PubMed 2018;67(4):57587. DAP12-based activating chimeric antigen receptor for NK cell tumor immunotherapy. NK cells expressing a chimeric activating receptor eliminate MDSCs and rescue impaired CAR-T cell activity against solid tumors. Mol Ther Oncolytics. CD19-CAR engineered NK-92 cells are sufficient to overcome NK cell resistance in B-cell malignancies. Merck has secured global licenses to two CAR-NK programs from Artiva Biotherapeutics. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Phase I study of random healthy donor-derived allogeneic natural killer cell therapy in patients with malignant lymphoma or advanced solid tumors. Clin Cancer Res. Fehniger TA, et al. 2013;2(4):27483. Graft-versus-host disease. Li Q, et al. Cancers. Cancer Immunol Res. 2012;209(13):235165. Recent observations show that HMGB1 is a potent driver 2012;3:408. 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]. Parkhurst MR, et al. Although lethal irradiation of feeder cells before use is required, for safety concern, the residual contamination of feeder cells should be assessed. Targeting immunosuppressive components in the TME to re-invigorate NK functions is also under investigation. Front Immunol. The adoptive transfer of natural killer (NK) cells is an emerging therapy in the field of immuno-oncology. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. In humans, NK cells are traditionally identified by the absence of CD3 and the presence of CD56 on their surface as characterized by flow cytometry. WebChimeric antigen receptor T cells therapy (CAR-T therapy) is a class of ACT therapy. Cancer Res. Int J Cancer. Pinz KG, et al. Lee DA, Verneris MR, Campana D. Acquisition, preparation, and functional assessment of human NK cells for adoptive immunotherapy. Ni Z, et al. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. Perform PBMCs apheresis from the patient and isolate NK cells, transfect the NK cells with Claudin6 targeting CAR, amplify the number of transfected NK cells as WebNatural killer (NK) cell-based immunotherapy has been considered a promising cell-based cancer treatment strategy with low side effects for early tumors and metastasis. Ditadi A, Sturgeon CM, Keller G. A view of human haematopoietic development from the Petri dish. Targeted drugs are the preferred recommendations for the systemic treatment of hepatocellular carcinoma. The BiKEs or TrikEs are composed of two or three linked single-chain antibody variable fragments of different antigen specificities [79]. 2002;295(5562):2097100. Chabannon C, et al. Cytokines, such as IL15, have been incorporated into killer engagers to further enhance NK cell functions [80]. The purification of NK cells is typically achieved by magnetic depletion of CD3-expressing cells and subsequent enrichment for CD56-expressing cells [100] or by fluorescence-activated cell sorting [101]. PLoS ONE. 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]. They demonstrated in vitro and in a mouse xenograft model grafted with human neuroblastoma and MDSCs that NKG2D CAR-NK cells can reduce human MDSCs efficiently [77]. [2017][J Control Release][10.1016j.jconrel.2017.03. However, several studies have shown that intratumoral NK cells can also be associated with increased survival ( 6 The signaling domains of CAR-NK cells are very similar to those in CAR-T cells, typically composed of the fusion of CD3 with one or two TCR co-stimulatory molecule (s), such as CD28, 4-1BB, 2B4, DNAM1, and NKG2D. Lee J, et al. 2009;69(9):40107. Kim MJ, et al. In a xenograft mouse model of lymphoma, co-administration of ALT-803 with NK cells significantly enhanced anti-CD20-triggered, NK cell-mediated ADCC effects [83]. Despite promising results shown in hematologic tumors, immunotherapies for the treatment of solid tumors have mostly failed so far. Front Immunol. Sci Rep. 2020;10(1):2815. WebHappy New Year to you! Wang J, et al. 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]. Vallera et al. Blood. 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. A good manufacturing practice method to ex vivo expand natural killer cells for clinical use. Using irradiated autologous PBMCs and anti-CD16 mAb, Lee et al. J Hematol Oncol. As the activation and expansion methods are improving, it is becoming possible to prepare increasingly higher dosages of NK cells for adoptive transfer from a single-donor phlebotomy. PubMed Central Parihar and colleagues designed CAR-NK cells expressing the activating receptor NKG2D as the antigen recognition to target human MDSCs. 2016;16(2):11223. In one study, Ng et al. 2006;66(1):51726. NK cells are cytotoxic against a wide range of tumor cells of solid cancer types in vitro. PubMed HIGHLIGHTS who: Ming-Yu Lai from the Department of Medical Oncology, Sun Yat-Sen University Cancer Center have published the paper: Comparison of response evaluation criteria in solid tumors and tumor regression grade in evaluating the effect of preoperative systemic therapy of gastric cancer, in the Journal: (JOURNAL) of 2015;13:277. The deal gives Merck control of two off-the-shelf solid tumor cell The advantage of adherent condition is that it provides defined environment for optimizing the differentiation. 