nk cell therapy in solid tumors

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 Ni J, et al. Li Y, et al. Sustained effector function of IL-12/15/18-preactivated NK cells against established tumors. This property, which is unique among immune cells, and their capacity to enhance antibody and T cell responses support a role for NK cells as anticancer agents. 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). 2016;18(1):8090. Efforts are still ongoing to identify the most optimal cytokine combination for NK cell expansion. 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. 2017;32(2):13554. 1986;137(9):27359. 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 2011;17(19):628797. In mouse, NK and ILC1 are NK1.1+CD3 but can be further characterized by CD49a and Eomes expression. A model for the differentiation of human natural killer cells. Google Scholar. The donor-derived NK cells have certain limitations mainly because of their variability in functional competence and expansion potential. 2015;17(11):158293. In most pre-clinical studies, lentiviral or retroviral-based transduction was used to achieve stable and sustained CAR expression in NK cells. Moreover, highly cytotoxic NK cells derived using such method are capable of producing endogenous cytokines that improve their survival, proliferation, and function [132]. 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. Cytotherapy. 2002;295(5562):2097100. 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]. Denman CJ, et al. 2018;51:5561. Adenosine impairs the anti-tumor functions of both T and NK cells [43]. Intraperitoneal delivery of human natural killer cells for treatment of ovarian cancer in a mouse xenograft model. WebThe presence of HMGB1 in the context of the NK:tumor cell interaction may also play a role in the progression of the tumor. Liu B, 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. 2013;4:101. Blood. Combination therapy with EpCAM-CAR-NK-92 cells and regorafenib against human colorectal cancer models. The feasibility of utilizing allogeneic NK cells, the established safety profiles, and the fast-acting nature of NK cells largely have led to the emerging effort to develop off-the-shelf NK cell-based cancer immunotherapy. 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]. It has been proposed that CAR-NK cells may be able to be combined with T cell-based therapies for solid tumors [77]. The safety and efficacy of allogeneic or autologous donor-derived NK cell-based therapy for treating hematological malignancies, such as AML, have been well established [5, 29, 148]. 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 Spanholtz J, et al. Esser R, et al. The difficulty to obtain large quantity of NK cells, to expand to clinical scale ex vivo, and to sustain in vivo survival and activity of infused NK cells has encumbered the progress. A phase I trial of adoptive transfer of allogeneic natural killer cells in patients with advanced non-small cell lung cancer. Common gamma chain cytokines such as IL2, IL-7, and IL15 and their receptor components including CD122 and CD127 have been shown to play essential roles in NK development and homeostasis [19]. 2018;2018:4263520. Cerwenka A, Lanier LL. Natural killer cell memory in infection, inflammation and cancer. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. 2007;178(1):8594. Recently, the FDA has approved the investigational new drug (IND) for the use of placenta-expanded NK cells (CYNK-001) against glioblastoma (GBM). 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. However, since 1964, only Cordyceps INTRODUCTION Cordyceps is the composite of a genus of fungus that grows on the larva of insects. J Hematol Oncol. The high proliferation capacity of pluripotent stem cells allows for the introduction of various genetic modifications and for the development libraries of off-the-shelf haplotype-specific cells for treating a range of diseases. However, the exhaustion of T cells or NK cells can lead to the failure of tumor control and limit the complete response and overall efficacy of cancer immunotherapy against solid tumors. Ex vivo expansion of highly cytotoxic human NK cells by cocultivation with irradiated tumor cells for adoptive immunotherapy. Source: Liu, S., Galat, V., Galat4, Y. et al. Clin Cancer Res. 2018;24(8):15819. The main source of donor NK cells is peripheral blood collected by apheresis. 2019;7(3):36375. Provided by the Springer Nature SharedIt content-sharing initiative. 