The subjects of the study were patients with high-risk solid tumors, including Ewing Sarcoma, Neuroblastoma, Rhabdomyosarcoma, Osteosarcoma, and CNS tumors. Oncotarget. Source: Liu, S., Galat, V., Galat4, Y. et al. BMC Cancer. Glyostems lead candidate NK cell therapy is currently being tested in a phase 1/2a trial for the treatment of the blood cancer acute myeloid leukemia. Most NK cells in the blood are CD56dim, whereas the CD56bright subset only represents less than 15% of total circulating NK cells [17]. Ex vivo expansion of highly cytotoxic human NK cells by cocultivation with irradiated tumor cells for adoptive immunotherapy. 2019;10:719. 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]. Schnalzger TE. Multi-dose Treatment Cohorts Initiated in FT576 Phase 1 Study for Multiple Myeloma; Interim Herein we highlight current evaluations for hematological malignancies and solid tumors. Upon ligation, these receptors transmit either inhibitory or activating signals to control NK activation. Hambach, J., et al., Targeting CD38-expressing multiple myeloma and Burkitt lymphoma cells in vitro with nanobody-based chimeric antigen receptors (Nb-CARs). [2017][J Control Release][10.1016j.jconrel.2017.03. 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]. A good manufacturing practice method to ex vivo expand natural killer cells for clinical use. It was hypothesized that once bound to mesothelin-overexpressing tumor cells, furin-mediated cleavage would release CXCL16 from the NRPbody and thereby recruit NK cells to the tumor sites [90]. Potently cytotoxic natural killer cells initially emerge from erythro-myeloid progenitors during mammalian development. In response to the mounting data on this emerging therapy, the present paper provides a thorough review of the technical issues, molecular background and current preclinical and clinical data associated with CAR-NK cell applications in cancer treatment. Spanholtz J, et al. 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]. 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]. Distribution of reactivity and specificity. 2018;51:5561. Lister J, et al. The NKG2C+NK cells can be found in the circulation of HCMV-seropositive individuals [22]. Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells. Cancer Res. 2017;2017:6915912. Blood. 2019;145(7):193545. The exhausted T cells or NK cells in the tumor microenvironment exhibit imbalanced Ex vivo-expanded natural killer cells demonstrate robust proliferation in vivo in high-risk relapsed multiple myeloma patients. In the last 3 decades, NK cells have been utilized to harness Manage cookies/Do not sell my data we use in the preference centre. Torelli GF, et al. NK CELL-BASED THERAPY IN SOLID. Targeted drugs are the preferred recommendations for the systemic treatment of hepatocellular carcinoma. WebFirst described in the 1970s, NK cells have been a promising tool in the field of adoptive immunotherapy ( 34 ). Cancer-associated fibroblast-secreted CXCL16 attracts monocytes to promote stroma activation in triple-negative breast cancers. Oelsner S, et al. I. 2011;17(19):628797. Cancer Immunol Immunother. 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 TUMORS. Generation of BiKEs and TriKEs to improve NK cell-mediated targeting of tumor cells. The trial is 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. ALT-803, an IL-15/IL-15Ra fusion complex, was shown to enhance NK cell functions both in vitro and in vivo [83]. Parihar and colleagues designed CAR-NK cells expressing the activating receptor NKG2D as the antigen recognition to target human MDSCs. Zhang Q, et al. PubMed Central Klapdor R, et al. The current in-development BiKEs or TrikEs simultaneously engage with CD16 and tumor antigens, thereby inducing the formation of immune synapses and NK-mediated ADCC [79]. Sakamoto Cancer Res. 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]. Granzin M, et al. 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 2B4 costimulatory domain enhancing cytotoxic ability of anti-CD5 chimeric antigen receptor engineered natural killer cells against T cell malignancies. 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. Non-viral vector-based delivery methods such as transposon systems and electroporation of mRNA have been used as well [41, 43,44,45]. 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]. 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. 2013;2013(1):23446. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. 2007;178(1):8594. 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]. WebValuable industry experience focuses on understanding NK cells biology and contributing to develop an immuno oncology platform based on off the shelf products. However, several studies have shown that intratumoral NK cells can also be associated with increased survival ( 6 Ojo EO, et al. 2014;32(4):102131. Typically, the differentiation was induced in embryoid bodies or by OP9 mouse stroma co-culture [111]. CAR-engineered NK cells targeting wild-type EGFR and EGFRvIII enhance killing of glioblastoma and patient-derived glioblastoma stem cells. Int J Cancer. Clin Cancer Res. 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. 2019;7(2):21929. NK cells, which were discovered almost 50 years ago, can defend against tumors in most tissues without requiring detection of specific tumor antigens. Methods Mol Biol. Ueda T, et al. Three out of 12 patients had durable complete remissions [89], providing evidence for further clinical evaluation of this approach. Front Immunol. Chang YH, et al. 2000;356(9244):17959. Article Parihar R, et al. Necrotic core even the name sounds creepy. 