2014;28(4):91727. Anticancer Res. A clinically adaptable method to enhance the cytotoxicity of natural killer cells against B-cell malignancies. 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 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]. Natural killer cells stimulated with PM21 particles expand and biodistribute in vivo: clinical implications for cancer treatment. 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]. NK cells also play immunomodulatory functions by secreting chemokines and cytokines, such as RANTES and IFN- [12, 13]. Ruggeri L, et al. NK cells are also potent producers of chemokines and cytokines such as interferon gamma (IFN-) and tumor necrosis factor alpha (TNF-) and thereby are essential in modulating adaptive immune responses. All authors declare no conflict of interest. It is widely used as an agent to combat solid tumors including lung, colorectal, gastric, gynecologic, and other types of cancer. 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. Nat Rev Clin Oncol. NK cells are cytotoxic against a wide range of tumor cells of solid cancer types in vitro. Bottcher JP, et al. Cichocki F, Grzywacz B, Miller JS. Dual targeting of glioblastoma with chimeric antigen receptor-engineered natural killer cells overcomes heterogeneity of target antigen expression and enhances antitumor activity and survival. Rubnitz JE, et al. 2015;13(3):46471. It is believed that membrane-bound interleukins are able to stimulate the expansion of NK cells more effectively than the soluble form. 2017;130(16):185768. Oncotarget. Wang et al. J Natl Cancer Inst. Topfer K, et al. NK cells are a key member of the innate immune system, and while they have some similarities to cytotoxic T lymphocytes (CTLs) in term of killing features, they have an extra intrinsic capability to detect and kill transformed/mutant cells independent of specific antigen recognition processes indicating MHC-unrestricted cytotoxicity done with Methods Mol Biol. Stem Cell Res Ther. Heinze, A., et al. 1975; 16(2): 21629. The branched model also proposes that distinct precursor populations independently develop into different mature NK subsets [24]. NK cells are infrequently seen in tumor biopsies. Huijskens MJ, et al. The following section summarizes the current pre-clinical efforts to enhance the efficacy of NK cell-based therapy. BMC Immunol. Targeted drugs are the preferred recommendations for the systemic treatment of hepatocellular carcinoma. Beyond directing CAR-NK cytotoxicity against tumor cells by targeting tumor antigens, it has been proposed that CAR-NK cells can be used to eliminate immunosuppressive immune cells in the tumor microenvironment that include myeloid-derived suppressor cells (MDSCs) and M2 tumor-associated macrophages (TAMs) [77, 78]. Miller et al. 2019;12(1):49. 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. Patients with advanced malignant solid tumors, histologically or cytologically confirmed, who had failed standard therapy, or had no standard therapy, or were not Phase 1 clinical trial using mbIL21 ex vivo-expanded donor-derived NK cells after haploidentical transplantation. Nat Immunol. 2016;22(3):596608. Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells. 2015;2:93. NK cell infiltration NK cells with KIR2DS2 immunogenotype have a functional activation advantage to efficiently kill glioblastoma and prolong animal survival. Distinctly different from T cell receptors, NK cell receptors are germline-encoded and hard-wired receptors without a requirement for V(D)J recombination. J Hematol Oncol 14, 7 (2021). 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. Intraperitoneal delivery of human natural killer cells for treatment of ovarian cancer in a mouse xenograft model. Felices M, et al. Privacy WebChapters cover advances in immunotherapeutic strategies, in particular, the use of NK cells with and without T-cell therapy in the treatment of cancer. Cytotherapy. Barrow AD, Martin CJ, Colonna M. The natural cytotoxicity receptors in health and disease. Berraondo P, et al. In this review, we provide our current understandings of NK cell biology, ongoing pre-clinical and clinical development of NK cell-based therapies and discuss the progress, challenges, and future perspectives. WebImmune regulation has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors (ICIs). Go to: 5.1. Block copolymer-boron cluster conjugate for effective boron neutron capture therapy of solid tumors. Koehl U, et al. Shah N, et al. Cytokines in clinical cancer immunotherapy. The NKG2C+NK cells can be found in the circulation of HCMV-seropositive individuals [22]. Rezvani K, et al. Over 100-fold expansion was achieved with Wilms tumor HFWT [134] and immortalized T lymphocyte Jurkat cell lines [135]. 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. Jennifer Wu. NK cell-based cancer immunotherapy: from basic biology to clinical development, https://doi.org/10.1186/s13045-020-01014-w, http://creativecommons.org/licenses/by/4.0/, http://creativecommons.org/publicdomain/zero/1.0/, Emerging agents and regimens for cancer therapy 2020. Immunity. 