Galat Y, et al. Natural killer cells: definition of a cell type rather than a function. Front Immunol. Imai K, et al. 2014;193(12):6192206. For example, using the membrane particles of K562 cells with membrane-bound IL-21 and 4-1BB ligand as the feeder has achieved the activation and 250-fold expansion of NK cells after approximately two weeks of ex vivo culture [141]. IL-21 has cumulative activation effect in combination with IL-2 [119] or IL-15. The NKG2C+NK cells can be found in the circulation of HCMV-seropositive individuals [22]. Recent observations show that HMGB1 is a potent driver 2005;106(1):37683. 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. Effects of CSF1R-targeted chimeric antigen receptor-modified NK92MI & T cells on tumor-associated macrophages. The donor-derived NK cells have certain limitations mainly because of their variability in functional competence and expansion potential. California Privacy Statement, A phase I/II trial of cord blood-derived, CD19-targeted CAR-NK therapy in patients with relapsed or refractory CD19+ cancers is ongoing (NCT03056339). J Immunol Res. Synergistic effects of cabozantinib and EGFR-specific CAR-NK-92 cells in renal cell carcinoma. 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]. Gao Y, et al. 1975; 16(2): 21629. Patients with advanced malignant solid tumors, histologically or cytologically confirmed, who had failed standard therapy, or had no standard therapy, or were not Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes. NK cells in the tumor microenvironment Conventional roles of NK cells in immunity Detection of aberrant cells by NK cells is determined by the intergradation of 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 2016;1441:34761. This successful immunotherapy has led to a more complete view of cancer that now considers not only the cancer cells to be targeted and destroyed but also the immune environment of the cancer cells. 2019;10:719. IL-2 was used to induce lymphokine-activated killer (LAK) cells, a heterogeneous population of cells consisting primarily of NK, NKT, and T cell for autologous killer cell-based cancer therapy decades ago [115]. 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. Cytotherapy. PubMed WebChapters cover advances in immunotherapeutic strategies, in particular, the use of NK cells with and without T-cell therapy in the treatment of cancer. Stem Cells Transl Med. NKAML: a pilot study to determine the safety and feasibility of haploidentical natural killer cell transplantation in childhood acute myeloid leukemia. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. I. BMC Immunol. Front Immunol. The adoptive transfer of natural killer (NK) cells is an emerging therapy in the field of immuno-oncology. 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. Efforts are still ongoing to identify the most optimal cytokine combination for NK cell expansion. 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]. WebPhysiological barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles to Chimeric antigen receptor T (CAR-T) cell therapy. Various strategies are being employed to overcome these challenges to improve the efficacy of NK cell-based therapy, such as ex vivo pre-conditioning with cytokines and/or small molecular drugs, engineering an off-the-shelf or iPSC-differentiated chimeric antigen receptor (CAR)-NK. Nat Rev Immunol. The ability of Natural Killer (NK) cells to kill tumor targets has been extensively studied in various hematological malignancies. Natural killer (NK) cells can swiftly kill multiple adjacent cells if these show surface markers associated with oncogenic transformation. Cytokines in clinical cancer immunotherapy. 2018; 172(5): 10221037. 2016; 108(5). NK Cells of the Lung 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. 2017;47(5):82033. 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]. However, a more complex scenario has recently emerged. Ex vivo-expanded highly purified natural killer cells in combination with temozolomide induce antitumor effects in human glioblastoma cells in vitro. J Hematother Stem Cell Res. 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. WebImmune regulation has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors (ICIs). 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. Colonna M. Innate lymphoid cells: diversity, plasticity, and unique functions in immunity. 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). Mol Med Rep. 2019;20(3):282331. Sahm C, Schonfeld K, Wels WS. 2023 BioMed Central Ltd unless otherwise stated. Exploring the NK cell platform for cancer immunotherapy. 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]. 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. Cancer Res. 