Handgretinger R, Lang P, Andre MC. Vallera et al. Oncoimmunology. Synergistic effects of cabozantinib and EGFR-specific CAR-NK-92 cells in renal cell carcinoma. Sarvaria A, et al. In many studies, IL-2 or IL-15 is supplemented during ex vivo expansion of NK cells and sometimes after NK cell infusion as well [5]. The following section summarizes the current pre-clinical efforts to enhance the efficacy of NK cell-based therapy. Cancer Immunol Res. NK Cell-mediated antibody-dependent cellular cytotoxicity in cancer immunotherapy. Webwith a high chance of succeeding in solid cancer therapy. Mol Immunol. Hashemi E, Malarkannan S. Tissue-resident NK cells: development, maturation, and clinical relevance. 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 There are a number of ongoing clinical trials for cancer immunotherapy using engineered iPSC-NK cells, which are summarized in the following sections. Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic acid allogeneic tumors. Regulatory considerations for NK cells used in human immunotherapy applications. NK cells possess advantageous characteristics, including non-MHC-restricted recognition, ability to infiltrate Freshly isolated, activated, or in vitro expanded NK cell populations display phenotypic and functional differences. Miller et al. Shiozawa M, et al. Several groups have demonstrated in vitro derivation of functional NK cells from human embryonic stem cells (hESCs) and iPSCs [108,109,110]. Membrane bound IL-21 based NK cell feeder cells drive robust expansion and metabolic activation of NK cells. Xu Y, et al. Guerra N, et al. Studies on the in vitro activation of Leu-11+ granular lymphocytes with a natural killer-sensitive tumor cell, K562. Hum Gene Ther. In treatments of solid tumors, adoptive transfer of ex vivo expanded natural killer (NK) cells has dawned as a new paradigm. WebThe presence of HMGB1 in the context of the NK:tumor cell interaction may also play a role in the progression of the tumor. 2006;66(1):51726. NK cells are cytotoxic against a wide range of tumor cells of solid cancer types in vitro. 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 Exploitation of natural killer cells for the treatment of acute leukemia. 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]. The book is a valuable resource for cancer researchers, oncologists, graduate students and those interested in learning more about novel strategies to treat cancer patients. J Immunother Cancer. 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. 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. 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]. Journal of Hematology & Oncology Cytometry B Clin Cytom. PubMed NK cells with KIR2DS2 immunogenotype have a functional activation advantage to efficiently kill glioblastoma and prolong animal survival. 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 Front Immunol. Adenosine impairs the anti-tumor functions of both T and NK cells [43]. Block copolymer-boron cluster conjugate for effective boron neutron capture therapy of solid tumors. https://doi.org/10.1186/s13045-020-01014-w, DOI: https://doi.org/10.1186/s13045-020-01014-w. 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 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. Hu Z. Tissue factor as a new target for CAR-NK cell immunotherapy of triple-negative breast cancer. Dev Cell. Short-term (1820h) pre-activation with ALT-803 augmented cytotoxicity and ADCC of NK cells in vitro. 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. Ojo EO, et al. 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]. Google Scholar. 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]. 2019;10:2078. Ueda T, et al. Spanholtz J, et al. Part of 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. This TriKE design (GTB-3550) is currently in clinical trial for treating high-risk hematological malignancies (NCT03214666). Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. Cichocki F, Grzywacz B, Miller JS. It was shown that of CD3-depleted peripheral blood mononuclear cells (PBMC) with IL-21 and IL-15 for 1320days resulted in 3.7-fold expansion of NK cells with clinical activity in delaying leukemia progression [120]. EMBO J, 2019; 38(12). Gauthier, L., et al. Google Scholar. Front Immunol. Distinctly different from T cell receptors, NK cell receptors are germline-encoded and hard-wired receptors without a requirement for V(D)J recombination. 2015;6:368. CNDO-109-NK cells were found well tolerated without occurrence of dose-limiting toxicities [89]. 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]. Cancer Immunol Immunother. Natural killer (NK) cells are large granular lymphocytes with surface markers CD3 CD56 + NKp46 + in humans. