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]. Cookies policy. Cytokines in clinical cancer immunotherapy. A phase I trial of adoptive transfer of allogeneic natural killer cells in patients with advanced non-small cell lung cancer. Development of cMET-specific chimeric antigen receptor-engineered natural killer cells with cytotoxic effects on human liver cancer HepG2 cells. North J, et al. CXCL16 positively correlated with M2-macrophage infiltration, enhanced angiogenesis, and poor prognosis in thyroid cancer. Uherek C, et al. Klapdor R, et al. CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma. 2019;10:719. Nat Rev Immunol. Other methods may include transgene of suicide gene or expression of a fluorescent marker in the feeder cell. Kim MJ, et al. Ex vivo activation and expansion of natural killer cells from patients with advanced cancer with feeder cells from healthy volunteers. Block copolymer-boron cluster conjugate for effective boron neutron capture therapy of solid tumors. 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. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. Google Scholar. The SNK02 clinical study will be a multi-center, open label, Phase 1 study of SNK02 in patients with advanced solid tumors who have failed at least one prior It is widely used as an agent to combat solid tumors including lung, colorectal, gastric, gynecologic, and other types of cancer. To improve the clinical outcome of adoptive NK cell therapy in patients with solid tumors, NK cells need to persist within the tumor microenvironment (TME) in Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population. Effects of CSF1R-targeted chimeric antigen receptor-modified NK92MI & T cells on tumor-associated macrophages. Ex vivo-expanded natural killer cells demonstrate robust proliferation in vivo in high-risk relapsed multiple myeloma patients. Cancer Immunol Res. An antibody designed to improve adoptive NK-cell therapy inhibits pancreatic cancer progression in a murine model. 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]. Spanholtz J, et al. Front Immunol. Expansion of cytotoxic natural killer cells using irradiated autologous peripheral blood mononuclear cells and anti-CD16 antibody. Br J Haematol. Tumor-primed human natural killer cells lyse NK-resistant tumor targets: evidence of a two-stage process in resting NK cell activation. All authors gave consent for publication of the manuscript. Mol Immunol. Liu E, et al. Necrotic core even the name sounds creepy. Pharmacologically upregulated carcinoembryonic antigen-expression enhances the cytolytic activity of genetically-modified chimeric antigen receptor NK-92MI against colorectal cancer cells. 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]. Various strategies are being employed to overcome these challenges to improve the efficacy of NK cell-based therapy, such as ex vivo pre-conditioning with cytokines and/or small molecular drugs, engineering an off-the-shelf or iPSC-differentiated chimeric antigen receptor (CAR)-NK. Anticancer Res. Zhang C., et al. Abel AM, et al. Mol Ther. Kang L, et al. However, NK92 is a transformed cell line that has limitations associated with its tumorigenic nature, and cytogenetic abnormalities, thus requiring irradiation for clinical use, which limits its life-time activity. Article Methods Mol Biol. 1975;5(2): 1127. Leukemia. 2016;1441:33346. Dev Cell. Membrane bound IL-21 based NK cell feeder cells drive robust expansion and metabolic activation of NK cells. When expanded it provides a list of search options that will switch the search inputs to match the current selection. Nat Commun. WebExperienced R&D leader in pharmaceutical industry focusing on biologics and cell therapy drug discovery for immuno-oncology. 2015;17(5):61320. Notably, certain tissues such as the mucosal barriers possess subsets of recently identified innate lymphoid cells (ILCs) that also share canonical markers of NK cells. Sarvaria A, et al. Production Process of CAR-NK 2020;53(2):22939. 2019;7(3):36375. GPC3 is Despite promising results shown in hematologic tumors, immunotherapies for the treatment of solid tumors have mostly failed so far. 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 Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine secretion. Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation. DAP12-based activating chimeric antigen receptor for NK cell tumor immunotherapy. Journal of Hematology & Oncology Sakamoto The adoptive transfer of natural killer (NK) cells is an emerging therapy in the field of immuno-oncology. The expanded human NK cells showed potent ADCC activities in vitro and superior tumor control in a mouse xenograft model of ovarian cancer when combined with Herceptin, an anti-HER2 antibody [87]. WebValuable industry experience focuses on understanding NK cells biology and contributing to develop an immuno oncology platform based on off the shelf products. 2013;73(6):177786. Recently, the differentiation method was also established in adherent monolayer cultures [108]. Clinical grade purification and expansion of NK cell products for an optimized manufacturing protocol. Skeate R, et al. Several groups have demonstrated in vitro derivation of functional NK cells from human embryonic stem cells (hESCs) and iPSCs [108,109,110]. Mu YX, et al. Part of Cytotherapy. Shimasaki N, 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]. But cancer cells can make themselves invisible, making it much more difficult for NK cells to find them and do their job. Mehta RS, Shpall EJ, Rezvani K. Cord blood as a source of natural killer cells. Kim EK, et al. 2010;28(6):9559. Koehl U, et al. NK cells can trigger target cell death by releasing cytotoxic granules containing granzymes and perforin and through death receptor-mediated pathways (e.g., FasL/Fas) [11]. Ex vivo expansion of natural killer cells from human peripheral blood mononuclear cells co-stimulated with anti-CD3 and anti-CD52 monoclonal antibodies. Ferrara JL, et al. Innate lymphoid cells: a proposal for uniform nomenclature. Smyth MJ, et al. Iliopoulou EG, et al. Additional markers such as lack of c-kit can be used to distinguish human NK (c-kit-) from ILC3s (c-kit+) [14]. 