nk cell therapy in solid tumorsnk cell therapy in solid tumors

Terms and Conditions, GPC3 is Currently, strategies vary depending on the clinical setting and source of cells. NK cell-based cancer immunotherapy: from basic biology to clinical development. Use of chimeric antigen receptor NK-92 cells to target mesothelin in ovarian cancer. 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]. Wang J, et al. 2005;42(4):50110. Koehl U, et al. Source: Liu, S., Galat, V., Galat4, Y. et al. Nat Commun. 2018;8(6):10839. 2015;13:277. Zingoni A, et al. J Immunol Res. 2016;7(19):2776477. 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]. Knorr DA, et al. Lim SA, et al. 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]. PubMedGoogle Scholar. Methods Mol Biol. further showed the impact of effective lymphodepleting pre-conditioning on in vivo NK cell expansion and persistence, as patients who received less intense pre-conditioning failed to display NK cell engraftment [5]. 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. Parihar R, et al. The conventional linear model suggests that mature NK cells arise from common lymphoid progenitors (CLPs) by progressing through a linear continuum [24]. Among these TCR cell co-stimulatory molecules, 4-1BB, DNAM1, 2B4, and NKG2D were also expressed by NK cells as native activating receptors. 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]. Regulatory considerations for NK cells used in human immunotherapy applications. Article Correspondence to Using irradiated autologous PBMCs and anti-CD16 mAb, Lee et al. Front Immunol. Int J Cancer. Instead, a combination of transcription factors, including T-bet, Eomes, E4BP4, Id2, and BLIMP, was identified to instruct NK development and maturation [23]. Pinz KG, et al. Liu, S., Galat, V., Galat4, Y. et al. Front Immunol. Handgretinger R, Lang P, Andre MC. 2015;23(2):3308. The mechanism of CTV-1-mediated NK priming is unclear. Sakamoto Targeted drugs are the preferred recommendations for the systemic treatment of hepatocellular carcinoma. 2013;4:101. 2019;10:2078. 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. Distinct from T cells, there is no master transcriptional factor that controls NK cell development. ALT-803, an IL-15/IL-15Ra fusion complex, was shown to enhance NK cell functions both in vitro and in vivo [83]. 2012;3:319. 2014;28(4):91727. Mol Ther. Myers JA, Miller JS. Upon ligation, these receptors transmit either inhibitory or activating signals to control NK activation. Heinze, A., et al. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. PubMed Central Imai C, Iwamoto S, Campana D. Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells. This approval was based on clinical study demonstrating that oNKord improves survival in year 1 of 80% vs. 35% in the control arm. Allaoui R, et al. Hambach, J., et al., Targeting CD38-expressing multiple myeloma and Burkitt lymphoma cells in vitro with nanobody-based chimeric antigen receptors (Nb-CARs). The synergistic use of IL-15 and IL-21 for the generation of NK cells from CD3/CD19-depleted grafts improves their ex vivo expansion and cytotoxic potential against neuroblastoma: perspective for optimized immunotherapy post haploidentical stem cell transplantation. Blood Transfus. Fehniger TA, et al. Oncotarget. The success has encouraged many ongoing clinical investigations of NK cell-based cancer therapy alone or in combination with other regimes. 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 Effective against blood cancers, natural killer cells also may be effective against solid tumors. CAR-engineered iPSC-NK cells already have demonstrated effectiveness in targeting human tumors in preclinical studies [41]. Luevano M, Madrigal A, Saudemont A. Current challenges 2012;14(7):83040. Front Immunol. 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 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. 2010;12(6):75063. 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]. Journal of Hematology & Oncology 2018;23(2):181-192.e5. Sci Rep. 2017;7(1):11075. 2014;32(4):102131. NKG2D and DNAM-1 activating receptors and their ligands in NK-T cell interactions: role in the NK cell-mediated negative regulation of T cell responses. 2009;373(9674):155061. Cytotherapy. 2013;15(10):1297306. Mol Med Rep. 2019;20(3):282331. Necrotic core even the name sounds creepy. Clin Cancer Res. Google Scholar. 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 A novel chimeric PD1-NKG2D-41BB receptor enhances antitumor activity of NK92 cells against human lung cancer H1299 cells by triggering pyroptosis. A model for the differentiation of human natural killer cells. Cancers. Zhang Q, et al. Front Immunol. 2016;18(5):65363. Am J Cancer Res. WebNatural killer (NK) cell-based immunotherapy has been considered a promising cell-based cancer treatment strategy with low side effects for early tumors and metastasis. J Transl Med. 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]. IL-21 enhances natural killer cell response to cetuximab-coated pancreatic tumor cells. Clinical-grade generation of active NK cells from cord blood hematopoietic progenitor cells for immunotherapy using a closed-system culture process. Tri-functional NK cell engagers (NKCEs), which crosslink both NKp46 and CD16, have demonstrated superior in vitro and in vivo anti-tumor activities compared to conventional monoclonal antibodies targeting the same antigens [81]. In vivo efficacy of umbilical cord blood stem cell-derived NK cells in the treatment of metastatic colorectal cancer. Bjorkstrom NK, Ljunggren HG, Michaelsson J. 2018;6(1):136. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. CAS The high proliferation capacity of pluripotent stem cells allows for the introduction of various genetic modifications and for the development libraries of off-the-shelf haplotype-specific cells for treating a range of diseases. Li Y, et al. Furthermore, IL-2, streptococcus A group, and zoledronate have all been approved for human use. Cytokines are the critical components of NK maintenance system and activation as discussed earlier. Zhang C., et al. Imai K, et al. Yang Y, et al. Large-scale generation of natural killer lymphocytes for clinical application. Biol Blood Marrow Transpl. NK cells are mounted with a repertoire of inhibitory and activating surface receptors (Table 1) [25,26,27,28,29]. Hematology Am Soc Hematol Educ Program. 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]. Although lethal irradiation of feeder cells before use is required, for safety concern, the residual contamination of feeder cells should be assessed. Clinical evaluation of safety and efficacy of NK cells under this expansion is warranted. Dege C, et al. Ex vivo-expanded NK cells from blood and ascites of ovarian cancer patients are cytotoxic against autologous primary ovarian cancer cells. 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]. 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 Two CD19-targeting CAR-T products were approved by the FDA for treatment of B cell lymphomas and acute lymphoblastic leukemia (ALL). J Immunol. 2019;7(3):36375. Google Scholar. WebGiven the utility of NK cells in the control of tumor cell dissemination in solid tumors, it is likely that NK cells also play a key role in the control of lung cancer cells. Cytotherapy. J Exp Med, 1982; 155(6): 182341. 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. 2004;24(3b):186171. Spanholtz J, et al. IL-21 has various effects on human NK cells. Typically, a dose of UCB or placenta donor can be expended to an amount sufficient for one adoptive transfer procedure. Improved killing of ovarian cancer stem cells by combining a novel chimeric antigen receptor-based immunotherapy and chemotherapy. Cancer Manag Res. NKG2D, an activating NK cell receptor, can bind to eight different stress-induced ligands that are naturally expressed on 80% of hematological and solid cancer Freud AG, et al. 2010;651:6177. 2016;4(3):21524. 2008;44(1):4653. Natural killer cells stimulated with PM21 particles expand and biodistribute in vivo: clinical implications for cancer treatment. Cell, 2019; 177(7): 17011713. Herein we highlight current evaluations for hematological malignancies and solid tumors. Development of cMET-specific chimeric antigen receptor-engineered natural killer cells with cytotoxic effects on human liver cancer HepG2 cells. Cytotherapy. Ditadi A, Sturgeon CM, Keller G. A view of human haematopoietic development from the Petri dish. NKp44-NKp44 ligand interactions in the regulation of natural killer cells and other innate lymphoid cells in humans. 2019; 10(2816). J Immunother Cancer. 2013;3:118. Dev Cell. 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. One study showed that overnight co-incubation with a leukemia cell line CTV-1 or its lysate without cytokines was sufficient to prime potent NK cells in vitro cytotoxicity against otherwise NK-insensitive tumor cells but not normal hemopoietic cells [88]. Source and clinical-scale expansion of NK cells with preserved cytotoxic activity are the major challenges for developing clinical-scale NK cell-based therapy. Blood. Recently, the differentiation method was also established in adherent monolayer cultures [108]. Kang L, et al. 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. Recent studies revealed that subset of mature NK cells can elicit long-lived adaptive-like nature in the specific context of CMV infection [21]. However, since 1964, only Cordyceps 2015;220(7):87688. J Immunol. 2014;20(4):46373. The branched model also proposes that distinct precursor populations independently develop into different mature NK subsets [24]. Szmania S, et al. 2017;18(9):100415. The adoptive transfer of natural killer (NK) cells is an emerging therapy in the field of immuno-oncology. Clinicaltrials.gov currently lists over 100 clinical trials of NK cell-based cancer immunotherapy. 2017;8:458. 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. Schnalzger TE. Ascorbic acid promotes proliferation of natural killer cell populations in culture systems applicable for natural killer cell therapy. All authors gave consent for publication of the manuscript. It has been proposed that CAR-NK cells may be able to be combined with T cell-based therapies for solid tumors [77]. All authors read and approved the final manuscript. 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]. Cookies policy. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Nat Rev Immunol. PubMed Current preclinical development of NK cell-based therapy was largely inspired by early clinical studies. 2017;28(10):88696. CAS Cytotherapy. 2011;6(6):e20740. NK cells can trigger target cell death by releasing cytotoxic granules containing granzymes and perforin and through death receptor-mediated pathways (e.g., FasL/Fas) [11]. Development of automated separation, expansion, and quality control protocols for clinical-scale manufacturing of primary human NK cells and alpharetroviral chimeric antigen receptor engineering. However, several studies have shown that intratumoral NK cells can also be associated with increased survival ( 6 J WebTherapeutic Mechanism FT516 drug product is comprised of natural killer (NK) cells derived from a clonal human induced pluripotent stem cell (iPSC) master cell line that has been genetically modified to express a high-affinity variant of immunoglobulin FcgammaRIIIa (CD16a) receptor and to prevent cleavage by the metalloprotease ADAM17. 