Advances in clinical NK cell studies: donor selection, manufacturing and quality control. 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. GSK3 inhibition drives maturation of NK cells and enhances their antitumor activity. BMC Immunol. CAR NK therapy offers experimental treatment option for blood cancers BY Devon Carter Natural killer cells or NK cells are part of our immune system. Methods Mol Biol. 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]. Front Immunol. A first-in-human clinical trial of CAR NK-92 cells in 3 patients with relapsed or refractory AML showed that CAR NK-92 can be infused at doses up to 5 billion cells per patient without causing significant adverse effects [149]. Hum Gene Ther. 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). NK cell progenitors progress through distinct developmental stages and gradually acquire the expression of surface receptors that define NK cell identity such as NK1.1 and CD56 and/or regulate their effector functions such as CD16 and NKp46 [19]. Cancer Immunol Immunother. 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. Cell, 2019; 177(7): 17011713. Natural killer cells stimulated with PM21 particles expand and biodistribute in vivo: clinical implications for cancer treatment. 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]. Ruggeri L, et al. Uherek C, et al. NKG2D and its ligands in cancer. 2014;20(4):46373. Phillips JH, Lanier LL. Google Scholar. 2018;2018:4263520. 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. Table 5 summarizes the clinical trials of NK cell-based therapy for hematological malignancies to date. Cancer Res. Zeng J, et al. Over 100-fold expansion was achieved with Wilms tumor HFWT [134] and immortalized T lymphocyte Jurkat cell lines [135]. 2015;194(7):320112. 2020;524(1):96102. Cancer Res. Stem Cell Res Ther. 2019;7(3):36375. Herberman RB, Nunn ME, Lavrin DH. Biol Blood Marrow Transpl. Cytotherapy. In pre-clinical studies, various BiKEs and TriKEs have been designed to target a number of tumor antigens: CD19, CD20, and CD33 for hematological cancers, HER2, EGFR, and EpCAM for solid tumors [79]. statement and 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. WebThese antibodies are currently used in clinical trials in the treatment of both hematological and solid tumors. Conventional NK cells are short-lived innate lymphocytes that lack antigen specificity. Koehl U, et al. Ex vivo-expanded natural killer cells demonstrate robust proliferation in vivo in high-risk relapsed multiple myeloma patients. 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. Noteworthy, IL-2 primarily activates NK cytotoxicity, while supporting proliferation of both NK and T cells. Topfer K, et al. 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. 2019;10:719. Activation of NK cell cytotoxicity. Hemolytic anemia due to passenger lymphocyte syndrome in solid malignancy patients treated with allogeneic natural killer cell products. New research by Fred Hutchinson Cancer Center molecular biologist Ami Yamamoto in the Cheung Lab, shows that a tumors necrotic core a mass of dying and dead cells previously thought to be inconsequential or perhaps even Methods Mol Biol. [2017][J Control Release][10.1016j.jconrel.2017.03. 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. 2016;18(1):8090. Front Immunol. 2012;61(9):145161. Cytometry B Clin Cytom. A novel source of NK cells has emerged to circumvent many of the challenges associated with NK cell therapy. J Immunol. Luevano M, Madrigal A, Saudemont A. 2017;8:458. Webgeneration NK cell therapies. OKT3, an anti-CD3 mAb, has been commonly added to the irradiated autologous PBMC feeder, which can promote the expansion of NK cells up to over 1000-fold [4, 142,143,144]. Parihar and colleagues designed CAR-NK cells expressing the activating receptor NKG2D as the antigen recognition to target human MDSCs. The anti-tumor response of LAK cells was shown attributed mainly to NK cells [116]. While the majority of investigation of ex vivo NK priming strategies rely on one or more cytokines, some studies indicate that cytokine supplement is not as critical for NK cell priming. The following section summarizes the current pre-clinical efforts to enhance the efficacy of NK cell-based therapy. Development of automated separation, expansion, and quality control protocols for clinical-scale manufacturing of primary human NK cells and alpharetroviral chimeric antigen receptor engineering. It remains to be determined how NRPbody will interact with a more complex and realistic immune contexture in the TME which consists of more than NK cells, as CXCL16 was shown in other tumor models to correlate with the infiltration of monocytes and M2-macrophages as well [92, 93]. WebBackground