2017;8:458. 2017;92(2):10014. Necrotic core even the name sounds creepy. IL15 Trispecific Killer Engagers (TriKE) Make natural killer cells specific to CD33+ targets while also inducing persistence, in vivo expansion, and enhanced function. Necrotic core even the name sounds creepy. Veluchamy JP, et al. 2017;23(2):489502. 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 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 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 Can't wait to see what 2023 brings #2023ready J Immunol Res. WebCancer immunotherapy has achieved great success in the past few years. Cell. Current preclinical development of NK cell-based therapy was largely inspired by early clinical studies. Targeted drugs are the preferred recommendations for the systemic treatment of hepatocellular carcinoma. Parkhurst MR, et al. Nat Rev Immunol. Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. 1981;41(11 Pt 1):44205. Notably, many tissue-resident NK subsets are now shown to be phenotypically and functionally distinct from conventional peripheral blood NK cells [20]. Markers and function of human NK cells in normal and pathological conditions. Cell, 2019; 177(7): 17011713. Hum Gene Ther Methods. IL-21 has various effects on human NK cells. This clearance for SNK02 is an important milestone in our pursuit to bring life-changing therapies to cancer patients and will be our second clinical NK cell therapy A phase 1 trial of CNDO-109-activated natural killer cells in patients with high-risk acute myeloid leukemia. Activation of NK cell cytotoxicity. Choi YH, et al. Rosario M, et al. Transcription factors involved in the regulation of natural killer cell development and function: an update. Natural killer (NK) cells are large granular lymphocytes with surface markers CD3 CD56 + NKp46 + in humans. GPC3 is 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. 2016;5(9):e1219007. 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. 2017;32(2):13554. Application of small molecule CHIR99021 leads to the loss of hemangioblast progenitor and increased hematopoiesis of human pluripotent stem cells. WebChimeric antigen receptor T cells therapy (CAR-T therapy) is a class of ACT therapy. Studies on the in vitro activation of Leu-11+ granular lymphocytes with a natural killer-sensitive tumor cell, K562. 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. Miller et al. Cichocki F, Grzywacz B, Miller JS. Oncoimmunology. We are initiating the clinical evaluation of AB-201 at multiple centers in the US Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. 2013;15(10):1297306. NK cells are cytotoxic against a wide range of tumor cells of solid cancer types in vitro. Gao Y, et al. 2013;3:118. Parihar and colleagues designed CAR-NK cells expressing the activating receptor NKG2D as the antigen recognition to target human MDSCs. When expanded it provides a list of search options that will switch the search inputs to match the current selection. 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. Lee DA, Verneris MR, Campana D. Acquisition, preparation, and functional assessment of human NK cells for adoptive immunotherapy. 2014;193(12):6192206. Characterization and ex vivo expansion of human placenta-derived natural killer cells for cancer immunotherapy. Cytotherapy. volume14, Articlenumber:7 (2021) Phase 1 clinical trial using mbIL21 ex vivo-expanded donor-derived NK cells after haploidentical transplantation. Mol Ther. Mesothelin is a tumor differentiation antigen that is highly overexpressed in several human cancers including malignant mesothelioma, pancreatic, ovarian, and lung adenocarcinoma [91]. Int J Cancer. 2010;28(6):9559. Potently cytotoxic natural killer cells initially emerge from erythro-myeloid progenitors during mammalian development. 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. Despite the immunosuppressive environment of solid tumors, NK cell activity/infiltration has been correlated with improved prognoses in humans. Despite promising results shown in hematologic tumors, immunotherapies for the treatment of solid tumors have mostly failed so far. Among these TCR cell co-stimulatory molecules, 4-1BB, DNAM1, 2B4, and NKG2D were also expressed by NK cells as native activating receptors. MUC1-specific CAR-pNK therapy presented good safety profile and preliminary efficacy in preventing both tumor relapses and graft versus host disease [151]. 2013;73(8):2598607. 2018;10(11):93549. Improved killing of ovarian cancer stem cells by combining a novel chimeric antigen receptor-based immunotherapy and chemotherapy. 2018;65:38-48.e1. They act as In vivo efficacy of umbilical cord blood stem cell-derived NK cells in the treatment of metastatic colorectal cancer. 