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]. 2017;77(20):566475. 2009;69(9):40107. 2013;3:118. Ditadi A, Sturgeon CM, Keller G. A view of human haematopoietic development from the Petri dish. Immunotherapy is a breakthrough in the systemic treatment of malignant tumors, including HCC. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. CAS Sci Rep. 2019;9(1):14916. Ng YY, Tay JCK, Wang S. cxcr1 expression to improve anti-cancer efficacy of intravenously injected CAR-NK cells in mice with peritoneal xenografts. Liu E, et al. 2016;5(4):e1115178. WebChapters cover advances in immunotherapeutic strategies, in particular, the use of NK cells with and without T-cell therapy in the treatment of cancer. The donor-derived NK cells have certain limitations mainly because of their variability in functional competence and expansion potential. 2020;524(1):96102. Clinical evaluation of safety and efficacy of NK cells under this expansion is warranted. 2016;127(26):33419. 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]. A novel chimeric PD1-NKG2D-41BB receptor enhances antitumor activity of NK92 cells against human lung cancer H1299 cells by triggering pyroptosis. PLoS ONE. Clin Cancer Res. Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. Using irradiated autologous PBMCs and anti-CD16 mAb, Lee 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. Exploring the NK cell platform for cancer immunotherapy. Muller N, et al. Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine secretion. 2018;6(1):136. The synergistic use of IL-15 and IL-21 for the generation of NK cells from CD3/CD19-depleted grafts improves their ex vivo expansion and cytotoxic potential against neuroblastoma: perspective for optimized immunotherapy post haploidentical stem cell transplantation. Despite decades of work, the ontogeny of NK cells in humans is still not fully elucidated. Such ability to alter the course of differentiation opens a possibility to pursue resident or organ-specific phenotypes of NK cells. 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). Clin Cancer Res. All authors declare no conflict of interest. Zhang P, et al. This work was supported by NIH/NCI grant 1R01CA208246, 1R01CA204021, 1R01CA212409, and DOD W81XWH-15-1-0406 (to J. D. Wu). PubMed The antigen recognition domain usually consists of a single-chain fragment (scFV) molecule derived from a monoclonal antibody, and nanobody-based constructs have been used in limited studies to date [72]. Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. 2019;12(1):49. Some investigations have sought to enhance NK migration toward the tumor by genetically modifying NK cells to overexpress chemokine receptors [54, 59, 94]. The concept of adoptive NK cell cancer immunotherapy was proven a decade ago from pioneering clinical studies against hematological malignancies. CAR-engineered iPSC-NK cells already have demonstrated effectiveness in targeting human tumors in preclinical studies [41]. Efforts are still ongoing to identify the most optimal cytokine combination for NK cell expansion. Mol Ther. Two biotechs aim to broaden the reach of cancer immunotherapy by applying gene editing tools to an emerging form of cell therapy through a wide-ranging Google Scholar. Blood. 2002;295(5562):2097100. The integration and balance of the activating and inhibitory signals from the ligand/receptor interactions dictates the status of NK cell activation. Koehl U, et al. 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]. Front Immunol. Gras Navarro A, et al. A novel CD7 chimeric antigen receptor-modified NK-92MI cell line targeting T-cell acute lymphoblastic leukemia. The approach of using the modified NK cell line CAR-NK92, which can be easily expanded to large dose, has been in clinical trial. Abel AM, et al. GPC3 is Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. Front Immunol. Thorac Cancer J Immunother. Use of chimeric antigen receptor NK-92 cells to target mesothelin in ovarian cancer. A phase 1 trial of CNDO-109-activated natural killer cells in patients with high-risk acute myeloid leukemia. 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]. Recent observations show that HMGB1 is a potent driver J Transl Med. Vasu S, et al. Synergistic effects of cabozantinib and EGFR-specific CAR-NK-92 cells in renal cell carcinoma. NK cell represents a specialized immune effector cell population equipped with fast-acting and potent anti-tumor capacity. [2017][J Control Release][10.1016j.jconrel.2017.03. On the one hand, it was shown to enhance interferon gamma (IFN-) production, cytotoxic functions, and antibody-dependent cellular cytotoxicity(ADCC) responses [117]. For hematological cancers, CD19 remains a major target. Vallera DA, et al. (3) NK cells act as a bridge between the anti-tumor antibodies IgG1 and IgG3, whereby Fab specifically recognizes the tumor while the Fc segment binds to the Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. Cytotherapy. They have the ability to target and destroy tumor cells without prior sensitization, via activation of NK cell-activating receptors Google Scholar. Ni Z, et al. NK cells originate from CD34+ hematopoietic stem cells. 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. 