The conventional linear model suggests that mature NK cells arise from common lymphoid progenitors (CLPs) by progressing through a linear continuum [24]. However, a more complex scenario has recently emerged. 2013;4:101. 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. Hu Z. Tissue factor as a new target for CAR-NK cell immunotherapy of triple-negative breast cancer. Mol Ther. Eur J Cancer. 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]. 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 Granzin M, et al. Use of chimeric antigen receptor NK-92 cells to target mesothelin in ovarian cancer. 2015;13(3):46471. Allaoui R, et al. North J, et al. Targeting immunosuppressive components in the TME to re-invigorate NK functions is also under investigation. For instance, healthy cells express no or minimal level of ligands for NK cell activating receptors, but express high levels of the major histocompatibility complex class I molecules (MHC I), also known as human leukocyte antigen (HLA), that ligates to the killer immunoglobulin-like (KIR) family inhibitory receptors on NK cells to protect them from NK attack [29]. Distinct from T cells, there is no master transcriptional factor that controls NK cell development. Rubnitz JE, et al. Patients with advanced malignant solid tumors, histologically or cytologically confirmed, who had failed standard therapy, or had no standard therapy, or were not CAS Chen X, et al. 2016;7(19):2776477. Hemolytic anemia due to passenger lymphocyte syndrome in solid malignancy patients treated with allogeneic natural killer cell products. 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 With the subcutaneous hypopharyngeal tumor xenograft model, it was shown that CXCR1-expressing CAR-NK cells had enhanced tumor infiltration and tumor control as compared to control CAR-NK cells [54]. Ditadi A, Sturgeon CM, Keller G. A view of human haematopoietic development from the Petri dish. Despite the immunosuppressive environment of solid tumors, NK cell activity/infiltration has been correlated with improved prognoses in humans. Eur J Immunol. 2017;8:329. Biol Blood Marrow Transpl. This work was supported by NIH/NCI grant 1R01CA208246, 1R01CA204021, 1R01CA212409, and DOD W81XWH-15-1-0406 (to J. D. Wu). ErbB2/HER2-specific NK cells for targeted therapy of glioblastoma. 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. WebImmune regulation has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors (ICIs). 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. Jennifer Wu. Peptide-specific recognition of human cytomegalovirus strains controls adaptive natural killer cells. 2017;19(2):23549. Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. The trial is While the CAR technology seeks to enhance NK cell functions by genetically directing their target specificity, there are active investigations on other strategies to effectively prime NK cells ex vivo or in vivo for optimal anti-tumor functions after their infusion. Cytokines in clinical cancer immunotherapy. 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. J Transl Med. Cancer Sci. Correspondence to Conceptually, iPSC-NK can provide a homogenously differentiated NK cell population that can be expanded to clinical scale as an off-the-shelf supply, overcoming the limitation of the NK-92 cell line. Gao Y, 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]. Fujisaki H, et al. WebPhysiological barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles to Chimeric antigen receptor T (CAR-T) cell therapy. Exposure of NK to unmodified NK cell-sensitive leukemia cells (K562) stimulates expansion and short-term proliferation [133]. In the clinical setting, each batch requires validation, which results in additional lag time before a patient receives infusion. Nat Rev Immunol. 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. Cancer Immunol Immunother. 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 Ueda T, et al. Killer (NK) cell activity against solid tumors. 7 Potent 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 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]. Miller et al. statement and 2015;13:277. Parihar R, et al. Hum Gene Ther Methods. PLoS ONE. To date, more than 350 Cordyceps-related species have been found worldwide based on fungus and/or insect host. WebHappy New Year to you! NKAML: a pilot study to determine the safety and feasibility of haploidentical natural killer cell transplantation in childhood acute myeloid leukemia. WebCorrigendum to Entrectinib in patients with ROS1 fusion-positive non-small cell lung cancer (NSCLC) or NTRK fusion-positive solid tumours: Analysis of response by line of therapy (Annals of Oncology (2020) 31(S4) (S472S473), (S0923753420406507), (10.1016/j.annonc.2020.08.654)). Ex vivo-expanded NK cells from blood and ascites of ovarian cancer patients are cytotoxic against autologous primary ovarian cancer cells. Clinical-scale derivation of natural killer cells from human pluripotent stem cells for cancer therapy. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Handgretinger R, Lang P, Andre MC. Production Process of CAR-NK 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. Zeng J, et al. 2019;120(1):615. 2010;59(12):17819. The broad spectrum of human natural killer cell diversity. As the activation and expansion methods are improving, it is becoming possible to prepare increasingly higher dosages of NK cells for adoptive transfer from a single-donor phlebotomy. Nat Rev Immunol. 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 PubMed In 2005, it was reported that haploidentical allogeneic NK cells Li Q, et al. Natural killer cells produce T cell-recruiting chemokines in response to antibody-coated tumor 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]. But what it does in the realm of cancer spread is creepier still. Cao B, et al. 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]. 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. Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. Del Zotto G, et al. Nat Rev Mol Cell Biol. 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 Clinical application of CAR-NK cell therapy in solid tumors. Chabannon C, et al. Clinicaltrials.gov currently lists over 100 clinical trials of NK cell-based cancer immunotherapy. Several groups have demonstrated in vitro derivation of functional NK cells from human embryonic stem cells (hESCs) and iPSCs [108,109,110]. 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 Carlsten M, et al. Despite decades of work, the ontogeny of NK cells in humans is still not fully elucidated. There are a number of ongoing clinical trials for cancer immunotherapy using engineered iPSC-NK cells, which are summarized in the following sections. NK Cells of the Lung NK cells are cytotoxic against a wide range of tumor cells of solid cancer types in vitro. The interim results showed that 8 out of 11 patients had an objective response to treatment without development of major toxic effects [150]. PubMed Cookies policy. Regulatory considerations for NK cells used in human immunotherapy applications. 2015;17(11):158293. 2018;10(11):93549. 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. 2005;106(1):37683. 2006;66(1):51726. Provided by the Springer Nature SharedIt content-sharing initiative. ALT-803, an IL-15/IL-15Ra fusion complex, was shown to enhance NK cell functions both in vitro and in vivo [83]. Go to: 5.1. 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. Over 100-fold expansion was achieved with Wilms tumor HFWT [134] and immortalized T lymphocyte Jurkat cell lines [135]. Front Immunol. Sci Rep. 2019;9(1):14916. Stem Cells. 1981;41(11 Pt 1):44205. 2013;73(8):2598607. Natural killer cell memory in infection, inflammation and cancer. Cancer Res. Oelsner S, et al. Recent studies revealed that subset of mature NK cells can elicit long-lived adaptive-like nature in the specific context of CMV infection [21]. Front Immunol. Front Med (Lausanne). 2. Childs RW, Berg M. Bringing natural killer cells to the clinic: ex vivo manipulation. WebBackground Acute ischemic stroke (AIS) due to large vessel occlusion (LVO) is a devastating cerebrovascular disorder, which could benefit from collateral circulation. Leong JW, et al. 2017;23(2):489502. 2013;15(10):1297306. 2012;3:319. Non-viral vector-based delivery methods such as transposon systems and electroporation of mRNA have been used as well [41, 43,44,45]. But what it does in the realm of cancer spread is creepier still. IL-21 has cumulative activation effect in combination with IL-2 [119] or IL-15. 2010;28(6):9559. 2014;193(12):6192206. Front Immunol. N Engl J Med. Oncoimmunology. Herein, we will provide an updated overview of the emerging endeavors for developing NK cell-based cancer immunotherapy from pre-clinical conceptual development, clinical grade expansion, and ongoing clinical development. 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]. Recently, the differentiation method was also established in adherent monolayer cultures [108]. Br J Cancer. Lee et al. An antibody designed to improve adoptive NK-cell therapy inhibits pancreatic cancer progression in a murine model. Front Immunol. J Exp Med, 1982; 155(6): 182341. 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). 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 NK cells originate from CD34+ hematopoietic stem cells. J Hematol Oncol 14, 7 (2021). NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Non-clinical efficacy, safety and stable clinical cell processing of induced pluripotent stem cell-derived anti-glypican-3 chimeric antigen receptor-expressing natural killer/innate lymphoid cells. Front Immunol. 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]. They have been recognized as a subset of innate lymphoid cells (ILCs) that lack antigen receptors with recombination activating gene (RAG)-dependent rearrangement [ 1, 2 ]. 2015;15:1011. Anticancer Res. IL-21 has various effects on human NK cells. 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. For hematological cancers, CD19 remains a major target. J Immunol Res. Selective inhibition of tumor growth by clonal NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor. [2017][J Control Release][10.1016j.jconrel.2017.03. Stem Cell Res Ther. 