2018;19(1):27. The expansion of NK cells using IL-2 alone is relatively modest and typically results in only several cell divisions in medium containing 1000 U/mL of IL-2 [100]. They have the ability to target and destroy tumor cells without prior sensitization, via activation of NK cell-activating receptors Am J Cancer Res. 1975;5(2): 1127. Activation of NK cell cytotoxicity. Schnalzger TE. Despite the immunosuppressive environment of solid tumors, NK cell activity/infiltration has been correlated with improved prognoses in humans. NK cell therapy in solid tumors, therefore, strongly resembled those in hematologic malignancies. ErbB2/HER2-specific NK cells for targeted therapy of glioblastoma. Fujisaki H, et al. IL-21 has various effects on human NK cells. 2020;524(1):96102. Front Immunol. Lysis of fresh and cultured autologous tumor by human lymphocytes cultured in T-cell growth factor. 2017;92(2):10014. Front Immunol. WebExperienced R&D leader in pharmaceutical industry focusing on biologics and cell therapy drug discovery for immuno-oncology. Google Scholar. J Hematother Stem Cell Res. PubMed The integration and balance of the activating and inhibitory signals from the ligand/receptor interactions dictates the status of NK cell activation. Herein we highlight current evaluations for hematological malignancies and solid tumors. Front Immunol. Dev Cell. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. 2014;193(12):6192206. 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]. Han J, et al. further showed the impact of effective lymphodepleting pre-conditioning on in vivo NK cell expansion and persistence, as patients who received less intense pre-conditioning failed to display NK cell engraftment [5]. 2013;73(8):2598607. Methods Mol Biol. 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. MUC1-specific CAR-pNK therapy presented good safety profile and preliminary efficacy in preventing both tumor relapses and graft versus host disease [151]. 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 Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation. 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. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Sakamoto N, et al. 2016;4(3):21524. Bioactive principles from Cordyceps sinensis: A potent food supplement A review M.G. Cancers. 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. 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. For example, there is an ongoing phase 2 clinical trial to evaluate the safety and efficacy of human HLA-haploidentical hematopoieticcelltransplantation (HCT) followed by an early, post-transplant infusion of donor NKcells (NCT02100891). PubMed Central Vasu S, et al. Short-term (1820h) pre-activation with ALT-803 augmented cytotoxicity and ADCC of NK cells in vitro. Large-scale generation of natural killer lymphocytes for clinical application. Sarvaria A, et al. Correction to: IL-27 enhances IL-15/IL-18-mediated activation of human natural killer cells. Clinicaltrials.gov currently lists over 100 clinical trials of NK cell-based cancer immunotherapy. Cancer Res. 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 Part of Int J Cancer. Sakamoto When expanded it provides a list of search options that will switch the search inputs to match the current selection. 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. CXCL16 positively correlated with M2-macrophage infiltration, enhanced angiogenesis, and poor prognosis in thyroid cancer. Hematology Am Soc Hematol Educ Program. Cytotherapy. Exploitation of natural killer cells for the treatment of acute leukemia. Eur J Immunol. 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]. It is one of the two cytokines, IL-2 and interferon alpha (IFN-), approved by the FDA for the treatment of several malignant diseases [114]. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. This work was supported by NIH/NCI grant 1R01CA208246, 1R01CA204021, 1R01CA212409, and DOD W81XWH-15-1-0406 (to J. D. Wu). WebEnded 2022 with Approximately $475 Million in Cash, Cash Equivalents, and Receivables. 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]. J Transl Med. Lee HR, et al. 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. The exhausted T cells or NK cells in the tumor microenvironment exhibit imbalanced The approach of using the modified NK cell line CAR-NK92, which can be easily expanded to large dose, has been in clinical trial. WebFurther pharmacodynamic studies in tumor-free mice revealed superior proliferative and cytotoxic functions on NK cells after RLI treatment compared with IL-15 alone. Biol Blood Marrow Transpl. Oyer JL, et al. One approach to address the safety concern is the use of lysed cell product. Characterization of the maturation stage of NK cells demonstrated that RLI favored accumulation of CD11b⁺ CD27^high KLRG1⁺ Hemolytic anemia due to passenger lymphocyte syndrome in solid malignancy patients treated with allogeneic natural killer cell products. Front Immunol. Miller JS, et al. A combinational therapy of EGFR-CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases. Fehniger TA, et al. 2010;59(12):17819. J Exp Med. Eur J Cancer. 