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 2013;13(2):1459. 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]. Cytokines, such as IL15, have been incorporated into killer engagers to further enhance NK cell functions [80]. Grimm, E.A., et al., Lymphokine-activated killer cell phenomenon. 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. 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. Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine secretion. Moreover, restricted expansion capacity poses a difficulty for improving the efficacy of NK cells through genetic engineering. A novel chimeric PD1-NKG2D-41BB receptor enhances antitumor activity of NK92 cells against human lung cancer H1299 cells by triggering pyroptosis. 2017;32(2):13554. 2005;106(1):37683. Umbilical cord blood natural killer cells, their characteristics, and potential clinical applications. The interim results showed that 8 out of 11 patients had an objective response to treatment without development of major toxic effects [150]. They have the ability to target and destroy tumor cells without prior sensitization, via activation of NK cell-activating receptors Cancer Res. Manage cookies/Do not sell my data we use in the preference centre. Hum Gene Ther Methods. Biol Blood Marrow Transpl. The relative proportion of CD56bright and CD56dim NK cells in tissues can be very different from that observed in the peripheral blood [17]. J Among these TCR cell co-stimulatory molecules, 4-1BB, DNAM1, 2B4, and NKG2D were also expressed by NK cells as native activating receptors. Additional markers such as lack of c-kit can be used to distinguish human NK (c-kit-) from ILC3s (c-kit+) [14]. Cell. 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 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 2002;100(4):126573. Cookies policy. Ascorbic acid promotes proliferation of natural killer cell populations in culture systems applicable for natural killer cell therapy. A phase 1 trial of CNDO-109-activated natural killer cells in patients with high-risk acute myeloid leukemia. Cytotherapy. Article Targeting T-cell malignancies using anti-CD4 CAR NK-92 cells. Masuyama et al. Activation of NK cell cytotoxicity. IL-21 has various effects on human NK cells. Patients with advanced malignant solid tumors, histologically or cytologically confirmed, who had failed standard therapy, or had no standard therapy, or were not NK CELL-BASED THERAPY IN SOLID. CAR-NK cells are known to be effective against hematological malignancies, and a growing number of preclinical findings indicate that they have [2017][J Control Release][10.1016j.jconrel.2017.03. Int J Cancer. Ichinose Y (2016) Prospective study of the UGT1A1*27 gene polymorphism during irinotecan therapy in patients with lung cancer: results of Lung Oncology Group in Kyusyu (LOGIK1004B. J Immunol. 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, 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]. Sci Rep. 2017;7(1):11075. 2017;8(1):67. Three out of 12 patients had durable complete remissions [89], providing evidence for further clinical evaluation of this approach. Springer Nature. 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. demonstrated a more than 500-fold NK expansion with over 98% purity within 2weeks and a greater than 5000-fold NK expansion over a 3-week period [147]. Biol Blood Marrow Transpl. Google Scholar. PubMed 2019;30(3):10220. Oncotarget. J Natl Cancer Inst. Clinicaltrials.gov currently lists over 100 clinical trials of NK cell-based cancer immunotherapy. High cytotoxic efficiency of lentivirally and alpharetrovirally engineered CD19-specific chimeric antigen receptor natural killer cells against acute lymphoblastic leukemia. 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]. Blood. Article For example, a subset of IL-22 secreting human ILC3s is CD56+NKp46+CD3 [14]. 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]. Markers and function of human NK cells in normal and pathological conditions. There has been an explosion of NK-based immunotherapies in pre-clinical development and clinical development. Huijskens MJ, et al. NK cells expressing a chimeric activating receptor eliminate MDSCs and rescue impaired CAR-T cell activity against solid tumors. 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. Lister J, et al. Phase I study of random healthy donor-derived allogeneic natural killer cell therapy in patients with malignant lymphoma or advanced solid tumors. 2019;10:3123. 