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]. 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. Xu Y, et al. Felices M, et al. Parkhurst MR, 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]. 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. Correction to: IL-27 enhances IL-15/IL-18-mediated activation of human natural killer cells. 2012;16(3):56981. 2020;524(1):96102. 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]. Cancer-associated fibroblast-secreted CXCL16 attracts monocytes to promote stroma activation in triple-negative breast cancers. NK cells expressing a chimeric activating receptor eliminate MDSCs and rescue impaired CAR-T cell activity against solid tumors. Engineering NK cells modified with an EGFRvIII-specific chimeric antigen receptor to overexpress CXCR4 improves immunotherapy of CXCL12/SDF-1alpha-secreting glioblastoma. 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. 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]. 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 chimeric receptor with NKG2D specificity enhances natural killer cell activation and killing of tumor cells. The BiKEs or TrikEs are composed of two or three linked single-chain antibody variable fragments of different antigen specificities [79]. 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]. 2018;24(8):15819. Lysis of fresh and cultured autologous tumor by human lymphocytes cultured in T-cell growth factor. 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]. Glyostems lead candidate NK cell therapy is currently being tested in a phase 1/2a trial for the treatment of the blood cancer acute myeloid leukemia. Ojo EO, et al. Advances in clinical NK cell studies: donor selection, manufacturing and quality control. Notably, many tissue-resident NK subsets are now shown to be phenotypically and functionally distinct from conventional peripheral blood NK cells [20]. 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. 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 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. 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]. NK cells engineered to express a GD2 -specific antigen receptor display built-in ADCC-like activity against tumour cells of neuroectodermal origin. Leukemia. However, the dose of NK cells being used for therapy is limited. 2018;67(4):57587. Zhang C., et al. 2016;1441:33346. Biol Blood Marrow Transpl. In most pre-clinical studies, lentiviral or retroviral-based transduction was used to achieve stable and sustained CAR expression in NK cells. Ex vivo-expanded natural killer cells demonstrate robust proliferation in vivo in high-risk relapsed multiple myeloma patients. 1975; 16(2): 21629. WebEnded 2022 with Approximately $475 Million in Cash, Cash Equivalents, and Receivables. J Immunother. Although lethal irradiation of feeder cells before use is required, for safety concern, the residual contamination of feeder cells should be assessed. Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. 2019;10:719. Immunity. A phase 1 trial of CNDO-109-activated natural killer cells in patients with high-risk acute myeloid leukemia. Koehl U, et al. Most recent studies showed that ex vivostimulation of human NK cells with the combination of IL-15/IL-18/IL-27 can achieve 17-fold expansion [122], and that the combination of IL-2 with IL-18 can achieve approximately 500-fold expansion over two-week period [123]. 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). 2013;13(2):1459. NK cell therapy in solid tumors, therefore, strongly resembled those in hematologic malignancies. 2016;7:105. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. The anti-CD3 mAb presumably activates T cells in feeder to secret cytokines which subsequently create a milieu favorable for NK cell expansion [145]. Engineering natural killer cells for cancer immunotherapy. Article Two CD19-targeting CAR-T products were approved by the FDA for treatment of B cell lymphomas and acute lymphoblastic leukemia (ALL). The NKG2C+NK cells can be found in the circulation of HCMV-seropositive individuals [22]. 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 Clin Cancer Res. 2010;651:6177. Characterization of the maturation stage of NK cells demonstrated that RLI favored accumulation of CD11b⁺ CD27^high KLRG1⁺ Sakamoto 2019;14(3):e0212455. Current challenges DNAM1 and 2B4 costimulatory domains enhance the cytotoxicity of anti-GPC3 chimeric antigen receptor-modified natural killer cells against hepatocellular cancer cells in vitro. You F, et al. Purinergic targeting enhances immunotherapy of CD73(+) solid tumors with piggyBac-engineered chimeric antigen receptor natural killer cells. Additional markers such as lack of c-kit can be used to distinguish human NK (c-kit-) from ILC3s (c-kit+) [14]. Moreover, highly cytotoxic NK cells derived using such method are capable of producing endogenous cytokines that improve their survival, proliferation, and function [132]. Front Immunol. Immunotherapy is a breakthrough in the systemic treatment of malignant tumors, including HCC. The combination of IL-2/IL-15/IL-21 can support up to eightfold expansion of NK cells [121]. Imai C, Iwamoto S, Campana D. Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells. Cytotherapy. NK cells are mounted with a repertoire of inhibitory and activating surface receptors (Table 1) [25,26,27,28,29]. The integration and balance of the activating and inhibitory signals from the ligand/receptor interactions dictates the status of NK cell activation. 2016;7:13050. Front Oncol. 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]. Lanier LL, et al. Manage cookies/Do not sell my data we use in the preference centre. Ng YY, Tay JCK, Wang S. cxcr1 expression to improve anti-cancer efficacy of intravenously injected CAR-NK cells in mice with peritoneal xenografts. Stem Cells Transl Med. 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 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]. Cancer Res. NK cells possess advantageous characteristics, including non-MHC-restricted recognition, ability to infiltrate Instead, a combination of transcription factors, including T-bet, Eomes, E4BP4, Id2, and BLIMP, was identified to instruct NK development and maturation [23]. Clin Cancer Res. PubMed Herein we highlight current evaluations for hematological malignancies and solid tumors. 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. Huang Y, et al. CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma. Nat Rev Clin Oncol. Characterization and ex vivo expansion of human placenta-derived natural killer cells for cancer immunotherapy. It yielded a greater than 1000-fold expansion of NK cells after 3weeks of culture [38, 125, 126]. 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. When expanded it provides a list of search options that will switch the search inputs to match the current selection. Myers JA, Miller JS. J Immunother Cancer. Stimulating antibodies is typically used along with irradiated allogeneic PBMC to further promote NK activation and expansion. Lee SJ, et al. Short-term (1820h) pre-activation with ALT-803 augmented cytotoxicity and ADCC of NK cells in vitro. Tanaka Y, et al. Nat Commun. 2019;7(2):21929. Cytotherapy. Clinical evaluation of safety and efficacy of NK cells under this expansion is warranted. WebThe presence of HMGB1 in the context of the NK:tumor cell interaction may also play a role in the progression of the tumor. Current preclinical development of NK cell-based therapy was largely inspired by early clinical studies. Chu J, et al. Zingoni A, et al. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. PubMed 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. Granzin M, et al. Sci Rep. 2020;10(1):2815. 2018;2018:4263520. 2016;5(4):e1119354. Part of 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. 2015;6:368. WebMy interests are based on basic science methodologies to improve the advanced science techniques which improve the cancer immunotherapy effects. Liu E, 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]. Szmania S, et al. Cancers (Basel), 2020; 12(6). Veluchamy JP, et al. Sakamoto N, et al. Choi I, et al. J Immunol. The anti-tumor response of LAK cells was shown attributed mainly to NK cells [116]. Merck has secured global licenses to two CAR-NK programs from Artiva Biotherapeutics. Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells. 2018;19(1):27. 2007;178(1):8594. CXCL16 positively correlated with M2-macrophage infiltration, enhanced angiogenesis, and poor prognosis in thyroid cancer. 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]. WebExperienced R&D leader in pharmaceutical industry focusing on biologics and cell therapy drug discovery for immuno-oncology. Generation of BiKEs and TriKEs to improve NK cell-mediated targeting of tumor cells. NK cell therapy in brain tumors is emerging as a promising tool, due to their superior safety profile, absence of graft-versus-host disease, cytokine storm and J Adoptive transfer of autologous natural killer cells leads to high levels of circulating natural killer cells but does not mediate tumor regression. 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]. Bottcher JP, et al. 2016;22(14):344050. In mouse strains lacking NK1.1 expression (e.g., BALB/c), CD49b is used for NK cell identification. 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]. 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. Google Scholar. Continuously expanding CAR NK-92 cells display selective cytotoxicity against B-cell leukemia and lymphoma. They are also summarized in Table 2. 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. The concept of adoptive NK cell cancer immunotherapy was proven a decade ago from pioneering clinical studies against hematological malignancies. The donor-derived NK cells have certain limitations mainly because of their variability in functional competence and expansion potential. J Exp Med. Front Immunol. Klapdor R, et al. 2015;220(7):87688. 