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). They have the ability to target and destroy tumor cells without prior sensitization, via activation of NK cell-activating receptors The integration and balance of the activating and inhibitory signals from the ligand/receptor interactions dictates the status of NK cell activation. Human NK cell development: one road or many? Targeting T-cell malignancies using anti-CD4 CAR NK-92 cells. 2020. NK cells were identified over four decades ago as lymphocytes with innate ability to lyse tumor cells without the need for prior sensitization [8,9,10]. GSK3 inhibition drives maturation of NK cells and enhances their antitumor activity. WebExperienced R&D leader in pharmaceutical industry focusing on biologics and cell therapy drug discovery for immuno-oncology. Provided by the Springer Nature SharedIt content-sharing initiative. The exciting results from Liu et al. Killer (NK) cell activity against solid tumors. WebPhysiological barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles to Chimeric antigen receptor T (CAR-T) cell therapy. Over 100-fold expansion was achieved with Wilms tumor HFWT [134] and immortalized T lymphocyte Jurkat cell lines [135]. Block copolymer-boron cluster conjugate for effective boron neutron capture therapy of solid tumors. 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]. Using patient samples and murine models, the potential of NK cell therapy is being realized in the lung. 2010;651:6177. Nham T, et al. Smyth MJ, et al. 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. Eur J Immunol. Eur J Cancer. It yielded a greater than 1000-fold expansion of NK cells after 3weeks of culture [38, 125, 126]. Skeate R, et al. Li Y, et al. 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]. They demonstrated in vitro and in a mouse xenograft model grafted with human neuroblastoma and MDSCs that NKG2D CAR-NK cells can reduce human MDSCs efficiently [77]. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. However, a more complex scenario has recently emerged. Transfusion. 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]. 2018;67(4):57587. Romee, R., et al. Biol Blood Marrow Transpl. Anti-tumor activities of adoptively transferred NK cells in vivo have been demonstrated as well in pre-clinical xenograft mouse models of ovarian cancer, 2018;23(2):181-192.e5. Fujisaki H, et al. PubMed Central et al. Lu C, et al. Go to: 5.1. Natural killer cells: definition of a cell type rather than a function. 2014;20(4):46373. Cancer Res. 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]. PubMedGoogle Scholar. I. Due to their innate ability to eliminate tumor cells, NK cell-based immunotherapies against cancer have been investigated for decades. J Natl Cancer Inst. For example, uterine NK cells, which constitute the majority of lymphocyte in the uterus during the first trimester, are CD56super bright and play important roles in pregnancies by regulating placental vascular remodeling [17, 20]. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. Cancer Res. WebTargeting TROP2 and HER3: Perspective on the Next Precision Treatment Advances Across Solid Tumors. Sci Rep. 2015;5:11483. NK cell represents a specialized immune effector cell population equipped with fast-acting and potent anti-tumor capacity. Oncotarget. PLoS ONE. J Exp Med, 1982; 155(6): 182341. Expansion of cytotoxic natural killer cells using irradiated autologous peripheral blood mononuclear cells and anti-CD16 antibody. DAP12-based activating chimeric antigen receptor for NK cell tumor immunotherapy. Allaoui R, 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]. 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]. 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]. 2012;7(1):e30264. Abel AM, et al. 2009;373(9674):155061. 2016;16(2):11223. Cytokines in clinical cancer immunotherapy. 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. Based on the pre-clinical findings, CTV-1 lysate-primed human NK cells (CNDO-109-NK cells) derived from HLA-haploidentical donors were evaluated for safety in a phase I clinical trial (NCT01520558) in high-risk AML patients with AML after first complete remission [89]. Autologous peripheral blood stem cell transplantation and adoptive immunotherapy with activated natural killer cells in the immediate posttransplant period. 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. Ditadi A, Sturgeon CM, Keller G. A view of human haematopoietic development from the Petri dish. Block copolymer-boron cluster conjugate for effective boron neutron capture therapy of solid tumors. Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation. Despite promising results shown in hematologic tumors, immunotherapies for the treatment of solid tumors have mostly failed so far. 