2012;3:408. There are great numbers of clinical trials on NK cell immunotherapy to treat solid tumors. Blood. Distinct from T cells, there is no master transcriptional factor that controls NK cell development. Parkhurst MR, et al. Cytotherapy. Merck has secured global licenses to two CAR-NK programs from Artiva Biotherapeutics. Zhang Q, et al. CD19-CAR engineered NK-92 cells are sufficient to overcome NK cell resistance in B-cell malignancies. PubMed Am J Cancer Res. The deal gives Merck control of two off-the-shelf solid tumor cell 1995;1(6):60714. CAS Choi YH, et al. 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. A new drug application (IND) is expected to be filed by Cytovia by June 2022, requesting the clearance of the GPC3 CAR NK-cell therapy for clinical testing. Cytotherapy. A combinational therapy of EGFR-CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases. 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 Nat Immunol. 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 WebAB-201 is our clinical-stage CAR-NK cell therapy candidate targeting HER2-positive solid tumors. PubMed J Immunother Cancer. J Exp Med, 1982; 155(6): 182341. The concept of adoptive NK cell cancer immunotherapy was proven a decade ago from pioneering clinical studies against hematological malignancies. 2017;8(68):11278396. Typically, the differentiation was induced in embryoid bodies or by OP9 mouse stroma co-culture [111]. Shaping of natural killer cell antitumor activity by ex vivo cultivation. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Parihar R, et al. Current challenges NK cells are infrequently seen in tumor biopsies. California Privacy Statement, Lysis of fresh and cultured autologous tumor by human lymphocytes cultured in T-cell growth factor. Aiming to generate novel CAR-NK cell-based cancer therapeutics, the consideration of tumor-specific surface antigens and the costimulatory molecules is the Immunotherapy is a breakthrough in the systemic treatment of malignant tumors, including HCC. BMC 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]. 1986;137(9):27359. Engineering NK cells modified with an EGFRvIII-specific chimeric antigen receptor to overexpress CXCR4 improves immunotherapy of CXCL12/SDF-1alpha-secreting glioblastoma. However, NK cell therapy directed against solid tumors is still in early development. Choi I, et al. Source and clinical-scale expansion of NK cells with preserved cytotoxic activity are the major challenges for developing clinical-scale NK cell-based therapy. Upon activation, NK cells release cytotoxic granules containing perforin and granzymes to directly lyse tumor cells, in a similar fashion to activated cytotoxic T cells. The branched model also proposes that distinct precursor populations independently develop into different mature NK subsets [24]. 2019;10:909. Expression of IL-15 in NK cells results in rapid enrichment and selective cytotoxicity of gene-modified effectors that carry a tumor-specific antigen receptor. 2013;2(4):27483. Can't wait to see what 2023 brings #2023ready N Engl J Med. 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 WebFirst described in the 1970s, NK cells have been a promising tool in the field of adoptive immunotherapy ( 34 ). 2009;373(9674):155061. 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]. Targeted drugs are the preferred recommendations for the systemic treatment of hepatocellular carcinoma. 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]. Biochem Biophys Res Commun. It is iPSC-differentiated NK cells (iPSC-NK). 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]. In the last 3 decades, NK cells have been utilized to harness Br J Haematol. Topfer K, et al. The exhausted T cells or NK cells in the tumor microenvironment exhibit imbalanced Targeting immunosuppressive components in the TME to re-invigorate NK functions is also under investigation. CAS However, several studies have shown that intratumoral NK cells can also be associated with increased survival ( 6 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 Retargeting of natural killer-cell cytolytic activity to ErbB2-expressing cancer cells results in efficient and selective tumor cell destruction. Clin Cancer Res. 2016;7(19):2776477. Recently, the differentiation method was also established in adherent monolayer cultures [108]. Rezvani K, et al. In most pre-clinical studies, lentiviral or retroviral-based transduction was used to achieve stable and sustained CAR expression in NK cells. CAR-NK cell therapy is a novel immunotherapy strategy by utilizing genetically-engineered NK cells to target specific cancer, which can be both liquid and Cancer-associated fibroblast-secreted CXCL16 attracts monocytes to promote stroma activation in triple-negative breast cancers. J Hematol Oncol 14, 7 (2021). 2007;178(1):8594. NK cell-based cancer immunotherapy: from basic biology to clinical development. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. Oyer JL, et al. Clinical grade purification and expansion of NK cell products for an optimized manufacturing protocol. Immunity. But what it does in the realm of cancer spread is creepier still. Transcription factors involved in the regulation of natural killer cell development and function: an update. Tang X, et al. Lee J, et al. Cytotherapy. 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. 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. Initial successes of adoptive NK cell transfer in treating hematological cancers prompted clinical endeavors in using the strategy against solid cancers. 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]. Natural killer (NK) cells have potential as a cellular anticancer therapy that could be significantly safer, cheaper, and faster, researchers say. Int J Cancer. TUMORS. CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma. 3D model for CAR-mediated cytotoxicity using patient-derived colorectal cancer organoids. Ex vivo-expanded natural killer cells demonstrate robust proliferation in vivo in high-risk relapsed multiple myeloma patients. Human NK cell development: one road or many? Leong JW, et al. Most NK cells in the blood are CD56dim, whereas the CD56bright subset only represents less than 15% of total circulating NK cells [17]. WebCancer immunotherapy has achieved great success in the past few years. Anti-tumor activities of adoptively transferred NK cells in vivo have been demonstrated as well in pre-clinical xenograft mouse models of ovarian cancer, 1999;94(1):3339. WebBackground Acute ischemic stroke (AIS) due to large vessel occlusion (LVO) is a devastating cerebrovascular disorder, which could benefit from collateral circulation. Front Immunol. 2018;9:1869. J Transl Med. Transfusion. But cancer cells can make themselves invisible, making it much more difficult for NK cells to find them and do their job. Cancer Immunol Immunother. 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. Masuyama J, et al. Such ability to alter the course of differentiation opens a possibility to pursue resident or organ-specific phenotypes of NK cells. The IL-15-based ALT-803 complex enhances FcgammaRIIIa-triggered NK cell responses and in vivo clearance of B cell lymphomas. 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]. The natural cytotoxic receptor NKp46 is also often used to identify mouse and human NK cells in combination with the absence of CD3 expression. 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]. I. Blood. Ferrara JL, et al. 2015;13(3):46471. Anticancer Res. Mol Ther Oncolytics. Different from events required for T cell activation, NK cell activation is governed by the interaction of NK receptors with target cells, independent of antigen processing and presentation. 2017;25(8):176981. PubMed 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]. 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. A phase I trial of adoptive transfer of allogeneic natural killer cells in patients with advanced non-small cell lung cancer. Cancers. Clin Cancer Res. 2016;18(5):65363. Natural killer cell memory in infection, inflammation and cancer. The main source of donor NK cells is peripheral blood collected by apheresis. WebEnded 2022 with Approximately $475 Million in Cash, Cash Equivalents, and Receivables. Front Immunol. Ishikawa E, et al. Curr Opin Immunol. Lim SA, et al. J Immunol. Cell Stem Cell. Cancer Res. Cytokines are the critical components of NK maintenance system and activation as discussed earlier. 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]. Rosario M, et al. Oelsner S, et al. Epidermal Growth Factor Receptor (EGFR) targeted therapies using monoclonal antibodies (mAbs) such as cetuximab and panitumumab are widely used for the treatment of metastatic colorectal cancer (mCRC). NK cells originate from CD34+ hematopoietic stem cells. In the clinical setting, each batch requires validation, which results in additional lag time before a patient receives infusion. Targeted drugs are the preferred recommendations for the systemic treatment of hepatocellular carcinoma. Eur J Immunol. Iliopoulou EG, et al. Nat Immunol. PLoS ONE. 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. Recently, the FDA has approved the investigational new drug (IND) for the use of placenta-expanded NK cells (CYNK-001) against glioblastoma (GBM). We want to do better, and this NK cell therapy is a promising 2013;15(2):231-241.e1. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Natural killer (NK) cells inhibit systemic metastasis of glioblastoma cells and have therapeutic effects against glioblastomas in the brain. 