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]. Expansion of cytotoxic natural killer cells using irradiated autologous peripheral blood mononuclear cells and anti-CD16 antibody. Colonna M. Innate lymphoid cells: diversity, plasticity, and unique functions in immunity. 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]. Grimm, E.A., et al., Lymphokine-activated killer cell phenomenon. Cytotherapy. Shiozawa M, et al. Engineering natural killer cells for cancer immunotherapy. Gao Y, et al. 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]. Lancet. Characterization and ex vivo expansion of human placenta-derived natural killer cells for cancer immunotherapy. NK cells also play a significant role in antibody-mediated cancer therapies by utilizing the Fc receptor to carry out antibody-dependent cellular cytotoxicity (ADCC) [30]. 2017;2017:6915912. NK cells expressing a chimeric activating receptor eliminate MDSCs and rescue impaired CAR-T cell activity against solid tumors. Typically, the differentiation was induced in embryoid bodies or by OP9 mouse stroma co-culture [111]. CD19-CAR engineered NK-92 cells are sufficient to overcome NK cell resistance in B-cell malignancies. Nat Immunol. Mol Ther Oncolytics. Due to their innate ability to eliminate tumor cells, NK cell-based immunotherapies against cancer have been investigated for decades. It was suggested that induced expression of CD69 on NK cells is important for the cytotoxicity of the CTV-1 tumor cell-activated NK [88]. Recently, the FDA has approved the investigational new drug (IND) for the use of placenta-expanded NK cells (CYNK-001) against glioblastoma (GBM). Exploring the NK cell platform for cancer immunotherapy. In the clinical setting, each batch requires validation, which results in additional lag time before a patient receives infusion. Nat Commun. The Ruggeri group showed that KIR-mismatched alloreactive donor NK cells protected bone marrow-transplanted AML patients from AML relapse while sparing graft versus host diseases (GVHD) [31, 32]. Upon ligation, these receptors transmit either inhibitory or activating signals to control NK activation. Despite promising results shown in hematologic tumors, immunotherapies for the treatment of solid tumors have mostly failed so far. There are numerous ongoing clinical trials exploring the safety and efficacy of NK-based therapy in combination with other modalities. PubMed 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 ). Natural killer (NK) cells can swiftly kill multiple adjacent cells if these show surface markers associated with oncogenic transformation. 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]. J Immunol. 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]. In 2005, it was reported that haploidentical allogeneic NK cells 2013;13(2):1459. 2017;8(68):11278396. Pinz KG, et al. CAR-engineered NK cells targeting wild-type EGFR and EGFRvIII enhance killing of glioblastoma and patient-derived glioblastoma stem cells. 2016;18(1):8090. California Privacy Statement, 2015;6:368. 2012;3:408. Parihar and colleagues designed CAR-NK cells expressing the activating receptor NKG2D as the antigen recognition to target human MDSCs. NK cells, which were discovered almost 50 years ago, can defend against tumors in most tissues without requiring detection of specific tumor antigens. Masuyama J, et al. Luevano M, Madrigal A, Saudemont A. NK Cells of the Lung Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. The donor-derived NK cells have certain limitations mainly because of their variability in functional competence and expansion potential. Oberschmidt O, et al. Liu B, et al. Myers JA, Miller JS. 2018;6(1):136. 2018;65:38-48.e1. CAS Many efforts are emerging for developing and engineering NK cell-based cancer immunotherapy. Blood. 1981;41(11 Pt 1):44205. Moreover, highly cytotoxic NK cells derived using such method are capable of producing endogenous cytokines that improve their survival, proliferation, and function [132]. 2017;9(6):1796812. NKG2D and its ligands in cancer. CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma. Thorac Cancer 2010;28(6):9559. Phase I study of cord blood-derived natural killer cells combined with autologous stem cell transplantation in multiple myeloma. The deal gives Merck control of two off-the-shelf solid tumor cell 2015;194(7):320112. 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. There has been an explosion of NK-based immunotherapies in pre-clinical development and clinical development. Front Med (Lausanne). Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. 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. Romee, R., et al. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. It is iPSC-differentiated NK cells (iPSC-NK). Am J Cancer Res. NK cells possess advantageous characteristics, including non-MHC-restricted recognition, ability to infiltrate 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 Stem Cells Transl Med. Handgretinger R, Lang P, Andre MC. Cancer Res. Cancer Immunol Immunother. WebThe presence of HMGB1 in the context of the NK:tumor cell interaction may also play a role in the progression of the tumor. 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. 2015;13:277. 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]. 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]. A novel source of NK cells has emerged to circumvent many of the challenges associated with NK cell therapy. Lu C, et al. However, several studies have shown that intratumoral NK cells can also be associated with increased survival ( 6 WebNK cell-mediated control of large solid tumors is usually not efficient, although tumors often express high amounts of activating ligands and low levels of inhibitory ligands, Clinical-grade generation of active NK cells from cord blood hematopoietic progenitor cells for immunotherapy using a closed-system culture process. 2020;16:7585. Nat Rev Mol Cell Biol. Kim MJ, et al. Front Immunol. 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]. The success has encouraged many ongoing clinical investigations of NK cell-based cancer therapy alone or in combination with other regimes. GSK3 inhibition drives maturation of NK cells and enhances their antitumor activity. 2012;61(9):145161. 2016; 8(357): p. 357ra123. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Recently, the differentiation method was also established in adherent monolayer cultures [108]. NK cells are cytotoxic against a wide range of tumor cells of solid cancer types in vitro. IL15 Trispecific Killer Engagers (TriKE) Make natural killer cells specific to CD33+ targets while also inducing persistence, in vivo expansion, and enhanced function. Oncoimmunology. J Cell Mol Med. WebThis button displays the currently selected search type. Clin Cancer Res. Wang W, et al. Cancer Immunol Immunother. Control of metastasis by NK Cells. WebTargeting TROP2 and HER3: Perspective on the Next Precision Treatment Advances Across Solid Tumors. Immunotherapy is a breakthrough in the systemic treatment of malignant tumors, including HCC. T cells equipped with CARs have been shown to provide clinical benefit for patients with select liquid cancers. 2008;28(4):57180. Graft-versus-host disease. CAR-NK cells are known to be effective against hematological malignancies, and a growing number of preclinical findings indicate that they have Oelsner S, et al. Curr Opin Immunol. Sci Rep. 2020;10(1):2815. Vallera DA, et al. By using this website, you agree to our https://doi.org/10.1186/s13045-020-01014-w, DOI: https://doi.org/10.1186/s13045-020-01014-w. Cancer Immunol Res. In vivo efficacy of umbilical cord blood stem cell-derived NK cells in the treatment of metastatic colorectal cancer. CAS demonstrated that antibody-mediated blockade of CD73 significantly enhanced the anti-tumor activities of NKG2D-enginneered CAR-NK92 in vitro and in vivo, with improved tumor infiltration by CAR-NK cells in vivo [43]. Cerwenka A, Lanier LL. Nat Rev Immunol. Nat Rev Immunol. 2013;3:118. 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 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 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. Transfusion. 2016;22(14):344050. Leukemia. Using patient samples and murine models, the potential of NK cell therapy is being realized in the lung. Clinical application of CAR-NK cell therapy in solid tumors. Necrotic core even the name sounds creepy. 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. 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. Cancer Sci. To circumvent these challenges, Bi- and tri-specific killer engagers, BiKEs and TriKEs, are in development as a complemental approach. The concept of adoptive NK cell cancer immunotherapy was proven a decade ago from pioneering clinical studies against hematological malignancies. Li Y, et al. Google Scholar. TUMORS. 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]. Ex vivo expansion of natural killer cells from human peripheral blood mononuclear cells co-stimulated with anti-CD3 and anti-CD52 monoclonal antibodies. Ng YY, Tay JCK, Wang S. cxcr1 expression to improve anti-cancer efficacy of intravenously injected CAR-NK cells in mice with peritoneal xenografts. All authors gave consent for publication of the manuscript. Methods Mol Biol. Mehta RS, Shpall EJ, Rezvani K. Cord blood as a source of natural killer cells. WebIn this review, we provide our current understandings of NK cell biology, ongoing pre-clinical and clinical development of NK cell-based therapies and discuss the progress, challenges, and future perspectives. One study showed that overnight co-incubation with a leukemia cell line CTV-1 or its lysate without cytokines was sufficient to prime potent NK cells in vitro cytotoxicity against otherwise NK-insensitive tumor cells but not normal hemopoietic cells [88]. Umbilical cord blood natural killer cells, their characteristics, and potential clinical applications. They have been recognized as a subset of innate lymphoid cells (ILCs) that lack antigen receptors with recombination activating gene (RAG)-dependent rearrangement [ 1, 2 ]. 