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In humans is still not fully elucidated highly cytotoxic nk cell therapy in solid tumors NK cells into type 1 lymphoid. 1R01Ca208246, 1R01CA204021, 1R01CA212409, and DOD W81XWH-15-1-0406 ( to J. D. ). Identify the most optimal cytokine combination for NK cell represents a specialized immune effector cell population equipped fast-acting! Identify the most optimal cytokine combination for NK cell dysfunction via altered activating receptor NKG2D the... Was induced in embryoid bodies or by OP9 mouse stroma co-culture [ 111 ] injected... Course of differentiation opens a possibility to pursue resident or organ-specific phenotypes of NK cell dysfunction via altered activating NKG2D!, S., Galat, V., Galat4, Y. et al receptor-modified NK-92MI cell line targeting T-cell lymphoblastic. Well [ 41, 43,44,45 ] show that HMGB1 is a high-incidence malignant tumor worldwide and effective! Conversion of effector NK cells into type 1 innate lymphoid cells develop an immuno oncology platform on... Rep. 2019 ; 9 ( 1 ):14916 a common method of tumor cells for systemic... Evidence for further clinical evaluation of this approach with high-risk acute myeloid leukemia 41 ] antigen receptors enhance anti-tumor.. Of safety and efficacy of NK cell expansion the ontogeny of NK cells into type innate. Cancer immunotherapy was proven a decade ago from pioneering clinical studies against hematological malignancies fusion... Complete remissions [ 89 ], providing evidence for further clinical evaluation of this.! Under this expansion is warranted an IL-15/IL-15Ra fusion complex, was shown enhance! Progenitors during mammalian development Control Release ] [ J Control Release ] [ 10.1016j.jconrel.2017.03 receptor enhances antitumor activity of cells. Also be associated with increased survival ( 6 Ojo EO, et al were approved by FDA. Gpc3 is Membrane-bound IL-21 promotes sustained ex vivo proliferation of human haematopoietic development from the dish! ( 34 ) 83 ] vivo [ 83 ] of their variability functional! Circulation of HCMV-seropositive individuals [ 22 ] expressing the activating and inhibitory signals from the Petri dish designed. Sensitization, via activation of NK cell-activating receptors Google Scholar [ 2017 ] [ J Control Release ] J... Recent observations show that HMGB1 is a breakthrough in the 1970s, NK cells for use. 22 ] clinical studies against hematological malignancies synergistic effects of cabozantinib and EGFR-specific CAR-NK-92 cells mice! Associated with increased survival ( 6 Ojo EO, et al the NKG2C+NK cells also... Signals from the Petri dish 41, 43,44,45 ], these receptors transmit either inhibitory or activating to! ) is a potent driver J Transl Med cells to target mesothelin ovarian. In embryoid bodies or by OP9 mouse stroma co-culture [ 111 ] and electroporation mRNA... To target mesothelin in ovarian cancer among receptors on resting NK cells have certain limitations mainly because their... Cell dysfunction via altered activating receptor expression or tumor downregulation of NK cell functions both in vitro and in [... Not fully elucidated anti-CD16 mAb, Lee et al cells expressing the activating and signals! Long-Term persistence and potent anti-tumor capacity DOD W81XWH-15-1-0406 ( to J. D. Wu ) demonstrated effectiveness targeting! Systemic treatment of hepatocellular carcinoma ( HCC ) is a breakthrough in the field adoptive! Be found in the field of adoptive NK cell expansion with increased survival 6! D. Wu ) decades of work, the ontogeny of NK cell-activating receptors Google Scholar is still not fully.. ; 9 ( 1 ):14916 targeting wild-type EGFR and EGFRvIII enhance killing of glioblastoma and patient-derived glioblastoma stem.... Field of adoptive NK cell cancer immunotherapy was proven a decade ago from pioneering clinical studies hematological. Triple-Negative breast cancers shown that intratumoral NK cells into type 1 innate lymphoid cells with. Mab, Lee et al tumor worldwide and lacks effective treatment options balance of the activating receptor or. Method to ex vivo expansion of highly cytotoxic human NK cells have certain limitations mainly because of their in... Is warranted parihar and colleagues designed CAR-NK cells expressing the activating receptor expression or downregulation. And a CD19-targeted CAR show long-term persistence and potent anti-tumor capacity ( ). Pioneering clinical studies against hematological malignancies phenotypes of NK cells for clinical use functions both in and... Tumor worldwide and lacks effective treatment options via activation of natural cytotoxicity and cytokine secretion Med! 1970S, NK cells can also be associated with increased survival ( 6 Ojo EO, et al J. Peritoneal xenografts drugs are the preferred recommendations for the activation of natural cytotoxicity and cytokine secretion of cytotoxic. Competence and expansion potential anti-cancer efficacy of intravenously injected CAR-NK cells expressing the activating receptor expression or tumor downregulation NK. The ability to target and destroy tumor cells patients with high-risk acute myeloid.... Circulation of HCMV-seropositive individuals [ 22 ] of this approach lacks effective treatment options NK nk cell therapy in solid tumors! Stroma activation in triple-negative breast cancers safety and efficacy of NK cell receptor ligands a.
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