2017;18(1):5667. There are great numbers of clinical trials on NK cell immunotherapy to treat solid tumors. Application of small molecule CHIR99021 leads to the loss of hemangioblast progenitor and increased hematopoiesis of human pluripotent stem cells. Front Immunol. 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]. Clinical-scale derivation of natural killer cells from human pluripotent stem cells for cancer therapy. You F, et al. 1999;94(1):3339. Donor-derived natural killer cells infused after human leukocyte antigen-haploidentical hematopoietic cell transplantation: a dose-escalation study. Front Immunol. 2005;106(1):37683. Autologous peripheral blood stem cell transplantation and adoptive immunotherapy with activated natural killer cells in the immediate posttransplant period. 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]. [2017][J Control Release][10.1016j.jconrel.2017.03. The cleavable CXCL16 containing NRPbody was shown to promote NK cell migration in vitro and infiltration into the tumor sites in vivo in xenografted mouse models of orthotopic and metastatic pancreatic cancer [90]. 7 Potent BMC Biotechnol. This method resulted in a 1,560-fold expansion of NK cells with a purity of 92.37% after 21days of ex vivo culture[107]. Cancer Res. In the last years, natural killer (NK) cell-based immunotherapy has emerged as a promising therapeutic approach for solid tumors and hematological malignancies. 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]. 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. Herein we highlight current evaluations for hematological malignancies and solid tumors. WebTargeting TROP2 and HER3: Perspective on the Next Precision Treatment Advances Across Solid Tumors. NK cells are CD49aEomes+, whereas ILC1s are CD49a+Eomes [15, 16]. observed in CAR NK cell therapy in liquid tumors have not yet been seen in 2019;7(1):211. Table 6 summarizes updated clinical trials of NK cell-based therapy for all solid tumors. 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. Immunity. NK cells are cytotoxic against a wide range of tumor cells of solid cancer types in vitro. Google Scholar. 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]. Science. Fujisaki H, et al. Natural killer (NK) cells are large granular lymphocytes with surface markers CD3 CD56 + NKp46 + in humans. 2017;25(8):176981. Front Immunol. J Transl Med. 2011;6(6):e20740. 2016;16(2):11223. Cancer Immunol Immunother. 2018;24(8):15819. Cancer Res. It is iPSC-differentiated NK cells (iPSC-NK). Liu, S., Galat, V., Galat4, Y. et al. Similar to CAR-T cells, CAR-NK cells are genetically modified to express CARs that recognize a specific antigen uniquely expressed or overexpressed by target cells. Leukemia. Oncoimmunology. Choi I, et al. Despite the immunosuppressive environment of solid tumors, NK cell activity/infiltration has been correlated with improved prognoses in humans. 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]. Parodi M, et al. Felices M, et al. Current preclinical development of NK cell-based therapy was largely inspired by early clinical studies. 2015;13:277. The mechanism of CTV-1-mediated NK priming is unclear. 1986;137(9):27359. The following section summarizes the current pre-clinical efforts to enhance the efficacy of NK cell-based therapy. 2016;4(3):21524. Ruggeri L, et al. CAS 2020;122:2006. Mesothelin is a tumor differentiation antigen that is highly overexpressed in several human cancers including malignant mesothelioma, pancreatic, ovarian, and lung adenocarcinoma [91]. Chu J, et al. J Immunol. Cancers (Basel), 2020; 12(6). Potently cytotoxic natural killer cells initially emerge from erythro-myeloid progenitors during mammalian development. 2012;14(7):83040. Necrotic core even the name sounds creepy. 2018;19(1):27. 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 Exploitation of natural killer cells for the treatment of acute leukemia. T cells equipped with CARs have been shown to provide clinical benefit for patients with select liquid cancers. The advantage of adherent condition is that it provides defined environment for optimizing the differentiation. Notably, many tissue-resident NK subsets are now shown to be phenotypically and functionally distinct from conventional peripheral blood NK cells [20]. Tang X, et al. 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. The relative proportion of CD56bright and CD56dim NK cells in tissues can be very different from that observed in the peripheral blood [17]. WebArtivas NK cells engineered to express chimeric antigen receptors, or CARs, have the potential to enhance the targeting and activity of the NK cells against either hematologic Koehl U, et al. Herein, we will provide an updated overview of the emerging endeavors for developing NK cell-based cancer immunotherapy from pre-clinical conceptual development, clinical grade expansion, and ongoing clinical development. For instance, the enhancement of the Wnt signaling pathway with GSK3b inhibitor induces definitive hematopoiesis [112, 113] NK cells developed in such conditions had more pronounced inflammatory cytokine production phenotype, whereas Wnt independent NK subsets, similar to primary fetal NK cells, formed a bias for increased cytotoxicity [110]. Wang J, et al. Sustained effector function of IL-12/15/18-preactivated NK cells against established tumors. Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes. Multi-dose Treatment Cohorts Initiated in FT576 Phase 1 Study for Multiple Myeloma; Interim Cao B, et al. Emerging insights into natural killer cells in human peripheral tissues. Cancer Res. J Immunol. Oncoimmunology. 2018;51:5561. Bjorkstrom NK, Ljunggren HG, Michaelsson J. Cancer Res. Conventional NK cells are short-lived innate lymphocytes that lack antigen specificity. Romee, R., et al. Despite promising results shown in hematologic tumors, immunotherapies for the treatment of solid tumors have mostly failed so far. Lee SJ, et al. WebPhysiological barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles to Chimeric antigen receptor T (CAR-T) cell therapy. 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