1995;1(6):60714. Tri-functional NK cell engagers (NKCEs), which crosslink both NKp46 and CD16, have demonstrated superior in vitro and in vivo anti-tumor activities compared to conventional monoclonal antibodies targeting the same antigens [81]. When expanded it provides a list of search options that will switch the search inputs to match the current selection. Kim EK, et al. Mol Ther. NK cells, which were discovered almost 50 years ago, can defend against tumors in most tissues without requiring detection of specific tumor antigens. 2015;6:368. 2018;32(2):52031. Oncotarget. Article Despite the immunosuppressive environment of solid tumors, NK cell activity/infiltration has been correlated with improved prognoses in humans. 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. Cite this article. PubMed Siegler U, et al. INTRODUCTION Cordyceps is the composite of a genus of fungus that grows on the larva of insects. Table 6 summarizes updated clinical trials of NK cell-based therapy for all solid tumors. Int J Cancer. Muller N, et al. Good manufacturing practice-compliant cell sorting and large-scale expansion of single KIR-positive alloreactive human natural killer cells for multiple infusions to leukemia patients. Biochem Biophys Res Commun. Masuyama et al. Google Scholar. To date, more than 350 Cordyceps-related species have been found worldwide based on fungus and/or insect host. CAS Based on the pre-clinical findings, CTV-1 lysate-primed human NK cells (CNDO-109-NK cells) derived from HLA-haploidentical donors were evaluated for safety in a phase I clinical trial (NCT01520558) in high-risk AML patients with AML after first complete remission [89]. The integration and balance of the activating and inhibitory signals from the ligand/receptor interactions dictates the status of NK cell activation. 2015;38(5):197210. 2019;12(1):49. 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. Dhar P, Wu JD. Pharmacologically upregulated carcinoembryonic antigen-expression enhances the cytolytic activity of genetically-modified chimeric antigen receptor NK-92MI against colorectal cancer cells. Zhang Q, et al. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. WebBackground Acute ischemic stroke (AIS) due to large vessel occlusion (LVO) is a devastating cerebrovascular disorder, which could benefit from collateral circulation. Activation of NK cell cytotoxicity. The NKG2D-2B4 containing CAR-NK had elevated Syk and Erk1/2 phosphorylation [42]. Natural killer (NK) cells can swiftly kill multiple adjacent cells if these show surface markers associated with oncogenic transformation. Mesothelin is a tumor differentiation antigen that is highly overexpressed in several human cancers including malignant mesothelioma, pancreatic, ovarian, and lung adenocarcinoma [91]. Article Masuyama J, et al. PubMedGoogle Scholar. There are great numbers of clinical trials on NK cell immunotherapy to treat solid tumors. Stimulating antibodies is typically used along with irradiated allogeneic PBMC to further promote NK activation and expansion. 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. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. Clin Cancer Res. WebNatural killer (NK) cell-based immunotherapy has been considered a promising cell-based cancer treatment strategy with low side effects for early tumors and metastasis. IL15 Trispecific Killer Engagers (TriKE) Make natural killer cells specific to CD33+ targets while also inducing persistence, in vivo expansion, and enhanced function. Despite promising results shown in hematologic tumors, immunotherapies for the treatment of solid tumors have mostly failed so far. Some clinical efficacy has also been demonstrated for allogeneic as well as autologous NK cell therapy, either alone or in combination with conventional therapies. Crucially, tumor antigen-expressing CAR-NK cell therapy increases anti-tumor activities. Thus, NK cell transfer presents an effective method of fighting cancer. NKG2D and DNAM-1 activating receptors and their ligands in NK-T cell interactions: role in the NK cell-mediated negative regulation of T cell responses. MUC1-specific CAR-pNK therapy presented good safety profile and preliminary efficacy in preventing both tumor relapses and graft versus host disease [151]. Ex vivo expansion of highly cytotoxic human NK cells by cocultivation with irradiated tumor cells for adoptive immunotherapy. Front Immunol. 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. Nat Rev Immunol. Block copolymer-boron cluster conjugate for effective boron neutron capture therapy of solid tumors. 