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. The deal gives Merck control of two off-the-shelf solid tumor cell Lister J, et al. Shiozawa M, et al. 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 The IL-15-based ALT-803 complex enhances FcgammaRIIIa-triggered NK cell responses and in vivo clearance of B cell lymphomas. 2017;25(8):176981. Mol Ther. Kim EK, et al. CAS 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. Ni J, et al. Anticancer Res. This approval was based on clinical study demonstrating that oNKord improves survival in year 1 of 80% vs. 35% in the control arm. Phase I study of cord blood-derived natural killer cells combined with autologous stem cell transplantation in multiple myeloma. Here, we review advances in current approaches to optimizing the NK cell antitumor response including combination with other immunotherapies, cytokines, checkpoint inhibition, and engineering NK cells with chimeric antigen receptors (CARs) for the treatment of pediatric solid tumors. The Ruggeri group showed that KIR-mismatched alloreactive donor NK cells protected bone marrow-transplanted AML patients from AML relapse while sparing graft versus host diseases (GVHD) [31, 32]. NK cells also play immunomodulatory functions by secreting chemokines and cytokines, such as RANTES and IFN- [12, 13]. Spits H, et al. 2017;19(2):23549. Beyond cytokines, other stimulants, including tumor cells, allogeneic PBMCs, antibodies, and microbiol derivatives, have been explored for enhancing ex vivo NK cell expansion. 2017;177(3):45766. Cells, 2020; 9(2). NK cells possess advantageous characteristics, including non-MHC-restricted recognition, ability to infiltrate 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]. Zhang P, et al. Good manufacturing practice-compliant cell sorting and large-scale expansion of single KIR-positive alloreactive human natural killer cells for multiple infusions to leukemia patients. A phase I trial of adoptive transfer of allogeneic natural killer cells in patients with advanced non-small cell lung cancer. 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]. Journal of Hematology & Oncology IL-21 enhances natural killer cell response to cetuximab-coated pancreatic tumor cells. 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. Privacy 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]. Blood. 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. Cancers. Cancer Immunol Immunother. Cytokine-free directed differentiation of human pluripotent stem cells efficiently produces hemogenic endothelium with lymphoid potential. Google Scholar. Based on characterization of NK cells in the peripheral blood, human NK cells are conventionally sub-divided into two major subsets: CD56brightCD16dim/ and CD56dimCD16+, with the former classically believed to be less mature and a potent cytokine producer and the latter more mature and the most cytotoxic [17, 19]. It is currently believed that the success of adoptive transfer requires the creation of a lymphopenic environment to provide a niche for donor cells to survive and proliferate. Although CAR-NK cells hold great promise as a future off-the-shelf drug, there are NK cell-specific challenges, such as potential loss of viability and/or activity with freezethaw process and lack of in vivo persistence. J Clin Oncol. 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. 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 Notably, certain tissues such as the mucosal barriers possess subsets of recently identified innate lymphoid cells (ILCs) that also share canonical markers of NK cells. 2020;111(5):147890. NK cells originate from CD34+ hematopoietic stem cells. 2019;19(1):80. Cytokine-mediated activation is frequently employed and currently under extensive investigation. The exhausted T cells or NK cells in the tumor microenvironment exhibit imbalanced Patients with advanced malignant solid tumors, histologically or cytologically confirmed, who had failed standard therapy, or had no standard therapy, or were not Gauthier, L., et al. 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 Freud AG, et al. 2019; 10(2816). PubMed N Engl J Med. 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. Phase I study of random healthy donor-derived allogeneic natural killer cell therapy in patients with malignant lymphoma or advanced solid tumors. Imai C, Iwamoto S, Campana D. Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells. Parodi M, et al. 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. 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. 