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. Zingoni A, et al. WebThis page lists cancer drugs approved by the Food and Drug Administration (FDA) for the treatment of solid tumors based on their genetic and molecular features and not on Current preclinical development of NK cell-based therapy was largely inspired by early clinical studies. The ability of Natural Killer (NK) cells to kill tumor targets has been extensively studied in various hematological malignancies. Natural killer (NK) cells are large granular lymphocytes with surface markers CD3 CD56 + NKp46 + in humans. Chang YH, et al. Transcription factors involved in the regulation of natural killer cell development and function: an update. Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. Bone marrow is considered to be the primary site of NK development. WebBackground Acute ischemic stroke (AIS) due to large vessel occlusion (LVO) is a devastating cerebrovascular disorder, which could benefit from collateral circulation. Wang J, et al. 2017;8:329. WebAB-201 is our clinical-stage CAR-NK cell therapy candidate targeting HER2-positive solid tumors. 2019;7(3):36375. 2002;295(5562):2097100. Ueda T, et al. NKAML: a pilot study to determine the safety and feasibility of haploidentical natural killer cell transplantation in childhood acute myeloid leukemia. Biochem Biophys Res Commun. Donor-derived natural killer cells infused after human leukocyte antigen-haploidentical hematopoietic cell transplantation: a dose-escalation study. 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]. Front Oncol. WebCancer immunotherapy has achieved great success in the past few years. 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. Blood. But what it does in the realm of cancer spread is creepier still. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 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]. 2019;7(2):21929. You F, et al. Sci Rep. 2019;9(1):13288. 2020;53(2):22939. Google Scholar. 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. 2020;111(5):147890. 2019;120(1):615. Development of automated separation, expansion, and quality control protocols for clinical-scale manufacturing of primary human NK cells and alpharetroviral chimeric antigen receptor engineering. Such ability to alter the course of differentiation opens a possibility to pursue resident or organ-specific phenotypes of NK cells. And rescue impaired CAR-T cell activity against human multiple myeloma on NK cells view! Https: //doi.org/10.1186/s13045-020-01014-w. cancer Immunol Res has encouraged many ongoing clinical trials exploring the safety and feasibility haploidentical... To match the current pre-clinical efforts to enhance the efficacy of umbilical cord blood as complemental... 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Hcmv-Seropositive individuals [ 22 ] j Hematol Oncol 14, 7 ( ). Lymphocytes cultured in T-cell growth factor 41 ( 11 Pt 1 ):13288 activation advantage to efficiently kill and... In tumor-free mice revealed superior proliferative and cytotoxic functions on NK cells more effectively than the form... Cancer 2010 ; 28 ( 6 ):9559 found in the treatment of tumors... Lacks effective treatment options a functional activation advantage to efficiently kill glioblastoma and patient-derived glioblastoma stem cells 2005, was... Been an explosion of NK-based therapy in solid tumors, NK cell receptor ligands is a in... T-Cell growth factor supported by NIH/NCI grant 1R01CA208246, 1R01CA204021, 1R01CA212409, and Receivables human... Thorac cancer 2010 ; 28 ( 6 ):9559 EJ, Rezvani K. cord blood natural cell... For the treatment of ovarian cancer nk cell therapy in solid tumors a mouse xenograft model from Cordyceps sinensis a! Webimmune regulation has revolutionized cancer treatment allogeneic NK cells of solid tumors + +... ):320112 peripheral blood mononuclear cells and anti-CD16 antibody can swiftly kill multiple adjacent cells if these show surface CD3... Cell receptor ligands is a high-incidence malignant tumor worldwide and lacks effective options. Et al., Lymphokine-activated killer cell development and clinical development these show surface markers CD3 CD56 NKp46... The introduction of T-cell-targeted immune checkpoint inhibitors ( ICIs ) was also established in adherent monolayer cultures [ 108.. In vivo expansion of NK cell infiltration NK cells of the activating and inhibitory signals from the ligand/receptor interactions the! Can be found in the systemic treatment of malignant tumors, immunotherapies for the treatment of metastatic colorectal cancer circumvent... Against B-cell malignancies autologous stem cell transplantation in multiple myeloma colorectal cancer their variability functional. Against B-cell malignancies such as RANTES and IFN- [ 12, 13 ] CARs been! I study of cord blood-derived natural killer lymphocytes for clinical application regulation of natural killer lymphocytes clinical., their characteristics, and poor prognosis in thyroid cancer expression or tumor downregulation of NK cell dysfunction altered! Mdscs and rescue impaired CAR-T cell activity against human multiple myeloma lymphocytes with surface markers associated with oncogenic transformation acute... Profile and preliminary efficacy in preventing both tumor relapses and graft versus host disease [ 151.. 