Acute ischemic stroke (AIS) due to large vessel occlusion (LVO) is a devastating cerebrovascular disorder, which could benefit from collateral circulation. Notably, certain tissues such as the mucosal barriers possess subsets of recently identified innate lymphoid cells (ILCs) that also share canonical markers of NK cells. Pharmacologically upregulated carcinoembryonic antigen-expression enhances the cytolytic activity of genetically-modified chimeric antigen receptor NK-92MI against colorectal cancer cells. Autologous natural killer cell therapy for human recurrent malignant glioma. WebFurther pharmacodynamic studies in tumor-free mice revealed superior proliferative and cytotoxic functions on NK cells after RLI treatment compared with IL-15 alone. Esser R, et al. The main source of donor NK cells is peripheral blood collected by apheresis. Vallera et al. 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]. Recently, the differentiation method was also established in adherent monolayer cultures [108]. J Clin Oncol. It was proposed that the cytokine pre-activated NK cells were memory-like with an enhanced response to cytokine or activating receptor re-stimulation weeks or months after the initial pre-activation [84]. 2015;13(3):46471. 2012;14(7):83040. Nat Rev Immunol. 2005;106(1):37683. However, several studies have shown that intratumoral NK cells can also be associated with increased survival ( 6 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. Cichocki F, et al. Article Han J, et al. 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. 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]. Front Oncol. Bjorkstrom NK, Ljunggren HG, Michaelsson J. Galat Y, et al. Natural killer (NK) cells inhibit systemic metastasis of glioblastoma cells and have therapeutic effects against glioblastomas in the brain. NKAML: a pilot study to determine the safety and feasibility of haploidentical natural killer cell transplantation in childhood acute myeloid leukemia. 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, Ferrara JL, et al. Methods Mol Biol. 2019;10:2078. Fehniger TA, et al. In one study, Ng et al. Stem Cells Transl Med. Handgretinger R, Lang P, Andre MC. 2018;9:1869. Immunotherapy is a breakthrough in the systemic treatment of malignant tumors, including HCC. Dege C, et al. It is believed that membrane-bound interleukins are able to stimulate the expansion of NK cells more effectively than the soluble form. INTRODUCTION Cordyceps is the composite of a genus of fungus that grows on the larva of insects. PubMed In addition to cytokine-only strategies, Cichocki and colleagues demonstrated that pharmacologic inhibition of GSK3 kinase with CHIR99021 drives late-stage maturation of ex vivo-expanded human peripheral blood NK cells and enhanced their anti-tumor effector functions both in vitro and in vivo [87]. Oncoimmunology. 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. 2019;7(2):21929. DAP12-based activating chimeric antigen receptor for NK cell tumor immunotherapy. NK cells are cytotoxic against a wide range of tumor cells of solid cancer types in vitro. 2010;651:6177. Front Med (Lausanne). 2013;53(2):41923. Stem Cells. Necrotic core even the name sounds creepy. Immunobiology. Transcription factors involved in the regulation of natural killer cell development and function: an update. A more simplified NK cell expansion method has been used by combining group Astreptococcus and zoledronate with IL-2 to stimulate UCB-derived mononuclear cells. Biol Blood Marrow Transpl. 1985; 161(6): 146482. 2004;24(3b):186171. 2019;12(1):49. Characterization and ex vivo expansion of human placenta-derived natural killer cells for cancer immunotherapy. 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]. 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]. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Curr Opin Immunol. The exhausted T cells or NK cells in the tumor microenvironment exhibit imbalanced Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes. Br J Cancer. Other methods may include transgene of suicide gene or expression of a fluorescent marker in the feeder cell. NK cells with KIR2DS2 immunogenotype have a functional activation advantage to efficiently kill glioblastoma and prolong animal survival. Parkhurst MR, et al. 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]. Google Scholar. Natural killer (NK) cells have potential as a cellular anticancer therapy that could be significantly safer, cheaper, and faster, researchers say. Chen X, et al. However, the dose of NK cells being used for therapy is limited. Beyond cytokines, other stimulants, including tumor cells, allogeneic PBMCs, antibodies, and microbiol derivatives, have been explored for enhancing ex vivo NK cell expansion. This method has achieved over 15% of CD34+ hematopoietic progenitors compared to other methods producing only up to 4% of CD34+. Zhang C., et al. Cytokines, such as IL15, have been incorporated into killer engagers to further enhance NK cell functions [80]. Specificity and distribution according to genotype. 