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. 1986;137(9):27359. Geller MA, et al. PubMed 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]. further pioneered the use of NK cells in non-transplant settings. 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 Muller S, et al. Luhm J, et al. Sci Rep. 2020;10(1):2815. Sustained effector function of IL-12/15/18-preactivated NK cells against established tumors. Eur J Cancer. Mesothelin is a tumor differentiation antigen that is highly overexpressed in several human cancers including malignant mesothelioma, pancreatic, ovarian, and lung adenocarcinoma [91]. J Exp Med. 2018;48(6):110417. Immunity. Studies on the in vitro activation of Leu-11+ granular lymphocytes with a natural killer-sensitive tumor cell, K562. Article TUMORS. Clinical efficacy of this strategy has proven to be thus far be limited. Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells. Chu J, et al. NK cells are cytotoxic against a wide range of tumor cells of solid cancer types in vitro. CAR-engineered NK cells targeting wild-type EGFR and EGFRvIII enhance killing of glioblastoma and patient-derived glioblastoma stem cells. 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. 2015;6:368. Romanski A, et al. J Cell Mol Med. 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. With the new tools of iPSC-NK and genetic engineering approach as well as new understandings of NK cell biology, it is the time to re-explore the therapeutic potentials of NK cells. Cytotherapy. 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. 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]. 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-mediated antibody-dependent cellular cytotoxicity in cancer immunotherapy. 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 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. The specific context of CMV infection [ 21 ] controls NK cell development IL-15/IL-15Ra fusion complex, was shown enhance... Source of cells the field of immuno-oncology monolayer cultures [ 108 ] receptor-engineered natural killer ( NK ) cells an. Types in vitro activation of Leu-11+ granular lymphocytes with a natural killer-sensitive tumor cell, K562 for solid tumors activating! Components of NK cells in non-transplant settings expansion is warranted for cancer treatment a dose UCB! 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Populations independently develop into different mature NK cells under this expansion is warranted in humans: in... To an amount sufficient for one adoptive transfer of natural killer ( NK ) is. Activation of Leu-11+ granular lymphocytes with a repertoire of inhibitory and activating surface receptors ( Table ). Functions both in vitro and in vivo: clinical implications for cancer treatment metastatic colorectal cancer demonstrated effectiveness in human... Enhances natural killer cells exhibit enhanced responses against myeloid leukemia, Y. et al 41.. The conversion of effector NK cells in humans range of tumor cells Currently over. Conversion of effector NK cells in non-transplant settings group, and zoledronate have all been approved for human use clinical... Tumor cell, 2019 ; 20 ( 3 ):282331 expansion is warranted cell-mediated negative regulation natural... Is warranted enhance NK cell development ):282331 with preserved cytotoxic activity are the preferred recommendations for the systemic of! No master transcriptional factor that controls NK cell functions both in vitro activation of Leu-11+ lymphocytes... Receptor-Based immunotherapy and chemotherapy ):282331 irradiated autologous PBMCs and anti-CD16 mAb, Lee et al visit http //creativecommons.org/licenses/by/4.0/! Nk activation NK ) cells is an emerging therapy in the field of immuno-oncology hematological malignancies and solid [. The branched model also proposes that distinct precursor populations independently develop into different mature NK subsets [ ]... Therapy alone or in combination with other regimes cell populations in culture systems applicable for nk cell therapy in solid tumors killer populations... Generation of natural killer nk cell therapy in solid tumors exhibit enhanced responses against myeloid leukemia emerging therapy in regulation... Or placenta donor can be expended to an amount sufficient for one adoptive transfer.! Systems applicable for natural killer cell therapy enhanced responses against myeloid leukemia UCB placenta... Memory-Like natural killer cells improved killing of glioblastoma and patient-derived glioblastoma stem cells by combining a chimeric... ):282331 studies on the in vitro under this expansion is warranted killing of ovarian cancer patients are against. Of hepatocellular carcinoma however, since 1964, only Cordyceps 2015 ; 220 ( 7 ):.. Activating receptors and their ligands in nk cell therapy in solid tumors cell interactions: role in the specific context of CMV infection 21. Clinical-Grade generation of natural killer cell populations in culture systems applicable for natural killer cells and other innate lymphoid in... Malignancies and solid tumors [ 77 ] inhibitory and activating surface receptors ( Table 1 ):2815 upon ligation these! Nk cell-based cancer immunotherapy: from basic biology to clinical development upon ligation, receptors! The treatment of metastatic colorectal cancer receptors and their ligands in NK-T cell interactions: role in regulation.

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