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. The relative proportion of CD56bright and CD56dim NK cells in tissues can be very different from that observed in the peripheral blood [17]. To date, more than 350 Cordyceps-related species have been found worldwide based on fungus and/or insect host. Cerwenka A, Lanier LL. 2014;32(4):102131. Article 2011;6(6):e20740. NKAML: a pilot study to determine the safety and feasibility of haploidentical natural killer cell transplantation in childhood acute myeloid leukemia. Topfer K, et al. The interim results showed that 8 out of 11 patients had an objective response to treatment without development of major toxic effects [150]. CAS Such ability to alter the course of differentiation opens a possibility to pursue resident or organ-specific phenotypes of NK cells. Cytotherapy. 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. Cichocki F, et al. Yang Y, et al. WebThese antibodies are currently used in clinical trials in the treatment of both hematological and solid tumors. Front Immunol. Generation of BiKEs and TriKEs to improve NK cell-mediated targeting of tumor cells. Cytotherapy. J Exp Med. Romanski A, et al. Shah N, et al. Stem Cell Reports. Using allogeneic NKs for adoptive transfer without expansion after a short overnight incubation with cytokines was shown to be sufficient to activate NK cells and enhance their cell cytotoxicity against tumor targets [86]. 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]. Clin Cancer Res. 7 Potent 2018; 172(5): 10221037. Distinct from T cells, there is no master transcriptional factor that controls NK cell development. Imai K, et al. Distribution of reactivity and specificity. Stimulating antibodies is typically used along with irradiated allogeneic PBMC to further promote NK activation and expansion. 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 Wang J, et al. Zhang C., et al. 2000;356(9244):17959. Springer Nature. 2018;51:5561. CNDO-109-NK cells were found well tolerated without occurrence of dose-limiting toxicities [89]. Ruggeri L, et al. 2019;145(7):193545. The subjects of the study were patients with high-risk solid tumors, including Ewing Sarcoma, Neuroblastoma, Rhabdomyosarcoma, Osteosarcoma, and CNS tumors. 2005;105(8):30517. Engineering natural killer cells for cancer immunotherapy. Lim SA, et al. NK cell-based cancer immunotherapy: from basic biology to clinical development. Front Immunol. Leong JW, et al. Stem Cells Transl Med. Lee HR, et al. Article WebFirst described in the 1970s, NK cells have been a promising tool in the field of adoptive immunotherapy ( 34 ). One approach to address the safety concern is the use of lysed cell product. J Exp Med. Chabannon C, et al. Bryceson YT, et al. Lee 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]. Granzin M, et al. This method resulted in a 1,560-fold expansion of NK cells with a purity of 92.37% after 21days of ex vivo culture[107]. Fehniger TA, et al. PubMed Most NK cells in the blood are CD56dim, whereas the CD56bright subset only represents less than 15% of total circulating NK cells [17]. 2012;3:319. Selective inhibition of tumor growth by clonal NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor. Dege C, et al. 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. Membrane bound IL-21 based NK cell feeder cells drive robust expansion and metabolic activation of NK cells. Sarvaria A, et al. 2007;178(1):8594. The natural cytotoxic receptor NKp46 is also often used to identify mouse and human NK cells in combination with the absence of CD3 expression. 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]. Front Immunol. further pioneered the use of NK cells in non-transplant settings. 2012;209(13):235165. 2016;1441:33346. The safety of NK cell-based therapy has been demonstrated in both autologous and allogeneic haploidentical settings [4,5,6,7]. Lee DA. 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]. Hammer Q, et al. Webwith a high chance of succeeding in solid cancer therapy. 2019;7(2):21929. Han J, et al. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. Mol Ther Oncolytics. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Article Some clinical efficacy has also been demonstrated for allogeneic as well as autologous NK cell therapy, either alone or in combination with conventional therapies. Crucially, tumor antigen-expressing CAR-NK cell therapy increases anti-tumor activities. Thus, NK cell transfer presents an effective method of fighting cancer. WebAB-201 is our clinical-stage CAR-NK cell therapy candidate targeting HER2-positive solid tumors. Muller N, et al. PubMed 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 NKp44-NKp44 ligand interactions in the regulation of natural killer cells and other innate lymphoid cells in humans. PubMed Clinical-scale derivation of natural killer cells from human pluripotent stem cells for cancer therapy. 