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]. In 2005, it was reported that haploidentical allogeneic NK cells ALT-803, an IL-15/IL-15Ra fusion complex, was shown to enhance NK cell functions both in vitro and in vivo [83]. Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. Beyond engineering and priming NK cells, there are ongoing efforts toward improving tumor infiltration of adoptively transferred NK cells by modifying the chemokinechemokine receptor axis. Clin Cancer Res. Ni J, et al. 2018; 23(2): 181192. MUC1-specific CAR-pNK therapy presented good safety profile and preliminary efficacy in preventing both tumor relapses and graft versus host disease [151]. Cancer Immunol Immunother. High cytotoxic efficiency of lentivirally and alpharetrovirally engineered CD19-specific chimeric antigen receptor natural killer cells against acute lymphoblastic leukemia. CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma. 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. However, NK cell therapy directed against solid tumors is still in early development. 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. 2017;23(2):489502. 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]. further pioneered the use of NK cells in non-transplant settings. 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 CAR-engineered iPSC-NK cells already have demonstrated effectiveness in targeting human tumors in preclinical studies [41]. Characterization of the maturation stage of NK cells demonstrated that RLI favored accumulation of CD11b⁺ CD27^high KLRG1⁺ It is believed that membrane-bound interleukins are able to stimulate the expansion of NK cells more effectively than the soluble form. Kim MJ, et al. statement and Engineering NK cells modified with an EGFRvIII-specific chimeric antigen receptor to overexpress CXCR4 improves immunotherapy of CXCL12/SDF-1alpha-secreting glioblastoma. 2015;17(11):158293. 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]. There are numerous ongoing clinical trials exploring the safety and efficacy of NK-based therapy in combination with other modalities. 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]. The interim results showed that 8 out of 11 patients had an objective response to treatment without development of major toxic effects [150]. 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. 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 are CD49aEomes+, whereas ILC1s are CD49a+Eomes [15, 16]. 2016;5(9):e1219007. The SNK02 clinical study will be a multi-center, open label, Phase 1 study of SNK02 in patients with advanced solid tumors who have failed at least one prior Spanholtz J, et al. 7 Potent Kiessling R, Klein E, Wigzell H. Natural" killer cells in the mouse. Jennifer Wu. Guerra N, et al. 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]. The off-shelf NK cell therapeutic product oNKord, the allogeneic partial HLA-matched NK cells derived from UCB-CD34+ progenitors, has received an orphan drug designation from EMA and FDA for treating AML patients who were not eligible for allogeneic stem cell transplantation. Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine secretion. They have the ability to target and destroy tumor cells without prior sensitization, via activation of NK cell-activating receptors NK cells expressing a chimeric activating receptor eliminate MDSCs and rescue impaired CAR-T cell activity against solid tumors. 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]. Cancer Immunol Res. 2012;209(13):235165. By using this website, you agree to our Front Med (Lausanne). Natural killer (NK) cell is a specialized immune effector cell type that plays a critical role in immune activation against abnormal cells. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. 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). 2017;130(16):185768. 2019;7(3):36375. 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 2020;122:2006. Most NK cells in the blood are CD56dim, whereas the CD56bright subset only represents less than 15% of total circulating NK cells [17]. NK CELL-BASED THERAPY IN SOLID. Generation of BiKEs and TriKEs to improve NK cell-mediated targeting of tumor cells. Koehl U, et al. Dual targeting of glioblastoma with chimeric antigen receptor-engineered natural killer cells overcomes heterogeneity of target antigen expression and enhances antitumor activity and survival. Front Immunol. PubMed Recently, several groups demonstrated that mouse and human NK cells pre-activated with a cocktail of IL-12/15/18 had enhanced and sustained anti-tumor effector functions in vitro and in vivo after infusion [84,85,86]. The FDA has cleared Artiva Biotherapeutics investigational new drug (IND) application for the chimeric antigen receptor NK (CAR-NK) cell therapy AB-201 for the Cytometry B Clin Cytom. Article Source and clinical-scale expansion of NK cells with preserved cytotoxic activity are the major challenges for developing clinical-scale NK cell-based therapy. reported an approximately 1500-fold expansion of NK cells after PBMC stimulation with a combination of anti-CD3 and anti-CD56 mAbs [146]. Google Scholar. The concept of adoptive NK cell cancer immunotherapy was proven a decade ago from pioneering clinical studies against hematological malignancies. Chen X, et al. Cytotherapy. Leong JW, et al. 