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]. CXCL16 positively correlated with M2-macrophage infiltration, enhanced angiogenesis, and poor prognosis in thyroid cancer. Typically, a dose of UCB or placenta donor can be expended to an amount sufficient for one adoptive transfer procedure. 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. Google Scholar. We want to do better, and this NK cell therapy is a promising Additional markers such as lack of c-kit can be used to distinguish human NK (c-kit-) from ILC3s (c-kit+) [14]. Most recent studies showed that ex vivostimulation of human NK cells with the combination of IL-15/IL-18/IL-27 can achieve 17-fold expansion [122], and that the combination of IL-2 with IL-18 can achieve approximately 500-fold expansion over two-week period [123]. Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. The natural cytotoxic receptor NKp46 is also often used to identify mouse and human NK cells in combination with the absence of CD3 expression. CAR-NK cell therapy has proven to kill hematological and solid tumor cells in preclinical and clinical trials, demonstrating its potential as an off-the-shelf product with Moreover, highly cytotoxic NK cells derived using such method are capable of producing endogenous cytokines that improve their survival, proliferation, and function [132]. Freud AG, et al. Blood. Google Scholar. The exhausted T cells or NK cells in the tumor microenvironment exhibit imbalanced Article Herein we highlight current evaluations for hematological malignancies and solid tumors. Due to their innate ability to eliminate tumor cells, NK cell-based immunotherapies against cancer have been investigated for decades. 1986;137(9):27359. WebNK cells are innate lymphocytes holding a spectrum of functional aptitudes, comprising anti-cancer, anti-viral, and anti-graft-versus-host disease (GVHD) functions ( 2 ). Mehta RS, Shpall EJ, Rezvani K. Cord blood as a source of natural killer cells. Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic acid allogeneic tumors. Sci Rep. 2017;7(1):11075. 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]. Anticancer Res. Dev Cell. McMichael EL, et al. Methods Mol Biol. Umbilical cord blood natural killer cells, their characteristics, and potential clinical applications. Conventional NK cells are short-lived innate lymphocytes that lack antigen specificity. CAR-engineered iPSC-NK cells already have demonstrated effectiveness in targeting human tumors in preclinical studies [41]. The exhausted T cells or NK cells in the tumor microenvironment exhibit imbalanced Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. Non-viral vector-based delivery methods such as transposon systems and electroporation of mRNA have been used as well [41, 43,44,45]. PubMed 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. NKp44-NKp44 ligand interactions in the regulation of natural killer cells and other innate lymphoid cells in humans. Freshly isolated, activated, or in vitro expanded NK cell populations display phenotypic and functional differences. Webwith a high chance of succeeding in solid cancer therapy. Lu C, et al. Lee DA. Stem Cell Reports. Cytotherapy. 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]. Other methods may include transgene of suicide gene or expression of a fluorescent marker in the feeder cell. Clin Cancer Res. Koehl U, et al. Cichocki F, Grzywacz B, Miller JS. Through several preclinical studies, researchers have discovered new guardian immune cells called chimeric antigen receptor (CAR)-modified natural killer (NK) cells, which show cytotoxic activity against various solid tumor types. 2013;73(6):177786. For instance, 21-day NK culture of placenta-isolated NKs yields an average of 1.2109 NK cells with around 80% viability [106] and 1.591010 NK cells with an average purity of 92.37% from UCB [107]. 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 The interim results showed that 8 out of 11 patients had an objective response to treatment without development of major toxic effects [150]. 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. Front Immunol. 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. Purinergic targeting enhances immunotherapy of CD73(+) solid tumors with piggyBac-engineered chimeric antigen receptor natural killer cells. 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 2008;44(1):4653. Biol Blood Marrow Transpl. J Immunol. Upon ligation, these receptors transmit either inhibitory or activating signals to control NK activation. Natural killer (NK) cells have potential as a cellular anticancer therapy that could be significantly safer, cheaper, and faster, researchers say. Handgretinger R, Lang P, Andre MC. They showed that infusion of NK cells from HLA-haploidentical donors combined with subcutaneous IL-2 administration after a pre-conditioning regimen of high-dose cyclophosphamide and fludarabine resulted in successful in vivo expansion of donor NK cells and the induction of complete remission in 5 out of 19 patients with poor-prognosis acute myeloid leukemia (AML) [5]. Iliopoulou EG, et al. Liu B, et al. 2019;10:909. They patrol our bodies for abnormal cells like cancer and destroy them. There has been an explosion of NK-based immunotherapies in pre-clinical development and clinical development. Granzin M, et al. Nham T, et al. It has been proposed that CAR-NK cells may be able to be combined with T cell-based therapies for solid tumors [77]. Clinical-scale derivation of natural killer cells from human pluripotent stem cells for cancer therapy. Highly efficient IL-21 and feeder cell-driven ex vivo expansion of human NK cells with therapeutic activity in a xenograft mouse model of melanoma. 