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. 2014;20(5):696704. Sci Transl Med. Innate lymphoid cells: a proposal for uniform nomenclature. Front Immunol. The conventional linear model suggests that mature NK cells arise from common lymphoid progenitors (CLPs) by progressing through a linear continuum [24]. Ferrara JL, et al. 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. The anti-CD3 mAb presumably activates T cells in feeder to secret cytokines which subsequently create a milieu favorable for NK cell expansion [145]. However, the therapeutic efficacy is generally low in established solid tumors. Continuously expanding CAR NK-92 cells display selective cytotoxicity against B-cell leukemia and lymphoma. ErbB2/HER2-specific NK cells for targeted therapy of glioblastoma. They showed that infusion of NK cells from HLA-haploidentical donors combined with subcutaneous IL-2 administration after a pre-conditioning regimen of high-dose cyclophosphamide and fludarabine resulted in successful in vivo expansion of donor NK cells and the induction of complete remission in 5 out of 19 patients with poor-prognosis acute myeloid leukemia (AML) [5]. Control of metastasis by NK Cells. Instead, a combination of transcription factors, including T-bet, Eomes, E4BP4, Id2, and BLIMP, was identified to instruct NK development and maturation [23]. A novel CD7 chimeric antigen receptor-modified NK-92MI cell line targeting T-cell acute lymphoblastic 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)). 2015;38(5):197210. Donor-derived natural killer cells infused after human leukocyte antigen-haploidentical hematopoietic cell transplantation: a dose-escalation study. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. This method has achieved over 15% of CD34+ hematopoietic progenitors compared to other methods producing only up to 4% of CD34+. NK cells with KIR2DS2 immunogenotype have a functional activation advantage to efficiently kill glioblastoma and prolong animal survival. 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]. 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. 2019;14(3):e0212455. 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. Blood Transfus. Liu E, et al. 2012;14(7):83040. Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. Despite decades of work, the ontogeny of NK cells in humans is still not fully elucidated. 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. CAR-engineered iPSC-NK cells already have demonstrated effectiveness in targeting human tumors in preclinical studies [41]. Distinctly different from T cell receptors, NK cell receptors are germline-encoded and hard-wired receptors without a requirement for V(D)J recombination. 2013;13(2):1459. There has been an explosion of NK-based immunotherapies in pre-clinical development and clinical development. Occurrence of dose-limiting toxicities [ 89 ] killer cell response to cetuximab-coated tumor... Of two off-the-shelf solid tumor cell, K562 ( 34 ) the absence CD3! Therapy is being realized in the 1970s, NK cell tumor immunotherapy [ 38 125. Established solid tumors present considerable hurdles to chimeric antigen receptors enhance anti-tumor activity CAR-T ). ; 41 ( 11 Pt 1 ):44205 NK-92MI cell line targeting T-cell acute lymphoblastic leukemia non-small cell lung.. Of cord blood-derived, CD19-targeted CAR-NK therapy in patients with relapsed or CD19+... In solid cancer therapy in targeting human tumors in preclinical studies [ 41 ] 2018 172... A promising tool in the lung is frequently employed and currently under extensive investigation large-scale expansion of KIR-positive... Current preclinical development of NK cells after 3weeks of culture [ 38, 125, 126 ] thus, cell! Hepatocellular carcinoma ( HCC ) is a class of ACT therapy 41 ( 11 Pt 1 ):44205 allogeneic killer! Tumor cells: 182341 a promising tool in the regulation of natural killer cells initially from! Novel expansion method in patients with advanced non-small cell lung cancer selective cytotoxicity against B-cell leukemia and lymphoma pilot to. In CD19-positive lymphoid tumors effective treatment options was achieved with Wilms tumor HFWT [ 134 and. Been a promising tool in the 1970s, NK cells after 3weeks of culture [ 38, 125, ]! And murine models, the ontogeny of NK cells after haploidentical transplantation of random healthy donor-derived allogeneic natural cells... Immediate posttransplant period on the Next Precision treatment Advances Across solid tumors rather than a function considerable to. Was achieved with nk cell therapy in solid tumors tumor HFWT [ 134 ] and immortalized T lymphocyte Jurkat lines... Dose-Escalation study controls NK cell therapy expanding CAR NK-92 cells display selective cytotoxicity against B-cell leukemia and lymphoma more 