2018;32(2):52031. Clin Cancer Res. 2012;3:408. Ojo EO, et al. CAS WebTherapeutic Mechanism FT516 drug product is comprised of natural killer (NK) cells derived from a clonal human induced pluripotent stem cell (iPSC) master cell line that has been genetically modified to express a high-affinity variant of immunoglobulin FcgammaRIIIa (CD16a) receptor and to prevent cleavage by the metalloprotease ADAM17. 2013;3:118. Heinze, A., et al. TUMORS. The main source of donor NK cells is peripheral blood collected by apheresis. Production Process of CAR-NK 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]. Moreover, highly cytotoxic NK cells derived using such method are capable of producing endogenous cytokines that improve their survival, proliferation, and function [132]. 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]. 2016;5(4):e1119354. Roda JM, et al. Galat Y, et al. Retargeting of natural killer-cell cytolytic activity to ErbB2-expressing cancer cells results in efficient and selective tumor cell destruction. Among these TCR cell co-stimulatory molecules, 4-1BB, DNAM1, 2B4, and NKG2D were also expressed by NK cells as native activating receptors. 3D model for CAR-mediated cytotoxicity using patient-derived colorectal cancer organoids. 2015;17(11):158293. Aiming to generate novel CAR-NK cell-based cancer therapeutics, the consideration of tumor-specific surface antigens and the costimulatory molecules is the Nat Rev Immunol. Uherek C, et al. 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 2012;7(1):e30264. Tumor boron neutron capture therapy (BNCT) subcutaneousC26 tumor-bearing BALB/c mice were intrave- nously injected PEG-b-P(Glu-SS-BSH)respectively 100mg/kg BSHbasis, when Studies on the in vitro activation of Leu-11+ granular lymphocytes with a natural killer-sensitive tumor cell, K562. WebValuable industry experience focuses on understanding NK cells biology and contributing to develop an immuno oncology platform based on off the shelf products. Chabannon C, et al. 2018;24(8):15819. ALT-803, an IL-15/IL-15Ra fusion complex, was shown to enhance NK cell functions both in vitro and in vivo [83]. 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 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. Cancer Cell. This successful immunotherapy has led to a more complete view of cancer that now considers not only the cancer cells to be targeted and destroyed but also the immune environment of the cancer cells. The presence of autologous feeder cells (typically CD3-depleted PBMCs) in culture additionally facilitates NK expansion [124]. PubMed Central 2016; 8(357): p. 357ra123. J Immunol. statement and Esser R, et al. Effective against blood cancers, natural killer cells also may be effective against solid tumors. Cancer Res. Markers and function of human NK cells in normal and pathological conditions. The natural cytotoxic receptor NKp46 is also often used to identify mouse and human NK cells in combination with the absence of CD3 expression. 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]. Biochem Biophys Res Commun. Other methods may include transgene of suicide gene or expression of a fluorescent marker in the feeder cell. 2019;120(1):615. 2010;28(6):9559. 2015;38(5):197210. Targeting T-cell malignancies using anti-CD4 CAR NK-92 cells. Expression of chimeric receptor CD4zeta by natural killer cells derived from human pluripotent stem cells improves in vitro activity but does not enhance suppression of HIV infection in vivo. Science. Blood. 2020;16:7585. Google Scholar. WebFirst described in the 1970s, NK cells have been a promising tool in the field of adoptive immunotherapy ( 34 ). 2017;77(20):566475. We are initiating the clinical evaluation of AB-201 at multiple centers in the US Tumor boron neutron capture therapy (BNCT) subcutaneousC26 tumor-bearing BALB/c mice were intrave- nously injected PEG-b-P(Glu-SS-BSH)respectively 100mg/kg BSHbasis, when Pharmacologically upregulated carcinoembryonic antigen-expression enhances the cytolytic activity of genetically-modified chimeric antigen receptor NK-92MI against colorectal cancer cells. Current preclinical development of NK cell-based therapy was largely inspired by early clinical studies. GSK3 inhibition drives maturation of NK cells and enhances their antitumor activity. 2017;28(10):88696. Shimasaki N, et al. NK Cell-mediated antibody-dependent cellular cytotoxicity in cancer immunotherapy. 2014;193(12):6192206. 2016;7:105. WebEnded 2022 with Approximately $475 Million in Cash, Cash Equivalents, and Receivables. 2018;19(1):27. A novel method to expand large numbers of CD56(+) natural killer cells from a minute fraction of selectively accessed cryopreserved cord blood for immunotherapy after transplantation. Targeted drugs are the preferred recommendations for the systemic treatment of hepatocellular carcinoma. NK cell-based cancer immunotherapy: from basic biology to clinical development. Source: Liu, S., Galat, V., Galat4, Y. et al. NK Cells of the Lung The approach of using the modified NK cell line CAR-NK92, which can be easily expanded to large dose, has been in clinical trial. Webgeneration NK cell therapies. 2016;16(5):31020. The deal gives Merck control of two off-the-shelf solid tumor cell The exhausted T cells or NK cells in the tumor microenvironment exhibit imbalanced Stem Cells. 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. WebPhysiological barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles to Chimeric antigen receptor T (CAR-T) cell therapy. Sakamoto Manufacturing natural killer cells as medicinal products. Vallera DA, et al. PubMed 2013;15(10):1297306. Siegler U, et al. The FDA has cleared Artiva Biotherapeutics investigational new drug (IND) application for the chimeric antigen receptor NK (CAR-NK) cell therapy AB-201 for the Different from events required for T cell activation, NK cell activation is governed by the interaction of NK receptors with target cells, independent of antigen processing and presentation. 2017;130(16):185768. However, several studies have shown that intratumoral NK cells can also be associated with increased survival ( 6 Two CD19-targeting CAR-T products were approved by the FDA for treatment of B cell lymphomas and acute lymphoblastic leukemia (ALL). Bjorkstrom NK, Ljunggren HG, Michaelsson J. Sci Rep. 2017;7(1):11075. The branched model also proposes that distinct precursor populations independently develop into different mature NK subsets [24]. 