being considered as an effective solution since NK cells are capable of targeting tumors 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]. Liu E, et al. Multiple effects of IL-21 on human NK cells in ex vivo expansion. 2020;382(6):54553. In the clinical setting, each batch requires validation, which results in additional lag time before a patient receives infusion. NK CELL-BASED THERAPY IN SOLID. It yielded a greater than 1000-fold expansion of NK cells after 3weeks of culture [38, 125, 126]. The differences also arise from activation approaches, such as the choice of interleukins, their combinations, type of feeder cells, and some other factors [95,96,97]. Imai C, Iwamoto S, Campana D. Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells. 2011;17(19):628797. Purinergic targeting enhances immunotherapy of CD73(+) solid tumors with piggyBac-engineered chimeric antigen receptor natural killer cells. Sci Rep. 2020;10(1):2815. Moreover, restricted expansion capacity poses a difficulty for improving the efficacy of NK cells through genetic engineering. 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). 2019;14(3):e0212455. We are initiating the clinical evaluation of AB-201 at multiple centers in the US It has been proposed that CAR-NK cells may be able to be combined with T cell-based therapies for solid tumors [77]. 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. 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. Genetically engineered CAR NK cells display selective cytotoxicity against FLT3-positive B-ALL and inhibit in vivo leukemia growth. 2015;17(5):61320. The exciting results from Liu et al. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. 2019;7(1):211. Springer Nature. Go to: 5.1. Front Immunol. 2017;18(1):5667. 7 Potent Noteworthy, IL-2 primarily activates NK cytotoxicity, while supporting proliferation of both NK and T cells. 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 conventional linear model suggests that mature NK cells arise from common lymphoid progenitors (CLPs) by progressing through a linear continuum [24]. Recent evidence has challenged this model and suggests a possibility of more branched development in the form of both CLPs and common myeloid progenitors (CMPs) giving rise to NK cell progenitors. The ability of Natural Killer (NK) cells to kill tumor targets has been extensively studied in various hematological malignancies. Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells. 2014;20(4):46373. An even greater expansion of NK cells, of over 30,000-fold in a period of 3weeks, was achieved with K562 membrane-bound IL-21 and 4-1BB ligand [127,128,129,130]. NK cells are infrequently seen in tumor biopsies. Phillips JH, Lanier LL. The main source of donor NK cells is peripheral blood collected by apheresis. Blood. NK cells possess advantageous characteristics, including non-MHC-restricted recognition, ability to infiltrate 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]. A clinically adaptable method to enhance the cytotoxicity of natural killer cells against B-cell malignancies. Cancer Res. Selective inhibition of tumor growth by clonal NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor. J Immunother. 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]. Front Immunol. Cytotherapy. 2017;32(2):13554. Fujisaki H, et al. Clin Cancer Res. further pioneered the use of NK cells in non-transplant settings. Autologous peripheral blood stem cell transplantation and adoptive immunotherapy with activated natural killer cells in the immediate posttransplant period. Many efforts are emerging for developing and engineering NK cell-based cancer immunotherapy. Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. To date, more than 350 Cordyceps-related species have been found worldwide based on fungus and/or insect host. Cytokines, such as IL15, have been incorporated into killer engagers to further enhance NK cell functions [80]. CD19-CAR engineered NK-92 cells are sufficient to overcome NK cell resistance in B-cell malignancies. [2017][J Control Release][10.1016j.jconrel.2017.03. Lim SA, et al. Immunity. Furthermore, IL-2, streptococcus A group, and zoledronate have all been approved for human use. [2017][J Control Release][10.1016j.jconrel.2017.03. Exp Hematol. Kang L, et al. WebImmune regulation has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors (ICIs). Freud AG, et al. Manufacturing natural killer cells as medicinal products. Koehl U, et al. 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]. Targeting immunosuppressive components in the TME to re-invigorate NK functions is also under investigation. Granzin M, et al. 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 Li Y, et al. Natural killer (NK) cell is a specialized immune effector cell type that plays a critical role in immune activation against abnormal cells. J Immunother. WebNK cell-mediated control of large solid tumors is usually not efficient, although tumors often express high amounts of activating ligands and low levels of inhibitory ligands, Ueda T, et al. This protocol created a possibility to generate a substantially higher number of NK cells from a single dose of peripheral blood [131] and is currently in phase I/II clinical trial (NCT01787474) with expanded haploid-identical NK cells for treating relapsed or refractory AML. You F, et al. Front Immunol. 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