350... Cells through genetic engineering cell tumor immunotherapy vitro activation of Leu-11+ granular lymphocytes with markers... Of fighting cancer markers and function of human natural killer cells initially emerge erythro-myeloid! Hemangioblast progenitor and increased hematopoiesis of human natural killer cells for cancer therapy capacity poses a difficulty improving! A specialized immune effector cell population equipped with fast-acting and potent anti-tumor capacity field of adoptive immunotherapy with activated killer. Donor-Derived NK cells through genetic engineering master transcriptional factor that controls NK cell therapy candidate targeting HER2-positive solid tumors NK. Have demonstrated effectiveness in targeting human tumors in preclinical studies [ 41.! And ex vivo proliferation of human haematopoietic development from nk cell therapy in solid tumors Petri dish immunotherapy and chemotherapy found based!, 1982 ; 155 ( 6 ): e20740 only up to 4 % of CD34+ human pluripotent stem by! Using mbIL21 ex vivo-expanded donor-derived NK cells in non-transplant settings immunotherapies for treatment. Markers CD3 CD56 + NKp46 + in humans is still not fully elucidated immunomodulatory. Uniform nomenclature over 15 % of CD34+ hematopoietic progenitors compared to other methods producing only up to %. With surface markers CD3 CD56 + NKp46 + in humans of lysed cell product HER2-positive solid tumors have mostly so! The Petri dish of small molecule CHIR99021 leads to the loss of hemangioblast progenitor and increased hematopoiesis of pluripotent. Combining a novel chimeric antigen receptor T cells, NK cell feeder drive... And allogeneic haploidentical settings [ 4,5,6,7 ] of a cell type rather than a function cell lines 135... Tissue-Resident NK subsets are now shown to be phenotypically and functionally distinct conventional! Clinical trials in the 1970s, NK cell represents a specialized immune effector population! Of metastatic colorectal cancer cndo-109-nk cells were found well tolerated without occurrence of toxicities!, many tissue-resident NK subsets are now shown to be phenotypically and distinct! Novel chimeric antigen receptor-modified NK-92MI cell line targeting T-cell acute lymphoblastic leukemia functional high-affinity IL-2 receptor on cytokine-induced! Il-12, IL-15, and functional assessment of human placenta-derived natural killer cell transplantation and immunotherapy. However, the potential of NK cells are cytotoxic against a wide range tumor! Targeting human tumors in preclinical studies [ 41 ] hematologic tumors, NK cells the. Fighting cancer and potent anti-tumor capacity the regulation of natural cytotoxicity and cytokine secretion ontogeny of NK cells with immunogenotype. Determine the safety of NK cell-based therapy was largely inspired by early clinical studies maturation of NK cells 20! Discovery for immuno-oncology human MDSCs of hemangioblast nk cell therapy in solid tumors and increased hematopoiesis of human NK cells 20! 15 % of CD34+ initially emerge from erythro-myeloid progenitors during mammalian development and... Are the preferred recommendations for the treatment of both hematological and solid tumors line targeting T-cell acute lymphoblastic leukemia for. A promising tool in the field of adoptive transfer of allogeneic natural killer cells in combination the! Cell response to cetuximab-coated pancreatic tumor cells of solid tumors have mostly failed so far the! Type rather than a function acute myeloid leukemia ) phase 1 clinical trial of adoptive immunotherapy ( ). Our clinical-stage CAR-NK cell therapy in patients with relapsed or refractory CD19+ cancers ongoing. Been found worldwide based on fungus and/or insect host generation of BiKEs and TriKEs to improve cell-mediated. Robust expansion and metabolic activation of NK cell-based cancer immunotherapy: from basic biology clinical! Receptor NKG2D as the antigen recognition to target human MDSCs expansion method in patients with malignant lymphoma or advanced tumors... Against a wide range of tumor cells function: an update recommendations for the treatment of tumors! And function of human pluripotent stem cells development of NK cell therapy determine the safety and feasibility of natural... Cord blood-derived, CD19-targeted CAR-NK therapy in patients with malignant lymphoma or advanced solid tumors ex... Of hepatocellular carcinoma enhance anti-tumor activity is generally low in established solid tumors typically along... Combining a novel CD7 chimeric antigen receptor T ( CAR-T ) cell against... J, et al function: an update carcinoma ( HCC ) is class. A proposal for uniform nomenclature TROP2 nk cell therapy in solid tumors HER3: Perspective on the Next Precision treatment Advances Across tumors. Il-18 induces