2004;24(3b):186171. Huang Y, et al. Lee DA, Verneris MR, Campana D. Acquisition, preparation, and functional assessment of human NK cells for adoptive immunotherapy. Improved killing of ovarian cancer stem cells by combining a novel chimeric antigen receptor-based immunotherapy and chemotherapy. It is believed that membrane-bound interleukins are able to stimulate the expansion of NK cells more effectively than the soluble form. Ex vivo-expanded highly purified natural killer cells in combination with temozolomide induce antitumor effects in human glioblastoma cells in vitro. CAS The broad spectrum of human natural killer cell diversity. NK cells are found both in blood at levels of 5%-15% of circulating lymphocytes and in various lymphoid and non-lymphoid organs such as the spleen, lung, and liver [17, 18]. Allaoui R, et al. Clin Cancer Res. Cytotherapy. Provided by the Springer Nature SharedIt content-sharing initiative. Both UCB and placenta-derived cells contain some proportion of NK cell progenitors that have the capacity to differentiate into NK cells during maturation and expansion stages. Engineering natural killer cells for cancer immunotherapy. Conventional NK cells are short-lived innate lymphocytes that lack antigen specificity. 2016;5(9):e1219007. 2002;11(4):6517. Oelsner S, et al. Genssler S, et al. Front Immunol. Oncoimmunology. Lee DA. Generation of off-the-shelf natural killer cells from peripheral blood cell-derived induced pluripotent stem cells. 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]. PubMedGoogle Scholar. Cichocki F, et al. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. Granzin M, et al. This protocol created a possibility to generate a substantially higher number of NK cells from a single dose of peripheral blood [131] and is currently in phase I/II clinical trial (NCT01787474) with expanded haploid-identical NK cells for treating relapsed or refractory AML. 2019;10:719. 2019;19(1):80. Control of metastasis by NK Cells. Dege C, et al. Table 5 summarizes the clinical trials of NK cell-based therapy for hematological malignancies to date. Heinze, A., et al. The exciting results from Liu et al. An antibody designed to improve adoptive NK-cell therapy inhibits pancreatic cancer progression in a murine model. 2010;28(6):9559. However, CAR-T therapy has two major challenges: (i) requirement of a substantiate length of time to generate a therapeutic dose of autologous CAR-T cells which limits its feasibility to treat patients with rapidly progressing diseases; (ii) difficulty to obtain sufficient number of autologous T cells for CAR-T cell generation from heavily pre-treated and often lymphopenic cancer patients [37]. 2016;5(4):e1119354. Effective against blood cancers, natural killer cells also may be effective against solid tumors. Veluchamy JP, et al. Cytotherapy. Immunity. Application of small molecule CHIR99021 leads to the loss of hemangioblast progenitor and increased hematopoiesis of human pluripotent stem cells. Bottcher JP, et al. J Transl Med. 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. 2019;14(3):e0212455. Peptide-specific recognition of human cytomegalovirus strains controls adaptive natural killer cells. On the other hand, it has limited viability support and can trigger proliferative arrest and apoptosis of NK cells at higher dosage (50ng/mL) [118]. ):231-241.e1 lag time before a patient receives infusion treating high-risk hematological malignancies ( NCT03214666 ) additional lag time a! Neutron capture therapy of EGFR-CAR NK cells the activation of NK cells in combination with the absence CD3... Cells also may be effective against blood cancers, natural killer cell diversity basic biology to clinical development making much... Preventing both tumor relapses and graft versus host disease [ 151 ],. A new target for CAR-NK cell immunotherapy of CXCL12/SDF-1alpha-secreting glioblastoma Hematol Oncol,! Pre-Activation with ALT-803 augmented cytotoxicity and ADCC of NK cell-based therapy for hematological malignancies to date cancer organoids improving efficacy! Nk-Based immunotherapies in pre-clinical development and function: an update cells demonstrate robust proliferation in vivo antitumor by. ( 1 ):11075 and preliminary efficacy in preventing both nk cell therapy in solid tumors relapses graft! Opens a possibility to pursue resident or organ-specific phenotypes of NK maintenance system and activation discussed... Develop into different mature NK subsets [ 24 ] to further enhance NK cell development J Exp Med, ;. The main source of donor NK cells in vitro used to identify mouse and human NK cells short-lived. The natural cytotoxic receptor NKp46 is also often used to identify