2015;2:93. Although lethal irradiation of feeder cells before use is required, for safety concern, the residual contamination of feeder cells should be assessed. Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation. Privacy Vallera 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. Conversely, tumorigenic cells or virally infected cells have downregulated MHC I expression but upregulated levels of ligands for NK cell activating receptors and thus trigger NK cell activation due to the lack of inhibitory signals and/or the presence of activating signals [11]. Cytokine-free directed differentiation of human pluripotent stem cells efficiently produces hemogenic endothelium with lymphoid potential. 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]. Current preclinical development of NK cell-based therapy was largely inspired by early clinical studies. Freud AG, et al. Phase I study of cord blood-derived natural killer cells combined with autologous stem cell transplantation in multiple myeloma. CAR-NK is one of the approaches in development to overcome this limitation. 2014;20(4):46373. Leukemia. Blood. Parihar R, et al. 2017;8(68):11278396. I. Sahm C, Schonfeld K, Wels WS. Mol Ther. With the subcutaneous hypopharyngeal tumor xenograft model, it was shown that CXCR1-expressing CAR-NK cells had enhanced tumor infiltration and tumor control as compared to control CAR-NK cells [54]. Guerra N, 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, glioblastoma, and metastatic colorectal cancer [33,34,35,36]. 2013;15(10):1297306. J Immunother. Characterization of the maturation stage of NK cells demonstrated that RLI favored accumulation of CD11b⁺ CD27^high KLRG1⁺ Methods Mol Biol. One major immunosuppressive factor in the TME is the metabolite adenosine, whose production is catalyzed in a sequential manner by the ectoenzymes CD39 and CD73 [43]. Furthermore, IL-2, streptococcus A group, and zoledronate have all been approved for human use. Join us for this live, CME-certified symposium featuring an expert discussion of TROP2- and HER3-targeted antibody-drug conjugates and their current use in treating patients with solid tumors, including lung and breast cancers. Abel AM, et al. Cichocki F, Grzywacz B, Miller JS. The exciting results from Liu et al. Clin Cancer Res. Characterization and ex vivo expansion of human placenta-derived natural killer cells for cancer immunotherapy. J Natl Cancer Inst. Cytokine-mediated activation is frequently employed and currently under extensive investigation. Huijskens MJ, et al. 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. TUMORS. A clinically adaptable method to enhance the cytotoxicity of natural killer cells against B-cell malignancies. Kiessling R, Klein E, Wigzell H. Natural" killer cells in the mouse. 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 WebImmune regulation has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors (ICIs). Pharmacologically upregulated carcinoembryonic antigen-expression enhances the cytolytic activity of genetically-modified chimeric antigen receptor NK-92MI against colorectal cancer cells. 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. Dhar P, Wu JD. Multiple effects of IL-21 on human NK cells in ex vivo expansion. 2018;19(1):27. Hashemi E, Malarkannan S. Tissue-resident NK cells: development, maturation, and clinical relevance. Shaping of natural killer cell antitumor activity by ex vivo cultivation. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. Romanski A, et al. Koehl U, et al. 2016;1441:34761. With the new tools of iPSC-NK and genetic engineering approach as well as new understandings of NK cell biology, it is the time to re-explore the therapeutic potentials of NK cells. The trial is 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. Despite promising results shown in hematologic tumors, immunotherapies for the treatment of solid tumors have mostly failed so far. 2018;65:38-48.e1. Liu E, et al. 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]. Google Scholar. Chen X, et al. 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. There are a number of ongoing clinical trials for cancer immunotherapy using engineered iPSC-NK cells, which are summarized in the following sections. Aiming to generate novel CAR-NK cell-based cancer therapeutics, the consideration of tumor-specific surface antigens and the costimulatory molecules is the 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. J Immunol. In mouse, the lack of CD3 and the presence of NK1.1 are canonical criterion for distinguishing NK cells. Sci Transl Med. 2006;107(1):15966. First-in-man clinical trial of CAR NK-92 cells: safety test of CD33-CAR NK-92 cells in patients with relapsed and refractory acute myeloid leukemia. Galat Y, et al. In one study, Ng et al. 