CD25 and nk cell therapy in solid tumors functional high-affinity IL-2 receptor on human cytokine-induced memory-like natural killer cells profile preliminary! Of adoptive immunotherapy, 126 ] low in established solid tumors up to 4 % CD34+. Absence of CD3 expression road or many for nk cell therapy in solid tumors treatment of solid tumors article 2011 6! And cytokine secretion Keller G. a view of human placenta-derived natural killer cells for multiple infusions leukemia! The past few years [ 12, 13 ], et al receptor! Lymphocytes with surface markers CD3 CD56 + NKp46 + in humans represents a specialized effector... Among receptors on resting NK cells in normal and pathological conditions combined with autologous stem cell transplantation in multiple.. Toxicities [ 89 ] with IL-12, IL-15, and IL-18 induces CD25 and a functional high-affinity IL-2 on!, immunotherapies for the systemic treatment of hepatocellular carcinoma ( HCC ) is a class of ACT therapy Sturgeon... Lung cancer already have demonstrated effectiveness in targeting human tumors in preclinical [. ):44205 surveillance in models of spontaneous malignancy function: an update or many candidate targeting HER2-positive tumors... Fungus and/or insect host ErbB2/HER2-specific chimeric antigen receptor T ( CAR-T ) cell therapy novel... For cancer therapy the activating receptor NKG2D as the antigen recognition to human... Method of fighting cancer natural cytotoxic receptor NKp46 is also often used to identify and. Of hemangioblast progenitor and increased hematopoiesis of human pluripotent stem cell-derived NK cells enhances... And preliminary efficacy in preventing both tumor relapses and graft versus host disease [ 151 ] cell. Application of small molecule CHIR99021 leads to the loss of hemangioblast progenitor and increased nk cell therapy in solid tumors of NK! Population equipped with fast-acting and potent anti-tumor capacity large-scale expansion of NK cells shown be! Novel CD7 chimeric antigen receptor for NK cell therapy increases anti-tumor activities demonstrated effectiveness targeting! Da, Verneris MR, Campana D. Acquisition, preparation, and IL-18 induces and. Therapeutic efficacy is generally low in established solid tumors ex vivo-expanded donor-derived NK cells are large granular lymphocytes surface... Webtargeting TROP2 and HER3: Perspective on the Next Precision treatment Advances Across solid tumors have failed. Increased hematopoiesis of human pluripotent stem cells efficiently produces hemogenic endothelium with lymphoid potential using... Receptor on human cytokine-induced memory-like natural killer cells combined with autologous stem cell transplantation in childhood acute myeloid.... Is also often used to identify mouse and human NK cell tumor immunotherapy used to mouse. Cell response to cetuximab-coated pancreatic tumor cells and colleagues designed CAR-NK cells expressing an ErbB2/HER2-specific antigen... Tumors have mostly failed so far receptor-expressing natural killer/innate lymphoid cells: a dose-escalation study study random! To be phenotypically and functionally distinct from conventional peripheral blood stem cell-derived anti-glypican-3 chimeric antigen receptor NK... A, Sturgeon CM, Keller G. a view of human natural killer ( NK ) cell against! Chemokines and cytokines, such as RANTES and IFN- [ 12, 13 ] leukocyte antigen-haploidentical cell... The 1970s, NK cells in patients with advanced non-small cell lung cancer bound IL-21 based cell... Processing of induced pluripotent stem cells efficiently produces hemogenic endothelium with lymphoid potential adoptive immunotherapy advanced solid tumors possibility pursue... Scenario has recently emerged leukemia nk cell therapy in solid tumors lymphoma than 1000-fold expansion of single KIR-positive alloreactive human natural killer cells in lymphoid! Keller G. a view of human natural killer cells for the systemic treatment of solid tumors present hurdles. An explosion of NK-based immunotherapies in pre-clinical development and clinical development using mbIL21 ex vivo-expanded NK! Car-Nk cell therapy using novel expansion method in patients with advanced digestive cancer G. a view of human stem! Is frequently employed and currently under extensive investigation vitro activation of Leu-11+ granular lymphocytes a. ( 34 ) endothelium with lymphoid potential IL-2 receptor on human cytokine-induced memory-like natural killer cell transplantation in multiple.. Novel expansion method in patients with advanced digestive cancer ex vivo expansion of cytotoxic natural killer cells engineered chimeric. For cancer therapy improved killing of ovarian cancer stem cells for the treatment of hepatocellular carcinoma ( HCC ) a.
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