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 To determine the safety and stable clinical cell processing of induced pluripotent stem cells for cancer immunotherapy proven... Expressing a chimeric activating receptor expression or tumor downregulation of NK cell dysfunction via altered receptor... 41, 43,44,45 ] 11 Pt 1 ):2815 $ 475 Million Cash. Receptor NK-92 cells: safety test of CD33-CAR NK-92 cells display selective cytotoxicity against leukemia! The current selection of BiKEs and TrikEs to improve adoptive NK-cell therapy inhibits pancreatic cancer progression in a murine.! Malignant tumor worldwide and lacks effective treatment options cells from blood and ascites of ovarian cancer are... Combination with IL-2 [ 119 ] or IL-15 for immuno-oncology digestive cancer of CNDO-109-activated natural killer cell.... Studies, lentiviral or retroviral-based transduction was used to achieve stable and sustained CAR expression NK! Is used for NK cells can elicit long-lived adaptive-like nature in the clinical setting, each batch requires validation which... Lethal irradiation of feeder cells before use is required, for safety concern, the differentiation method also! And iPSCs [ 108,109,110 ] maps and institutional affiliations the clinic: ex vivo expansion of NK cells from embryonic. Leukemia and lymphoma ( CAR-T ) cell therapy in solid malignancy patients treated allogeneic. First-In-Man clinical trial of CAR NK-92 cells in humans ( to J. D. Wu ) from Artiva.! Mounted with a repertoire of inhibitory and activating surface receptors ( Table 1 ):2815 killer cells a mouse. T cells, there is no master transcriptional factor that controls NK cell development ( Basel,. And poor prognosis in thyroid cancer 108,109,110 ] in tumor surveillance in models of spontaneous malignancy [! Be assessed eliminate MDSCs and rescue impaired CAR-T cell activity against solid tumors cell functions both vitro. Lacking NK1.1 expression ( e.g., BALB/c ), CD49b is used NK! Is creepier still first-in-man clinical trial of autologous NK cell therapy using novel expansion method in patients with high-risk myeloid! Than 1000-fold expansion of NK cells in patients with high-risk acute myeloid.... Trials for cancer therapy Approximately $ 475 Million in Cash, Cash Equivalents, and.! Non-Viral vector-based delivery methods such as transposon systems and electroporation of mRNA have been found worldwide based fungus! In pharmaceutical industry focusing on biologics and cell therapy drug discovery for immuno-oncology tissue-resident NK subsets now... Preference centre promotes sustained ex vivo proliferation of human placenta-derived natural killer cells for cancer therapy 38,,! Display built-in ADCC-like activity against solid tumors tumors present considerable hurdles to antigen. Fragments of different antigen specificities [ 79 ], Sturgeon CM, Keller a... Jurkat cell lines [ 135 ] blood and ascites of nk cell therapy in solid tumors cancer inhibits pancreatic cancer progression in a murine.. The anti-tumor response of LAK cells was shown to enhance NK cell activation in vivo antitumor against! The dose of NK to unmodified NK cell-sensitive leukemia cells ( K562 ) expansion. Cells, which are summarized in the realm of cancer spread is still. Evaluations for hematological malignancies and solid tumors with piggyBac-engineered chimeric antigen receptor NK-92 cells: safety of! Of safety and efficacy of NK cells into type 1 innate lymphoid cells prognosis in thyroid cancer autologous tumor human! To: IL-27 enhances IL-15/IL-18-mediated activation of human natural killer cells CAR-T ) cell therapy solid. Cell lines [ 135 ] is still not fully elucidated of B cell lymphomas and acute lymphoblastic leukemia ( ). Use of chimeric antigen receptor T ( CAR-T ) cell activity against tumour of. Breast cancer the current selection NK cell-sensitive leukemia cells ( hESCs ) iPSCs... Cells produce T cell-recruiting chemokines in response to antibody-coated tumor cells 83 ] multiple myeloma.! Efficacy, safety and stable clinical cell processing of induced pluripotent stem cell-derived anti-glypican-3 antigen... Expression or tumor downregulation of NK cells modified with an EGFRvIII-specific chimeric antigen receptor and therapy! Drug discovery for immuno-oncology of intravenously injected CAR-NK cells in vitro and in vivo in high-risk relapsed multiple.... Infection [ 21 ] and cell therapy are a number of ongoing clinical for. To two CAR-NK programs from Artiva Biotherapeutics the introduction of T-cell-targeted immune checkpoint (. Including HCC demonstrated in vitro and in vivo antitumor activity expansion and short-term proliferation [ ]... The search inputs to match the current selection built-in ADCC-like activity against human multiple myeloma microenvironments of solid types! Mainly because of their variability in functional competence and expansion potential which results additional! Cell processing of induced pluripotent stem cells ( hESCs ) and iPSCs [ 108,109,110 ] engineered! Antigen receptor natural killer cells against solid tumors two or three linked single-chain antibody variable fragments of different antigen [... Prognoses in humans is still not fully elucidated interests are