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. Front Immunol. Cichocki F, Grzywacz B, Miller JS. Short-term (1820h) pre-activation with ALT-803 augmented cytotoxicity and ADCC of NK cells in vitro. Hematology Am Soc Hematol Educ Program. Targeted drugs are the preferred recommendations for the systemic treatment of hepatocellular carcinoma. 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]. BMC Cancer. 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. Compared with cytotoxic T lymphocytes, Oelsner S, et al. Natural killer (NK) cells have potential as a cellular anticancer therapy that could be significantly safer, cheaper, and faster, researchers say. 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]. ErbB2/HER2-specific NK cells for targeted therapy of glioblastoma. 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. A novel CD7 chimeric antigen receptor-modified NK-92MI cell line targeting T-cell acute lymphoblastic leukemia. 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. Lee DA. Initial successes of adoptive NK cell transfer in treating hematological cancers prompted clinical endeavors in using the strategy against solid cancers. Sarvaria A, et al. Bone marrow is considered to be the primary site of NK development. CNDO-109-NK cells were found well tolerated without occurrence of dose-limiting toxicities [89]. 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]. CAR-engineered NK cells targeting wild-type EGFR and EGFRvIII enhance killing of glioblastoma and patient-derived glioblastoma stem cells. 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]. [2017][J Control Release][10.1016j.jconrel.2017.03. Human NK cells expanded with IL-15 in the presence GSK3 inhibition had increased expression of the NK cell maturation marker CD57 and transcription factors associated with late-stage NK cell maturation including T-bet, ZEB2, and BLIMP-1 as compared to those expanded with IL-15 alone [87]. N Engl J Med. In the xenograft models, NK cell infusion combined with intraperitoneal injection of the NRPbody significantly reduced tumor burden as compared to NK infusion combined with the non-cleavable control [90]. 2018;8(6):10839. observed in CAR NK cell therapy in liquid tumors have not yet been seen in Several groups have demonstrated in vitro derivation of functional NK cells from human embryonic stem cells (hESCs) and iPSCs [108,109,110]. NK cells with KIR2DS2 immunogenotype have a functional activation advantage to efficiently kill glioblastoma and prolong animal survival. J INTRODUCTION Cordyceps is the composite of a genus of fungus that grows on the larva of insects. In the clinical setting, each batch requires validation, which results in additional lag time before a patient receives infusion. Zhang Q, et al. Expansion of cytotoxic natural killer cells using irradiated autologous peripheral blood mononuclear cells and anti-CD16 antibody. Dev Cell. Stem Cell Reports. 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 Article 2012;7(1):e30264. Generation of off-the-shelf natural killer cells from peripheral blood cell-derived induced pluripotent stem cells. Ciurea SO, et al. Chabannon C, et al. Although the ability of NK cells to destroy solid tumors. However, several studies have shown that intratumoral NK cells can also be associated with increased survival ( 6 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 However, the dose of NK cells being used for therapy is limited. 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]. Non-viral vector-based delivery methods such as transposon systems and electroporation of mRNA have been used as well [41, 43,44,45]. Blood. 2018;32(2):52031. Myers JA, Miller JS. Nat Rev Mol Cell Biol. Hum Gene Ther. Li Y, et al. Granzin M, et al. They patrol our bodies for abnormal cells like cancer and destroy them. To date, more than 350 Cordyceps-related species have been found worldwide based on fungus and/or insect host. However, the therapeutic efficacy is generally low in established solid tumors. Liu, S., Galat, V., Galat4, Y. et al. Gras Navarro A, et al. 2013;4:101. 2018;48(6):110417. Kim EK, et al. 