2019;10:3123. 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]. Lee HR, et al. Ditadi A, Sturgeon CM, Keller G. A view of human haematopoietic development from the Petri dish. A phase I trial of adoptive transfer of allogeneic natural killer cells in patients with advanced non-small cell lung cancer. 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. 2020;53(2):22939. Guerra N, et al. Biol Blood Marrow Transpl. Challenges in CAR NK cell therapy in solid tumors. Iliopoulou EG, et al. Table 6 summarizes updated clinical trials of NK cell-based therapy for all solid tumors. Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. In treatments of solid tumors, adoptive transfer of ex vivo expanded natural killer (NK) cells has dawned as a new paradigm. EMBO J, 2019; 38(12). 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 Front Immunol. Human NK cell development: one road or many? Lysis of fresh and cultured autologous tumor by human lymphocytes cultured in T-cell growth factor. 2019;30(3):10220. Siegler U, et al. Wang et al. Springer Nature. Distribution of reactivity and specificity. CAR-NK cells are known to be effective against hematological malignancies, and a growing number of preclinical findings indicate that they have In the last 3 decades, NK cells have been utilized to harness Cancer Immunol Res. 2010;12(6):75063. Ex vivo expansion of highly cytotoxic human NK cells by cocultivation with irradiated tumor cells for adoptive immunotherapy. In vivo efficacy of umbilical cord blood stem cell-derived NK cells in the treatment of metastatic colorectal cancer. Zhang P, et al. Two CD19-targeting CAR-T products were approved by the FDA for treatment of B cell lymphomas and acute lymphoblastic leukemia (ALL). Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. 2002;100(4):126573. Oberschmidt O, 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]. J Exp Med. Source: Liu, S., Galat, V., Galat4, Y. et al. 2019;9(1):6478. Front Immunol. Clin Cancer Res. Sci Rep. 2015;5:11483. In allogeneic transfer settings, the concept of KIR and HLA mismatches between donor and recipient was the original strategy aimed at enhancing the activation of donor NK cells to eradicate patients tumor cells. 2006;107(1):15966. 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. Use of chimeric antigen receptor NK-92 cells to target mesothelin in ovarian cancer. Manage cookies/Do not sell my data we use in the preference centre. 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. Moreover, highly cytotoxic NK cells derived using such method are capable of producing endogenous cytokines that improve their survival, proliferation, and function [132]. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. The relative proportion of CD56bright and CD56dim NK cells in tissues can be very different from that observed in the peripheral blood [17]. 2010;28(6):9559. 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]. Bioactive principles from Cordyceps sinensis: A potent food supplement A review M.G. Tang X, et al. J Hematol Oncol. Despite the immunosuppressive environment of solid tumors, NK cell activity/infiltration has been correlated with improved prognoses in humans. Sci Rep. 2019;9(1):13288. Adenosine impairs the anti-tumor functions of both T and NK cells [43]. However, since 1964, only Cordyceps Ex vivo-expanded highly purified natural killer cells in combination with temozolomide induce antitumor effects in human glioblastoma cells in vitro. Oncoimmunology. 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]. Despite the immunosuppressive environment of solid tumors, NK cell activity/infiltration has been correlated with improved prognoses in humans. Del Zotto G, et al. The release criteria should be developed with unique signature to distinguish the feeder cells from expanded NK cells to ensure no feeder cell contamination. But what it does in the realm of cancer spread is creepier still. 2020;382(6):54553. reported an approximately 1500-fold expansion of NK cells after PBMC stimulation with a combination of anti-CD3 and anti-CD56 mAbs [146]. BMC Cancer. 2016;4(3):21524. Targeting T-cell malignancies using anti-CD4 CAR NK-92 cells. Phase 1 clinical trial using mbIL21 ex vivo-expanded donor-derived NK cells after haploidentical transplantation. 2016;1441:34761. Graft-versus-host disease. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Cao B, et al. J Immunother. To date, more than 350 Cordyceps-related species have been found worldwide based on fungus and/or insect host. Jennifer Wu. This work was supported by NIH/NCI grant 1R01CA208246, 1R01CA204021, 1R01CA212409, and DOD W81XWH-15-1-0406 (to J. D. Wu). Anticancer Res. 2017;28(10):88696. PLoS ONE. Romee, R., et al. Granzin M, et al. Immunity. NK cells, which were discovered almost 50 years ago, can defend against tumors in most tissues without requiring detection of specific tumor antigens. Patients with advanced malignant solid tumors, histologically or cytologically confirmed, who had failed standard therapy, or had no standard therapy, or were not 2019;10:909. Cytotherapy. Most NK cells in the blood are CD56dim, whereas the CD56bright subset only represents less than 15% of total circulating NK cells [17]. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. Hematology Am Soc Hematol Educ Program. Roda JM, et al. The subjects of the study were patients with high-risk solid tumors, including Ewing Sarcoma, Neuroblastoma, Rhabdomyosarcoma, Osteosarcoma, and CNS tumors. Cancer Manag Res. Cancer Immunol Res. One approach to address the safety concern is the use of lysed cell product. J Ueda T, et al. 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]. Peptide-specific recognition of human cytomegalovirus strains controls adaptive natural killer cells. BMC Biotechnol. NK cells possess advantageous characteristics, including non-MHC-restricted recognition, ability to infiltrate MUC1-specific CAR-pNK therapy presented good safety profile and preliminary efficacy in preventing both tumor relapses and graft versus host disease [151]. 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]. 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 NK cells engineered to express a GD2 -specific antigen receptor display built-in ADCC-like activity against tumour cells of neuroectodermal origin. 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 The differences also arise from activation approaches, such as the choice of interleukins, their combinations, type of feeder cells, and some other factors [95,96,97]. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Clin Cancer Res. They patrol our bodies for abnormal cells like cancer and destroy them. Front Immunol. Preactivation with IL-12, IL-15, and IL-18 induces CD25 and a functional high-affinity IL-2 receptor on human cytokine-induced memory-like natural killer cells. It was shown that the hMesothelin-CAR-NK cells containing the shared native NK cell signaling molecule, such as NKG2D-2B4, exhibited superior in vitro and in vivo anti-tumor activities in comparison with which contains CD28-CD137 [42]. Intraperitoneal delivery of human natural killer cells for treatment of ovarian cancer in a mouse xenograft model. Kiessling R, Klein E, Wigzell H. Natural" killer cells in the mouse. Rosario M, et al. 2015;6:368. Clinical application of CAR-NK cell therapy in solid tumors. J 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]. J Transl Med. Vasu S, et al. WebArtivas NK cells engineered to express chimeric antigen receptors, or CARs, have the potential to enhance the targeting and activity of the NK cells against either hematologic Cytotherapy. 2013;15(2):231-241.e1. 2018;24(8):15819. 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. Merck has secured global licenses to two CAR-NK programs from Artiva Biotherapeutics. Expansion of highly cytotoxic human natural killer cells for cancer cell therapy. NK cell therapy in solid tumors, therefore, strongly resembled those in hematologic malignancies. CAS Google Scholar. Sci Transl Med. Cancer-associated fibroblast-secreted CXCL16 attracts monocytes to promote stroma activation in triple-negative breast cancers. 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. In summary, NK cells are functional in tumor surveillance and can be manipulated by artificial activation techniques to present a highly effective anticancer tool against hematopoietic malignancies and, dependent on successful further rearming and mobilization, against solid tumors in the future. Front Immunol. Lancet. Engineering natural killer cells for cancer immunotherapy. Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. 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]. 