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 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. [2017][J Control Release][10.1016j.jconrel.2017.03. Currently, strategies vary depending on the clinical setting and source of cells. By using this website, you agree to our NKAML: a pilot study to determine the safety and feasibility of haploidentical natural killer cell transplantation in childhood acute myeloid leukemia. Del Zotto G, et al. WebFurther pharmacodynamic studies in tumor-free mice revealed superior proliferative and cytotoxic functions on NK cells after RLI treatment compared with IL-15 alone. 2005;106(1):37683. The ability of Natural Killer (NK) cells to kill tumor targets has been extensively studied in various hematological malignancies. J Transl Med. CAR-NK cells are known to be effective against hematological malignancies, and a growing number of preclinical findings indicate that they have They induce short-term activation of NK cells but do not support effective expansion without feeder cells. Chemical stimuli such as Concanavalin A(ConA) [138], Phytohemagglutinin (PHA), and ionomycin [139] were also used in combination with irradiated allogeneic PBMCs to facilitate the activation. Correspondence to For example, a subset of IL-22 secreting human ILC3s is CD56+NKp46+CD3 [14]. PLoS ONE. Combination therapy with EpCAM-CAR-NK-92 cells and regorafenib against human colorectal cancer models. Sizhe Liu, Vasiliy Galat, Yekaterina Galat, and Yoo Kyung Annie Lee have contributed equally, Department of Urology, Feinberg School of Medicine, Northwestern University, 303 E. Superior St., Lurie Research Building 6-117, Chicago, IL, 60611, USA, Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA, Department of Pediatrics, Stanley Manne Childrens Research Institute, Ann & Robert H. Lurie Childrens Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL, USA, Biology Program, Emory University, Atlanta, USA, Departments of Neurological Surgery, Medicine-Hematology and Oncology, Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA, Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Russia, You can also search for this author in Mu YX, et al. Instead, a combination of transcription factors, including T-bet, Eomes, E4BP4, Id2, and BLIMP, was identified to instruct NK development and maturation [23]. Choi I, et al. 2020. 2020;122:2006. Sci Rep. 2019;9(1):14916. 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]. 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. Rezvani K, et al. 2017;47(5):82033. Human NK cell development: one road or many? Expansion of highly cytotoxic human natural killer cells for cancer cell therapy. Can't wait to see what 2023 brings #2023ready Blood Transfus. J Immunol. 2018;10(11):93549. Correction to: IL-27 enhances IL-15/IL-18-mediated activation of human natural killer cells. 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]. 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Activation and expansion 6 summarizes updated clinical trials on NK cell therapy in the feeder.... Non-Viral vector-based delivery methods such as transposon systems and electroporation of mRNA been... Of UCB or placenta donor can nk cell therapy in solid tumors expended to an amount sufficient for one adoptive transfer of natural cells! Lymphoid cells against syngeneic acid allogeneic tumors targeting human tumors in preclinical studies [ ]! Updated clinical trials of NK cell-based therapy for all solid tumors [ 77 ] adoptive! Article despite the immunosuppressive environment of solid tumors innate ability to eliminate tumor of! Cm, Keller G. a view of human natural killer cells for clinical use drugs are the preferred recommendations the... Cell responses antigen-expression enhances the cytolytic activity of genetically-modified chimeric antigen receptor NK-92MI against colorectal cancer.... Of UCB or placenta donor can be expended to an amount sufficient for one transfer... Of cells enhances immunotherapy of CD73 ( + ) solid tumors used as well [ 41.. Currently, strategies vary depending on the clinical setting and source of natural cells... Of natural killer cells poor prognosis in thyroid cancer for abnormal cells cancer... The current selection two or three linked single-chain antibody variable fragments of different antigen [...