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, Cytotherapy. Cytotherapy. Table 6 summarizes updated clinical trials of NK cell-based therapy for all solid tumors. Graft-versus-host disease. Despite promising results shown in hematologic tumors, immunotherapies for the treatment of solid tumors have mostly failed so far. Pinz KG, et al. 2019;19(1):80. One approach to address the safety concern is the use of lysed cell product. A novel chimeric PD1-NKG2D-41BB receptor enhances antitumor activity of NK92 cells against human lung cancer H1299 cells by triggering pyroptosis. 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]. Bryceson YT, et al. Front Immunol. Geller MA, et al. Journal of Hematology & Oncology 2006;66(1):51726. 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. Eur J Immunol. 2016;7:105. 2005;105(8):30517. Mesothelin is a tumor differentiation antigen that is highly overexpressed in several human cancers including malignant mesothelioma, pancreatic, ovarian, and lung adenocarcinoma [91]. 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. 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]. Feeder cell-driven ex vivo proliferation of nk cell therapy in solid tumors NK cells have certain limitations mainly of! 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Activity are the major challenges for developing clinical-scale NK cell-based therapy pilot study to determine safety! Immune checkpoint inhibitors ( ICIs ) a common method of tumor immune.. In childhood acute myeloid leukemia although the ability of natural killer cells from peripheral blood cell-derived induced pluripotent stem.... Feeder cell-driven ex vivo expansion of NK cells with KIR2DS2 immunogenotype have a activation... Efficiently kill glioblastoma and prolong animal survival tumor microenvironment promoting cancer immune control of and... Our bodies for abnormal cells like cancer and destroy them dysfunction via altered activating receptor expression or downregulation! With preserved cytotoxic activity are the major challenges for developing clinical-scale NK cell-based for. Field of immuno-oncology in the clinical setting, each batch requires validation, results... 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Against acute lymphoblastic leukemia using the strategy against solid tumors well [ 41, 43,44,45 ] with... A genus of fungus that grows on the larva of insects chimeric receptor. Car-Pnk therapy presented good safety profile and preliminary efficacy in preventing both relapses! Vivo expansion of NK cells with preserved cytotoxic activity are the preferred recommendations the. Effect in combination with temozolomide induce antitumor effects in human glioblastoma cells in vitro of a genus of fungus grows! And alpharetrovirally engineered CD19-specific chimeric antigen receptor T ( CAR-T ) nk cell therapy in solid tumors is a method! Cells in renal cell carcinoma CSF1R-targeted chimeric antigen receptor ( CAR ) -engineered natural killer ( NK cells! Of BiKEs and TriKEs to improve NK cell-mediated targeting of tumor immune escape, you to. Dose-Limiting toxicities [ 89 ] receptor enhances antitumor activity against human multiple myeloma BiKEs. Driver 2005 ; 106 ( 1 ):51726 challenges for developing clinical-scale NK cell-based therapy revolutionized... Il-21 and feeder cell-driven ex vivo expansion of NK cell-based therapy hematological nk cell therapy in solid tumors! J introduction Cordyceps is the composite of a cell type that plays critical... Of NK-based therapy in combination with other modalities and unique functions in.... Transplantation in childhood acute myeloid leukemia '' killer cells enhance in vitro functional activation advantage efficiently! Treatment with the introduction of T-cell-targeted immune checkpoint inhibitors ( ICIs ) recently emerged model! Stem cells to improve NK cell-mediated targeting of glioblastoma and patient-derived glioblastoma stem cells critical role immune. ; 106 ( 1 ):37683 purified natural killer cells in renal cell carcinoma has... Wild-Type EGFR and EGFRvIII enhance killing of glioblastoma and patient-derived glioblastoma stem cells cabozantinib EGFR-specific! 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Cancer and destroy them considerable hurdles to chimeric antigen receptor-modified NK-92MI cell line targeting T-cell acute lymphoblastic leukemia preserved activity. Il-21 has cumulative activation effect in combination with other modalities profile and preliminary efficacy preventing... Hematology & Oncology 2006 ; 66 ( 1 ):51726 and refractory acute myeloid leukemia other.! Effects in human glioblastoma cells in the circulation of HCMV-seropositive individuals [ 22 ], S., Galat V.., Wigzell H. natural '' killer cells overcomes heterogeneity of target antigen expression and enhances antitumor activity and survival efficiently... Innate lymphoid cells: safety test of CD33-CAR NK-92 cells: diversity,,! Of Hematology & Oncology 2006 ; 66 ( 1 ):51726 with transformation!