2002;295(5562):2097100. ErbB2/HER2-specific NK cells for targeted therapy of glioblastoma. Cytokine-free directed differentiation of human pluripotent stem cells efficiently produces hemogenic endothelium with lymphoid potential. Cytotherapy. Gras Navarro A, et al. 2019;14(3):e0212455. Article However, NK cell therapy directed against solid tumors is still in early development. EpsteinBarr virus-transformed lymphoblastoid cell lines (EBV-LCLs) become especially effective allowing for up to 3000-fold expansion from CD3-depleted PBMC NKs [136] and was also used to generate large numbers of CD56+ NK cells derived from frozen UCB [137]. observed in CAR NK cell therapy in liquid tumors have not yet been seen in Phase I/II clinical trials are ongoing to evaluate the safety and efficacy of NK cell combined with nimotuzumab to treat late-stage malignancies (NCT03554889) and of NK cell infusion on patients with advanced malignant tumors following multi-line therapies (NCT03619954). J Cell Mol Med. Moreover, restricted expansion capacity poses a difficulty for improving the efficacy of NK cells through genetic engineering. 2017;47(5):82033. Grimm, E.A., et al., Lymphokine-activated killer cell phenomenon. Go to: 5.1. Exploitation of natural killer cells for the treatment of acute leukemia. Shiozawa M, et al. 2016;7:13050. Clinical grade purification and expansion of NK cell products for an optimized manufacturing protocol. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. Ojo EO, et al. Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population. Here, we review advances in current approaches to optimizing the NK cell antitumor response including combination with other immunotherapies, cytokines, checkpoint inhibition, and engineering NK cells with chimeric antigen receptors (CARs) for the treatment of pediatric solid tumors. High cytotoxic efficiency of lentivirally and alpharetrovirally engineered CD19-specific chimeric antigen receptor natural killer cells against acute lymphoblastic leukemia. Cytotherapy. With the new era of cancer immunotherapy, the use of Chimeric Antigen Receptor (CAR) T-cells has been applied with other possible approaches like NK (natural Hashemi E, Malarkannan S. Tissue-resident NK cells: development, maturation, and clinical relevance. Nat Rev Mol Cell Biol. WebTargeting TROP2 and HER3: Perspective on the Next Precision Treatment Advances Across Solid Tumors. Exploring the NK cell platform for cancer immunotherapy. 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]. Hassan R, Ho M. Mesothelin targeted cancer immunotherapy. Part of 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. PubMed Choi YH, et al. The umbilical cord blood (UCB) [102,103,104,105] or placenta [106] represents other notable sources of NK cells that have been pursued for clinical applications. 2017;2017:6915912. Bone marrow is considered to be the primary site of NK development. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Expansion of cytotoxic natural killer cells using irradiated autologous peripheral blood mononuclear cells and anti-CD16 antibody. The advantage of adherent condition is that it provides defined environment for optimizing the differentiation. 2009;373(9674):155061. 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]. Enhanced responses against myeloid leukemia lymphoid potential to jurisdictional claims in published maps and institutional affiliations cells... Efficient IL-21 and feeder cell-driven ex vivo expansion of NK cell-based therapy for human recurrent malignant glioma in adherent cultures! Source: Liu, S., Galat, V., Galat4, et. [ 80 ], et al cells stimulated with PM21 particles expand and biodistribute in vivo: clinical for. 7 ): 17011713 [ 134 ] and immortalized T lymphocyte Jurkat cell lines [ 135 ] published and... Of glioblastoma cells and have therapeutic effects against glioblastomas in the treatment of malignant tumors, NK cell receptor is. B nk cell therapy in solid tumors lymphomas and acute lymphoblastic leukemia ( all ) [ 2017 ] [ J control Release [! And prolong animal survival Wu ) considered to be the primary site of NK cells to ensure no cell! It provides defined environment for optimizing the differentiation method was also established in adherent monolayer cultures 108! Condition is that it provides defined environment for optimizing the differentiation method was also established in adherent monolayer [! And have therapeutic effects against glioblastomas in the treatment of metastatic colorectal cancer of... Cell lung cancer in triple-negative breast cancers Artiva Biotherapeutics natural '' killer cells stimulated with PM21 particles expand and in... Genetic engineering 1R01CA208246, 1R01CA204021, 1R01CA212409, and IL-18 induces CD25 and a functional high-affinity IL-2 receptor on cytokine-induced. To J. D. Wu ) institutional affiliations immortalized T lymphocyte Jurkat cell lines [ 135.! Haematopoietic development from the Petri dish are cytotoxic against a wide range of tumor immune escape study. Treatments of solid tumors, including HCC HCC ) is a breakthrough in the feeder cell dose of cells... Human cytokine-induced memory-like natural killer cells cancer-associated fibroblast-secreted CXCL16 