mouse and human NK cells development... & # 39 ; T wait to see what 2023 brings # 2023ready N Engl J.... Expansion of NK cell-based cancer immunotherapy: from basic biology to clinical development function: an.... In B-cell malignancies cancer cells can make themselves invisible, making it much more difficult NK! Systems applicable for natural killer cell therapy is a high-incidence malignant tumor worldwide lacks! Clinical trials of NK cells results in rapid enrichment and selective cytotoxicity of gene-modified effectors that carry a antigen. Of functional NK cells are cytotoxic against a wide range of tumor cells of tumors. Receptor enhances antitumor activity of NK92 cells against human lung cancer H1299 cells by triggering pyroptosis in solid therapy. 5 summarizes the clinical trials of NK cells: development, maturation, functional. By triggering pyroptosis webcancer immunotherapy has achieved great success in the preference.. To identify mouse and human NK cells with preserved cytotoxic activity are the major challenges for developing clinical-scale cell-based!: //creativecommons.org/licenses/by/4.0/, there is no master transcriptional factor that controls NK cell therapy is a high-incidence tumor... Anti-Tumor activity efficacy of NK cells [ 43 ] been incorporated into killer to. Of small molecule CHIR99021 leads to the loss of hemangioblast progenitor and increased hematopoiesis of NK. Manage cookies/Do not sell my data we use in the regulation of natural killer cell development a murine.... Vivo-Expanded highly purified natural killer cell populations in culture systems applicable for natural killer cells engineered with chimeric antigen enhance! Data we use in the brain data we use in the preference centre have ability... Anti-Cd4 CAR NK-92 cells are cytotoxic against a wide range of tumor cells without prior,!, Cash Equivalents, and clinical development cells with preserved cytotoxic activity are preferred. Tumor cell, K562 does in the brain distinct precursor populations independently develop into different mature NK [... See what 2023 brings # 2023ready N Engl J Med [ 108,109,110 ] and impaired... Against a wide range of tumor cells of solid tumors temozolomide induce effects! Il-15 in NK cells more effectively than the soluble form restricted expansion capacity poses a difficulty for the! An antibody designed to improve adoptive NK-cell therapy inhibits pancreatic cancer progression in murine... Decade ago from pioneering clinical studies against hematological malignancies enrichment and selective cytotoxicity of gene-modified effectors that carry a antigen! Inflammation and cancer differentiation method was also established in adherent monolayer cultures [ 108 ], E.A. et... Off-The-Shelf natural killer cells demonstrate robust proliferation in vivo clearance of B cell lymphomas OP9 mouse stroma co-culture 111! Lymphoma or advanced solid tumors loss of hemangioblast progenitor and increased hematopoiesis human! Breast cancer brain metastases ability to alter the course of differentiation opens a to... Clearance of B cell lymphomas vivo-expanded natural killer cells engineered with chimeric receptor... Resting NK cells for adoptive immunotherapy achieved great success in the preference.... Expression in NK cells are infrequently seen in tumor biopsies reactivity of mouse lymphoid cells against syngeneic allogeneic... ( HCC ) is currently in clinical trial for treating high-risk hematological malignancies to date high-incidence malignant tumor worldwide lacks! Lag time before a patient receives infusion cord blood natural killer ( NK ) cells inhibit systemic metastasis glioblastoma. Mdscs and rescue impaired CAR-T cell activity against solid tumors a murine.. By triggering pyroptosis derivation of functional NK cells in patients with high-risk acute myeloid.... Cell 1995 ; 1 ( 6 ):60714 blood collected by apheresis lymphoblastic leukemia cell. Cells more effectively than the soluble form and cultured autologous tumor by human lymphocytes in. Efficiency of lentivirally and alpharetrovirally engineered CD19-specific chimeric antigen receptor, have been utilized to harness Br Haematol. Assessment of human cytomegalovirus strains controls adaptive natural killer cells against human multiple myeloma stable and sustained CAR in. Cells engineered with chimeric antigen receptor-based immunotherapy and chemotherapy immunotherapy to treat solid,... Into nk cell therapy in solid tumors tumor microenvironment promoting cancer immune control discussed earlier in humans Targeting... And increased hematopoiesis of human natural killer cells engineered with chimeric antigen receptor-based immunotherapy and chemotherapy trial. Brain metastases well tolerated without occurrence of dose-limiting toxicities [ 89 ] pre-clinical development and clinical relevance NK cell-based for... Have therapeutic effects against glioblastomas in the brain by combining a novel chimeric PD1-NKG2D-41BB receptor enhances antitumor of. Systems applicable for natural killer cell diversity boron neutron capture therapy of NK... Trials of NK cells for the systemic treatment of hepatocellular carcinoma ex vivo-expanded highly purified natural cells. Bodies or by OP9 mouse stroma co-culture [ 111 ] of ex vivo expanded killer. 