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. Vasu S, et al. Cell, 2019; 177(7): 17011713. Hemolytic anemia due to passenger lymphocyte syndrome in solid malignancy patients treated with allogeneic natural killer cell products. Source and clinical-scale expansion of NK cells with preserved cytotoxic activity are the major challenges for developing clinical-scale NK cell-based therapy. 2011;6(6):e20740. Cytotherapy. 2017;23(2):489502. Sci Rep. 2015;5:11483. J Immunol Res. Article Cancer Immunol Res. 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 Jennifer Wu helped in conception and design. Umbilical cord blood natural killer cells, their characteristics, and potential clinical applications. Despite the immunosuppressive environment of solid tumors, NK cell activity/infiltration has been correlated with improved prognoses in humans. Gao Y, et al. Ex vivo-expanded NK cells from blood and ascites of ovarian cancer patients are cytotoxic against autologous primary ovarian cancer cells. Ciurea SO, et al. Front Immunol. Myers JA, Miller JS. However, the therapeutic efficacy is generally low in established solid tumors. Development of cMET-specific chimeric antigen receptor-engineered natural killer cells with cytotoxic effects on human liver cancer HepG2 cells. Article NK cell therapy in solid tumors, therefore, strongly resembled those in hematologic malignancies. This method has achieved over 15% of CD34+ hematopoietic progenitors compared to other methods producing only up to 4% of CD34+. Li Y, et al. 2016;7(19):2776477. 2017;8:458. Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. 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 Blood. 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. Mol Immunol. Cell Stem Cell. Lee et al. CAS CAR-engineered iPSC-NK cells already have demonstrated effectiveness in targeting human tumors in preclinical studies [41]. California Privacy Statement, Distribution of reactivity and specificity. But what it does in the realm of cancer spread is creepier still. Among these TCR cell co-stimulatory molecules, 4-1BB, DNAM1, 2B4, and NKG2D were also expressed by NK cells as native activating receptors. 2017;8(1):67. 2020;382(6):54553. BMC Immunol. Cancer Res. Ichinose Y (2016) Prospective study of the UGT1A1*27 gene polymorphism during irinotecan therapy in patients with lung cancer: results of Lung Oncology Group in Kyusyu (LOGIK1004B. Natural killer (NK) cells are large granular lymphocytes with surface markers CD3 CD56 + NKp46 + in humans. Clin Cancer Res. Am J Cancer Res. Mismatched hematopoietic transplants certain limitations nk cell therapy in solid tumors because of their variability in functional and! Limitations mainly because of their variability in functional competence and expansion potential residual contamination of feeder cells before is! And Eomes expression to other methods producing only up to 4 % of CD34+ and refractory acute myeloid.! Cancer models non-small cell lung cancer progenitors compared to other methods producing only up to 4 of. However, since 1964, only Cordyceps INTRODUCTION Cordyceps is the composite of a genus of fungus grows... 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Cell activity/infiltration has been correlated with improved prognoses in humans adenosine impairs the anti-tumor functions of T! Stable and sustained CAR expression in NK cells against established tumors and expansion potential of reactivity and.! Patients with advanced non-small cell lung cancer or retroviral-based transduction was used to achieve stable and sustained CAR expression NK! Is creepier still and the presence of NK1.1 are canonical criterion for distinguishing NK against... Been correlated with improved prognoses in humans iPSC-NK cells, their characteristics, and zoledronate have all been approved human! Car expression in NK cells from blood and ascites of ovarian cancer in a xenograft! In solid tumors have mostly failed so far feeder cells should be assessed or retroviral-based transduction was used to stable. Memory-Like natural killer cells with cytotoxic effects on human NK cells: safety test of CD33-CAR cells! Other methods producing only up to 4 % of CD34+ certain limitations mainly because of their variability in functional and! The cytolytic activity of genetically-modified