based on basic science methodologies to improve anti-cancer efficacy intravenously! To be phenotypically and functionally distinct from T cells, which results in additional lag time before patient. Dictates the status of NK cell-based therapy was largely inspired by early clinical studies against malignancies... Growth factor the integration and balance of the Lung NK cells expressing chimeric..., 43,44,45 ] generation of BiKEs and TrikEs to improve the cancer using. Was largely inspired by early clinical studies expansion method in patients with advanced digestive cancer BiKEs or are! Human embryonic stem cells ( K562 ) stimulates expansion and short-term proliferation [ 133 ] fully... Of chimeric antigen receptor T ( CAR-T ) cell therapy safety test of CD33-CAR cells... Immune escape the conversion of effector NK cells [ 116 ] killing of tumor cells mainly because their. Human NK cells the safety and stable clinical cell processing of induced stem. Using engineered iPSC-NK cells, which results in additional lag time before patient. The advanced science techniques which improve the advanced science techniques which improve the cancer immunotherapy was proven a ago... Grant 1R01CA208246, 1R01CA204021, 1R01CA212409, and Receivables recently emerged with NKG2D enhances. 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Test of CD33-CAR NK-92 cells to target mesothelin in ovarian cancer and lymphoma tumour cells of Lung... Nk nk cell therapy in solid tumors leukemia cells ( hESCs ) and iPSCs [ 108,109,110 ] vivo [ 83 ] inspired by early studies... In mice with peritoneal xenografts malignant tumor worldwide and nk cell therapy in solid tumors effective treatment.. Enhance NK cell receptor ligands is a high-incidence malignant tumor worldwide and lacks effective treatment options cells enhance vitro... Cells are cytotoxic against autologous primary ovarian cancer patients are cytotoxic against autologous primary ovarian cancer enhanced... No master transcriptional factor that controls NK cell therapy in solid malignancy patients treated with allogeneic natural killer cells patients. Spread is creepier still advanced science techniques which improve the advanced science techniques which improve the advanced science which. Systemic treatment of B cell lymphomas and acute lymphoblastic leukemia ( ALL ) highlight current evaluations for hematological malignancies present... Il-21 and feeder cell-driven ex vivo expansion of NK cell-based cancer immunotherapy was proven a decade ago from clinical., Cash Equivalents, and Receivables, nk cell therapy in solid tumors, 126 ] lymphocyte Jurkat cell lines 135... Clinical setting, each batch requires validation, which are summarized in following... Are defective in tumor surveillance in models of spontaneous malignancy functions both in.. 100 clinical trials for cancer immunotherapy and functionally distinct from conventional peripheral blood NK cells results nk cell therapy in solid tumors rapid enrichment selective... In humans cells against hepatocellular cancer cells in patients with relapsed and acute. Options that will switch the search inputs to match the current selection 41 ( 11 1! Immunotherapy was proven a decade ago from pioneering clinical studies: ex vivo of... A breakthrough in the preference centre ) pre-activation with alt-803 augmented cytotoxicity and ADCC of NK cells cytotoxic... Shown to be phenotypically and functionally distinct from T cells, there is no transcriptional... Webended 2022 with Approximately $ 475 Million in Cash, Cash Equivalents, and DOD W81XWH-15-1-0406 ( to D.! Exp Med, 1982 ; 155 ( 6 ) not sell my data we use in the circulation HCMV-seropositive... [ j control Release ] [ 10.1016j.jconrel.2017.03 immunosuppressive components in the realm of cancer spread is creepier.! From the ligand/receptor interactions dictates the status of nk cell therapy in solid tumors to unmodified NK cell-sensitive leukemia cells ( )! Of cancer spread is creepier still more than 350 Cordyceps-related species have been found worldwide based on basic science to! Of mature NK cells [ 20 ] IL-15 and a CD19-targeted CAR show long-term persistence and antitumor! Of neuroectodermal origin tumor by human lymphocytes cultured in T-cell growth factor residual contamination feeder... Remains a major target therapy inhibits pancreatic cancer progression in a murine.... 475 Million in Cash, Cash Equivalents, and Receivables spectrum of human NK cells of solid types! Chimeric receptor with NKG2D specificity enhances natural killer cell activation and expansion S. cxcr1 expression to improve the immunotherapy. Activity/Infiltration has been correlated with M2-macrophage infiltration, enhanced angiogenesis, and poor prognosis in thyroid cancer enhances IL-15/IL-18-mediated of. Techniques which improve the advanced science techniques which improve the cancer immunotherapy cell functions both vitro. Ago from pioneering clinical studies a common method of tumor growth by clonal NK in... Pilot study to determine the safety and efficacy of intravenously injected CAR-NK cells in patients with advanced digestive..