2015;13:277. WebOne of the most exciting developments in the fight against cancer is the advent of cell-based immunotherapy, a personalized treatment that kills cancer by using the patients Front Immunol. 2016;20(7):128794. There are also many ongoing clinical trials to evaluate the safety and efficacy of tumor-targeting CAR-NK cells, including using HER2-specific CAR-NK cell to treat advanced or metastatic HER2-expressing solid tumors (NCT04319757), ROBO1-specific CAR-NK cell to treat a broad spectrum of solid tumors (NCT03940820), and MUC1-specific CAR-pNK to treat patients with MUC1-positive relapsed or refractory solid tumor (NCT02839954). Natural killer (NK) cells are an essential part of tumor immunosurveillance, evidenced by higher cancer susceptibility and metastasis in association with diminished NK activity in mouse models and clinical studies [1,2,3]. Despite the immunosuppressive environment of solid tumors, NK cell activity/infiltration has been correlated with improved prognoses in humans. Correspondence to Such ability to alter the course of differentiation opens a possibility to pursue resident or organ-specific phenotypes of NK cells. Sci Rep. 2019;9(1):13288. 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 2017;18(9):100415. Cichocki F, Grzywacz B, Miller JS. In order to avoid critical side effects, such as GVHD caused by alloreactive T cells [98] or a passenger lymphocyte syndrome caused by donor-derived B cells [99], purification is recommended for allogeneic NK cells before the expansion to restrict contaminating total T cells to less than 15105/Kg. J Immunother Cancer. Cells, 2020; 9(2). Furthermore, IL-2, streptococcus A group, and zoledronate have all been approved for human use. Innate lymphoid cells: a proposal for uniform nomenclature. J Transl Med. When expanded it provides a list of search options that will switch the search inputs to match the current selection. Current challenges 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]. Despite decades of work, the ontogeny of NK cells in humans is still not fully elucidated. Denman CJ, et al. Anti-tumor activities of adoptively transferred NK cells in vivo have been demonstrated as well in pre-clinical xenograft mouse models of ovarian cancer, The ability of Natural Killer (NK) cells to kill tumor targets has been extensively studied in various hematological malignancies. The interim results showed that 8 out of 11 patients had an objective response to treatment without development of major toxic effects [150]. PLoS ONE. J Exp Med. Table 5 summarizes the clinical trials of NK cell-based therapy for hematological malignancies to date. 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 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]. Natural killer (NK) cells are large granular lymphocytes with surface markers CD3 CD56 + NKp46 + in humans. 2017;92(2):10014. Article Cancer Manag Res. I. Cancer Immunol Res. Article Cell Stem Cell. 2002;295(5562):2097100. Development of cMET-specific chimeric antigen receptor-engineered natural killer cells with cytotoxic effects on human liver cancer HepG2 cells. Moreover, the CAR-NK cells secrete pro-inflammatory cytokines and chemokines which may improve the infiltration and functions of subsequently infused CAR-T cells in the mouse model [77]. 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]. Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. J Cell Mol Med. 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]. 2015;15:1011. In solid tumors, both autologous and allogeneic NK cells have demonstrated potential efficacy. Improved killing of ovarian cancer stem cells by combining a novel chimeric antigen receptor-based immunotherapy and chemotherapy. 2014;32(4):102131. Immunity. Gauthier, L., et al. PubMed Central NK cell progenitors progress through distinct developmental stages and gradually acquire the expression of surface receptors that define NK cell identity such as NK1.1 and CD56 and/or regulate their effector functions such as CD16 and NKp46 [19]. Web- mWTX-330 is designed as a systemically delivered, conditionally activated IL-12 therapy and is a member of a novel class of INDUKINE therapeutics - - Preclinical data support 2017;177(3):45766. Ex vivo expansion of highly cytotoxic human NK cells by cocultivation with irradiated tumor cells for adoptive immunotherapy. J Exp Med, 1982; 155(6): 182341. Part of Some investigations have sought to enhance NK migration toward the tumor by genetically modifying NK cells to overexpress chemokine receptors [54, 59, 94]. Can't wait to see what 2023 brings #2023ready Go to: 5.1. Cytokine-free directed differentiation of human pluripotent stem cells efficiently produces hemogenic endothelium with lymphoid potential. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. 2012;16(3):56981. Cytotherapy. 2019;30(3):10220. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. This clearance for SNK02 is an important milestone in our pursuit to bring life-changing therapies to cancer patients and will be our second clinical NK cell therapy Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. Lu C, et al. Immunity. Upon ligation, these receptors transmit either inhibitory or activating signals to control NK activation. The anti-CD3 mAb presumably activates T cells in feeder to secret cytokines which subsequently create a milieu favorable for NK cell expansion [145]. 2018;65:38-48.e1. 1995;1(6):60714. 2015;38(1):2436. A study by Campana and coworkers has shown that stimulation of NK cells with gene-modified K562 expressing the NK-stimulatory molecules 4-1BB ligand and IL-15 induced a median 21.6-fold expansion during a 7-day culture period. 2020;12:324755. https://doi.org/10.1186/s13045-020-01014-w, DOI: https://doi.org/10.1186/s13045-020-01014-w. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. Google Scholar. N Engl J Med. 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]. , both autologous and allogeneic NK cells by combining a novel chimeric antigen receptor-based immunotherapy and chemotherapy Nat Rev...., Y. et al [ 124 ] approved for human use precursor populations independently develop different... 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