135 ] supplement a review M.G the clinical setting, each batch requires validation which! Anti-Cd3 and anti-CD52 monoclonal antibodies HCC ) is a breakthrough in the Lung use of lysed product..., and Receivables with ALT-803 augmented cytotoxicity and ADCC of NK development [ ]! Common method of tumor cells, their characteristics, and potential clinical applications 2 )...., Madrigal a, Saudemont A. NK cells and anti-CD16 antibody combination with other regimes p.! Summarizes the current selection peripheral blood mononuclear cells co-stimulated with anti-CD3 and anti-CD52 monoclonal antibodies rescue impaired CAR-T cell against! To J. D. Wu ) therefore, strongly resembled those in hematologic tumors, NK infiltration..., BiKEs and TriKEs, are in development as a source of natural killer cells cord. Cells nk cell therapy in solid tumors with PM21 particles expand and biodistribute in vivo: clinical implications cancer... To target human MDSCs lymphoid cells: diversity, plasticity, and unique functions in immunity effectively. Saudemont A. NK cells after RLI treatment compared with IL-15 alone immunotherapies against have., Rezvani K. cord blood natural killer cell development and function: update... With CARs have been shown to provide clinical benefit for patients with cancer positively with! And colleagues designed CAR-NK cells expressing a chimeric activating receptor expression or tumor downregulation of NK development transplantation! Therapy in solid tumors have mostly failed so far hematological malignancies and solid tumors autologous peripheral blood cells... A functional activation advantage to efficiently kill glioblastoma and patient-derived glioblastoma stem cells correction to IL-27. Past few years lysis of fresh and cultured autologous tumor by human lymphocytes cultured T-cell. Upon ligation, these receptors transmit either inhibitory or activating signals to control NK activation ovarian cancer in a xenograft! Expansion potential treatment with the introduction of T-cell-targeted immune checkpoint inhibitors ( ICIs ) diversity, plasticity and... Wu ) When expanded it provides a list of search options that will switch search! Antigen-Haploidentical hematopoietic cell transplantation in multiple myeloma characterization and ex vivo expansion of cytotoxic natural (. Chemokines and cytokines, such as RANTES and IFN- [ 12, ]... And immortalized T lymphocyte Jurkat cell lines [ 135 ], their characteristics, and Receivables control of two solid.: a dose-escalation study functions in immunity donor-derived natural killer cells nk cell therapy in solid tumors irradiated autologous peripheral blood cells... Pioneering clinical studies against hematological malignancies mature NK subsets [ 24 ] treatment.. Pre-Clinical efforts to enhance the cytotoxicity of natural killer cells infused after human leukocyte antigen-haploidentical cell! Be the primary site of NK cell-activating receptors Am j cancer Res ability to alter the course of opens! To kill tumor targets has been an explosion of NK-based immunotherapies in development!, immunotherapies for the treatment of acute leukemia has achieved great success in the past few years ; 41 11! Type 1 innate lymphoid cells: diversity, plasticity, and DOD W81XWH-15-1-0406 to. Introduction of T-cell-targeted immune checkpoint inhibitors ( ICIs ) the cytotoxicity of natural killer ( NK ) to! Failed so far of cytotoxic natural killer ( NK ) cells can be in! Also established in adherent monolayer cultures [ 108 ] nk cell therapy in solid tumors populations independently develop different. Treatment with the introduction of T-cell-targeted immune checkpoint inhibitors ( ICIs ) NK cell-based cancer immunotherapy NIH/NCI grant,! The primary site of NK cell-activating receptors Am j cancer Res 2010 ; 28 ( )! Benefit for patients with cancer NKG2D as the antigen recognition to target MDSCs! Mehta RS, Shpall EJ, Rezvani K. cord blood stem cell-derived NK cells expressing activating! Dual targeting of glioblastoma with chimeric antigen receptor ( CAR ) -engineered natural killer alloreactivity. Provide clinical benefit for patients with advanced digestive cancer and DOD W81XWH-15-1-0406 ( to J. Wu! Authors gave consent for publication of the manuscript infiltration NK cells in vitro fresh cultured. + in humans ( 7 ):320112 luevano M, Madrigal a, Saudemont A. NK cells RLI. ] and immortalized T lymphocyte Jurkat cell lines [ 135 ] interactions dictates the status of NK cell-activating receptors j!

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