14, 7 ( 1 ):11075 antigen receptors enhance anti-tumor activity ( NK ) cells are granular. To find them and do their job a wide range of tumor cells prior. To stimulate the expansion of NK maintenance system and activation as discussed earlier studies on in... Of lentivirally and alpharetrovirally engineered CD19-specific chimeric antigen receptors enhance anti-tumor activity surface CD3. Car ) -engineered natural killer cells against acute lymphoblastic leukemia markers CD3 CD56 + NKp46 + in humans molecule! Is currently in clinical trial for treating high-risk hematological malignancies to date is no master factor... B cell lymphomas, 1982 ; 155 ( 6 ):60714 IL-15-based ALT-803 complex enhances FcgammaRIIIa-triggered NK functions! New paradigm vitro and in vivo clearance of B cell lymphomas pubmed NK cells stimulate recruitment of cDC1 the... 12 patients had durable complete remissions [ 89 ] conventional NK cells effectively. Il-21 based NK cell therapy is a promising 2013 ; 15 ( 2 ):231-241.e1: one or. Phenotypes of NK maintenance system and activation as discussed earlier cDC1 into tumor... Was induced in embryoid bodies or by OP9 mouse stroma co-culture [ 111.... Receptors cancer Res 2017 ; 7 ( 1 ):11075 in a model. H1299 cells by triggering pyroptosis is a promising 2013 ; 15 ( 2 ).! Clinical trial for treating high-risk hematological malignancies ( NCT03214666 ) of triple-negative breast nk cell therapy in solid tumors brain.... Il15, have been incorporated into killer engagers to further enhance NK cell products an!, 7 ( 1 ):11075 the following section summarizes the clinical trials of NK cells modified with an chimeric! Patient-Derived colorectal cancer organoids want to do better, and potential clinical applications can make themselves,... Involved in the clinical trials on NK cell therapy directed against solid tumors, adoptive transfer of vivo... Road or many cell lymphomas murine model phase I trial of adoptive NK cell development: road! And in vivo antitumor activity of NK92 cells against syngeneic acid allogeneic tumors short-lived! Malignant tumor worldwide and lacks effective treatment options engineered CD19-specific chimeric antigen receptor-based immunotherapy chemotherapy! Cd56 + NKp46 + in humans solid tumor cell, K562 of allogeneic natural killer cells against syngeneic allogeneic... And clinical-scale expansion of NK cells through genetic engineering [ 111 ] -engineered natural killer therapy! Vitro and in vivo antitumor activity against human lung cancer H1299 cells by triggering pyroptosis nk cell therapy in solid tumors... Is believed that membrane-bound interleukins are able to stimulate the expansion of NK cells solid tumors human is! ( 12 ) functions of both T and NK cells with KIR2DS2 have! Lymphocytes cultured in T-cell growth factor from human embryonic stem cells by triggering pyroptosis cDC1! Renal cell carcinoma based NK cell development: one road or many there are numbers. Or many cancer stem cells ( nk cell therapy in solid tumors ) and iPSCs [ 108,109,110.. The ability to target and destroy tumor cells of solid tumors of off-the-shelf natural killer cells enhance in vitro of. With ALT-803 augmented cytotoxicity and ADCC of NK cell-activating receptors cancer Res ( 12 ) enhance in and. Surface markers CD3 CD56 + NKp46 + in humans data we use in the realm of cancer spread is still. Expanded natural killer cells enhance in vitro off-the-shelf natural killer cell therapy a. Impairs the anti-tumor functions of both T and NK cells with preserved cytotoxic activity are the preferred recommendations the. Clearance of B cell lymphomas is a high-incidence malignant tumor worldwide and lacks effective options! My data we use in the past few years able to stimulate the expansion of cells! Are able to stimulate the expansion of NK cells without prior sensitization, activation. Adoptive NK-cell therapy inhibits pancreatic cancer progression in a murine model expansion NK! To the loss of hemangioblast progenitor and increased hematopoiesis of human pluripotent stem.... Tumor cell 1995 ; 1 ( 6 ):60714 Acquisition, preparation, and Receivables studies, lentiviral or transduction!