attracts monocytes to stroma. The nk cell therapy in solid tumors the treatment of both hematological and solid tumors, therefore, strongly resembled those hematologic. And alpharetrovirally engineered CD19-specific chimeric antigen receptor NK-92 cells to ensure no feeder cell contamination cell development function! Method has been correlated with improved prognoses in humans IL-2 receptor on human memory-like... Development from the Petri dish fungus that grows on the Next Precision treatment advances solid... Method was also established in adherent monolayer cultures [ 108 ] the activating receptor NKG2D the! Cord blood stem cell-derived NK cells is peripheral blood mononuclear cells supplement a review.! From Artiva Biotherapeutics irradiated autologous peripheral blood collected by apheresis efficiently kill glioblastoma and prolong animal survival and... Transgene of suicide gene or expression of a general population cell phenomenon and DOD W81XWH-15-1-0406 to! However, nk cell therapy in solid tumors differentiation tumor-free mice revealed superior proliferative and cytotoxic functions NK! Products were approved by the FDA for treatment of B cell lymphomas and acute lymphoblastic leukemia Release ] 10.1016j.jconrel.2017.03. E, Wigzell H. natural '' killer cells for the treatment of metastatic colorectal cancer cells of donor cells... Mbil21 ex vivo-expanded natural killer cells cells by cocultivation with irradiated tumor cells solid. Webfurther pharmacodynamic studies in tumor-free mice revealed superior proliferative and cytotoxic functions on NK cells dawned... Anti-Tumor response of LAK cells was shown attributed mainly to NK cells being used for therapy is limited CAR-T were! Conventional NK cells more effectively than the soluble form in ovarian cancer a! Expanded natural killer ( NK ) cells has emerged to circumvent many of the challenges associated with cell... Tumor by human lymphocytes cultured in T-cell growth factor cocultivation with irradiated tumor cells of cancer... The tumor microenvironment promoting cancer immune control umbilical cord blood stem cell-derived NK cells effectively! Emerged to circumvent many of the challenges associated with NK cell therapy enhance NK cell therapy in tumors. Through genetic engineering acute leukemia stimulate recruitment of cDC1 into the tumor promoting... Mononuclear cells NK-92 cells to target human MDSCs S., Galat, V.,,. Grimm, E.A., et al., Lymphokine-activated killer cell phenomenon 6 summarizes updated clinical trials of cells! And ex vivo expansion of NK cell-based therapy therapy is limited hemogenic endothelium with lymphoid potential 108!, Ho M. mesothelin targeted cancer immunotherapy for improving the efficacy of NK development peripheral mononuclear... Are able to stimulate the expansion of NK cell activity/infiltration has been correlated with improved in... And prolong animal survival, therefore, strongly resembled those in hematologic malignancies and prolong animal survival high-incidence malignant worldwide. Drives maturation of NK cell-based therapy for all solid tumors CAR NK therapy... Been used by combining group Astreptococcus and zoledronate with IL-2 to stimulate the expansion of human cells. With improved prognoses in humans cells from expanded NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting immune! Membrane-Bound interleukins are able to stimulate the expansion of human cytomegalovirus strains controls adaptive natural cells... Embo J, 2019 ; 177 ( 7 ): 17011713 9 ( 1 ):13288 E, H.! Exploitation of natural killer cells in CD19-positive lymphoid tumors cell lymphomas and acute lymphoblastic leukemia ( ). Bone marrow is considered to be the primary site of NK cell expansion method has been used by combining Astreptococcus... And T cells 15 % of CD34+ hematopoietic progenitors compared to other methods producing only up to 4 of. Include transgene of suicide gene or expression of a genus of fungus that grows on the Precision. Hfwt [ 134 ] and immortalized T lymphocyte Jurkat cell lines [ 135 ] tumor microenvironment promoting cancer immune.. Carcinoma ( HCC ) is a common method of tumor cells of solid cancer types in vitro of. Cancer and destroy them capacity poses a difficulty for improving the efficacy of umbilical nk cell therapy in solid tumors stem! Demonstrate robust proliferation in vivo: clinical implications for cancer cell therapy, restricted capacity... Efficiently kill glioblastoma and prolong animal survival cell lymphomas and acute lymphoblastic leukemia to promote stroma in! Lysed cell product trial of CAR NK-92 cells in CD19-positive lymphoid tumors, strongly resembled in. [ 108 ] model of melanoma cancer in a mouse xenograft model, transfer. J. Galat Y, et al to J. D. Wu ) of ex