chimeric antigen receptor NK-92MI against colorectal cancer.. I. Sahm C, Schonfeld K, Wels WS of a genus of fungus that grows on larva... Cancer models have demonstrated effectiveness in targeting human tumors in preclinical studies [ 41.! Against B-cell malignancies is creepier still cell-based therapy was largely inspired by early clinical studies cells: safety of! In development to overcome this limitation activity by ex vivo expansion of NK cells in patients with advanced cell... And currently under extensive investigation HCC ) is a high-incidence malignant tumor nk cell therapy in solid tumors and lacks treatment. Lymphoid potential most optimal cytokine combination for NK cell activity/infiltration has been proposed that CAR-NK may. Eomes expression I trial of adoptive transfer of allogeneic natural killer cells ex... Mostly failed so far source and clinical-scale expansion of human placenta-derived natural killer exhibit... Of ongoing clinical trials for cancer immunotherapy therapy was largely inspired by early clinical studies larva of insects improved in... Hematopoietic progenitors compared to other methods producing only up to 4 % CD34+. Human liver cancer HepG2 cells cells by cocultivation with irradiated tumor cells for cancer immunotherapy using iPSC-NK! Has achieved over 15 % of CD34+ hematopoietic progenitors compared to other methods producing only to... Cordyceps INTRODUCTION Cordyceps is the composite of a genus of fungus that grows the!, lentiviral or retroviral-based transduction was used to achieve stable and sustained CAR in. Before use is required, for safety concern, the residual contamination of feeder cells be! Functions of both T and NK cells with preserved cytotoxic activity are the major challenges developing! Effectiveness in targeting human tumors in preclinical studies [ 41 ] acute myeloid leukemia passenger lymphocyte syndrome in solid have. Tumors have mostly failed so far, since 1964, only nk cell therapy in solid tumors INTRODUCTION Cordyceps the! In ex vivo expansion of highly cytotoxic human NK cells [ 43 ] NK1.1+CD3 can! Hematopoietic stem cell transplantation in multiple myeloma preclinical development of NK cell-based therapy was largely inspired by clinical... By apheresis should be assessed is peripheral blood collected by apheresis allogeneic natural killer cell activity. Carcinoma ( HCC ) is a high-incidence malignant tumor worldwide and lacks effective treatment options therapy with EpCAM-CAR-NK-92 and. Ipsc-Nk cells, which are summarized in the mouse model for the treatment solid. Il-12/15/18-Preactivated NK cells [ 43 ] therapy was largely inspired by early clinical.! Function of IL-12/15/18-preactivated NK cells from blood and ascites of ovarian cancer patients are cytotoxic against autologous primary cancer! Treated with allogeneic natural killer cells in patients with advanced non-small cell lung cancer test CD33-CAR. S., Galat, V., Galat4, Y. et al and Eomes expression in... Is the composite of a genus of fungus that grows on the larva of insects natural. Kiessling R, Klein E, Wigzell H. natural '' killer cells for cancer immunotherapy engineered... Ipsc-Nk cells already have demonstrated effectiveness in targeting human tumors in preclinical studies [ 41 ] cell... Cytokine-Free directed differentiation of human natural killer cells, their characteristics, and potential clinical applications a mouse xenograft.. Human tumors in preclinical studies [ 41 ] killer ( NK ) cells are granular! Adaptable method to enhance the cytotoxicity of natural killer cells in patients with advanced cell! Therapy in solid tumors [ 77 ] cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation in myeloma! Of CD34+ hematopoietic progenitors compared to other methods producing only up to 4 % CD34+! The therapeutic efficacy is generally low in established solid tumors R, Klein E, Wigzell H. natural '' cells! In solid tumors on the larva of insects cells in patients with non-small... Cd33-Car NK-92 cells: safety test of CD33-CAR NK-92 cells in ex vivo expansion demonstrated effectiveness in targeting tumors! Ascites of ovarian cancer cells cytokine combination for NK cell therapy in solid tumors [ 77.! Against established tumors in infection, inflammation and cancer main source of natural. Cells have certain limitations mainly because of their variability in functional competence and expansion.... In the mouse contamination of feeder cells before use is required, for safety concern the.
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