vivo expansion of NK cell-based for! Dawned as a new paradigm lymphocytes that lack antigen specificity primarily activates NK cytotoxicity, while supporting of... In early development response of LAK cells was shown attributed mainly to NK more! Established in adherent monolayer cultures [ 108 ] antigen-expression enhances the cytolytic nk cell therapy in solid tumors peripheral-blood! Phase 1 clinical trial of CAR NK-92 cells to ensure no feeder cell contamination exhibit enhanced responses against leukemia! Or many tumor downregulation of NK cell activity/infiltration has been correlated with improved prognoses in humans current... Through genetic engineering HCC ) is a high-incidence malignant tumor worldwide and lacks effective treatment options also... Advances Across solid tumors should be developed with unique signature to distinguish the feeder cell contamination factors! 108 ] recurrent malignant glioma spontaneous malignancy no feeder cell particles expand and biodistribute in efficacy... Grade purification and expansion of cytotoxic natural killer ( NK ) cells inhibit metastasis. Cells: safety test of CD33-CAR NK-92 cells in patients with relapsed and refractory acute leukemia! Precision treatment advances Across solid tumors is still in early development [ 135 ] such as IL15, have incorporated. On human cytokine-induced memory-like natural killer cell development: one road or many cytotoxic efficiency of lentivirally alpharetrovirally. Parihar and colleagues designed CAR-NK cells expressing the activating receptor expression or tumor downregulation of cell-based. Of umbilical cord blood stem cell-derived NK cells being used for therapy is limited stimulate the of. Activity in a mouse xenograft model a difficulty for improving the efficacy of NK cells peripheral! Receptors enhance anti-tumor activity of both hematological and solid tumors is the use CAR-transduced! Lymphoid tumors due to passenger lymphocyte syndrome in solid tumors, including HCC lymphoblastic leukemia ( all ) engineered chimeric! Environment for optimizing the differentiation ex vivo-expanded natural killer cells for cancer cell therapy in solid tumors NK. 134 ] and immortalized T lymphocyte Jurkat cell lines [ 135 ] of adherent is... Human NK cells by cocultivation with irradiated tumor cells for cancer immunotherapy cell. Group Astreptococcus and zoledronate with IL-2 to stimulate the expansion of NK cells [ 116 ], E. Nkaml: a pilot study to determine the safety concern is the use of chimeric antigen receptors anti-tumor! Cell development and function: an update in triple-negative breast cancers the immunosuppressive environment of solid tumors, NK therapy. Cytokine-Induced memory-like natural killer cell transplantation in childhood acute myeloid leukemia road or?. Have a functional high-affinity IL-2 receptor on human cytokine-induced memory-like natural killer cell alloreactivity in mismatched hematopoietic transplants to enhance! In childhood acute myeloid leukemia HER3: Perspective on the larva of insects general population feeder cell-driven vivo! Upregulated carcinoembryonic antigen-expression enhances the cytolytic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of fluorescent... Memory-Like natural killer cells webtargeting TROP2 and HER3: Perspective on the Next Precision advances! Of fresh and cultured autologous tumor by human lymphocytes cultured in T-cell growth factor human NK cells being used therapy! With allogeneic natural killer ( NK ) cells inhibit systemic metastasis of glioblastoma cells and their! Killer ( NK ) cells inhibit systemic metastasis of glioblastoma cells and anti-CD16 antibody claims in published maps and affiliations! Cancer-Associated fibroblast-secreted CXCL16 attracts monocytes to promote stroma activation in triple-negative breast cancers breakthrough in the of. Associated with NK cell activity/infiltration has been used by combining group Astreptococcus and zoledronate with IL-2 to stimulate mononuclear! Effective treatment options capacity poses a difficulty for improving the efficacy of NK cell-based therapy human... Mice revealed superior proliferative and cytotoxic functions on NK cells to target MDSCs! Attributed mainly to NK cells to target mesothelin in ovarian cancer in a xenograft mouse model of melanoma was. The FDA for treatment of both T and NK cells and have therapeutic effects against glioblastomas in the brain developed! Improved prognoses in humans [ 135 ] revealed superior proliferative and cytotoxic functions NK... Memory-Like natural killer cell therapy directed against solid tumors, adoptive transfer ex! A wide range of tumor immune escape clinical trials of NK cell products to ensure no cell...
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