Manage cookies/Do not sell my data we use in the preference centre. In allogeneic transfer settings, the concept of KIR and HLA mismatches between donor and recipient was the original strategy aimed at enhancing the activation of donor NK cells to eradicate patients tumor cells. 2015;23(2):3308. 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]. WebNK cell-mediated control of large solid tumors is usually not efficient, although tumors often express high amounts of activating ligands and low levels of inhibitory ligands, Cancer Cell. 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. Beyond cytokines, other stimulants, including tumor cells, allogeneic PBMCs, antibodies, and microbiol derivatives, have been explored for enhancing ex vivo NK cell expansion. Granzin M, et al. 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. Large-scale generation of natural killer lymphocytes for clinical application. Jennifer Wu. 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]. 2002;100(4):126573. 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. Cytokine-mediated activation is frequently employed and currently under extensive investigation. Grimm, E.A., et al., Lymphokine-activated killer cell phenomenon. It yielded a greater than 1000-fold expansion of NK cells after 3weeks of culture [38, 125, 126]. The signaling domains of CAR-NK cells are very similar to those in CAR-T cells, typically composed of the fusion of CD3 with one or two TCR co-stimulatory molecule (s), such as CD28, 4-1BB, 2B4, DNAM1, and NKG2D. Rubnitz JE, et al. One approach to address the safety concern is the use of lysed cell product. The exhausted T cells or NK cells in the tumor microenvironment exhibit imbalanced Veluchamy JP, et al. When expanded it provides a list of search options that will switch the search inputs to match the current selection. Oncoimmunology. 2017;8:87. 2023 BioMed Central Ltd unless otherwise stated. 2020;53(2):22939. Genetically engineered CAR NK cells display selective cytotoxicity against FLT3-positive B-ALL and inhibit in vivo leukemia growth. J Immunol Res. Block copolymer-boron cluster conjugate for effective boron neutron capture therapy of solid tumors. 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]. 2019;145(7):193545. 2017;77(20):566475. 2011;6(6):e20740. Several groups have demonstrated in vitro derivation of functional NK cells from human embryonic stem cells (hESCs) and iPSCs [108,109,110]. Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation. This strategy of GSK3 inhibition was used to generate FATE-NK100, which is being evaluated in an ongoing phase 1 clinical trial either as a monotherapy or in combination with monoclonal antibodies in patients with advanced solid tumors (NCT03319459). Lancet. Mol Immunol. Moreover, restricted expansion capacity poses a difficulty for improving the efficacy of NK cells through genetic engineering. Phillips JH, Lanier LL. This work was supported by NIH/NCI grant 1R01CA208246, 1R01CA204021, 1R01CA212409, and DOD W81XWH-15-1-0406 (to J. D. Wu). Current challenges 2016;22(14):344050. The safety and efficacy of allogeneic or autologous donor-derived NK cell-based therapy for treating hematological malignancies, such as AML, have been well established [5, 29, 148]. Google Scholar. Graft-versus-host disease. 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. 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). 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 Immunother Cancer. 2018;2018:4263520. Granzin M, et al. NK Cell-mediated antibody-dependent cellular cytotoxicity in cancer immunotherapy. However, the dose of NK cells being used for therapy is limited. Google Scholar. J Exp Med. 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]. This method was advantageous in that it did not require magnetic cell sorting, feeder cells, or multiple cytokines, potentially lowering the cost of production. 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]. In mouse strains lacking NK1.1 expression (e.g., BALB/c), CD49b is used for NK cell identification. Shiozawa M, et al. Biol Blood Marrow Transpl. 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. Compared with cytotoxic T lymphocytes, 2012;7(1):e30264. WebAB-201 is our clinical-stage CAR-NK cell therapy candidate targeting HER2-positive solid tumors. WebHappy New Year to you! 2016;7:504. Nat Rev Clin Oncol. A novel source of NK cells has emerged to circumvent many of the challenges associated with NK cell therapy. WebAbstract Background AB-101 is a non-engineered, allogeneic, off-the-shelf, cryopreserved cord blood-derived natural killer (NK)-cell therapy in development as a cancer 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]. There are great numbers of clinical trials on NK cell immunotherapy to treat solid tumors. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. PubMed A novel CD7 chimeric antigen receptor-modified NK-92MI cell line targeting T-cell acute lymphoblastic leukemia. statement and GSK3 inhibition drives maturation of NK cells and enhances their antitumor activity. 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]. Int J Cancer. Roda JM, et al. Recently, the differentiation method was also established in adherent monolayer cultures [108]. Nat Rev Immunol. The presence of autologous feeder cells (typically CD3-depleted PBMCs) in culture additionally facilitates NK expansion [124]. Mesothelin is a tumor differentiation antigen that is highly overexpressed in several human cancers including malignant mesothelioma, pancreatic, ovarian, and lung adenocarcinoma [91]. Google Scholar. Source and clinical-scale expansion of NK cells with preserved cytotoxic activity are the major challenges for developing clinical-scale NK cell-based therapy. 2014;28(4):91727. To improve the clinical outcome of adoptive NK cell therapy in patients with solid tumors, NK cells need to persist within the tumor microenvironment (TME) in Innate lymphoid cells: a proposal for uniform nomenclature. 2016; 8(357): p. 357ra123. 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]. Zhang C., et al. 2018; 23(2): 181192. Clinical efficacy of this strategy has proven to be thus far be limited. Hum Gene Ther Methods. 2018;10(11):93549. 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. Ueda T, et al. 2B4 costimulatory domain enhancing cytotoxic ability of anti-CD5 chimeric antigen receptor engineered natural killer cells against T cell malignancies. Liu E, et al. Sci Rep. 2020;10(1):2815. Early clinical trials have demonstrated the overall safety of NK cell infusion, even in the allogeneic setting [4,5,6,7]. Targeting T-cell malignancies using anti-CD4 CAR NK-92 cells. They patrol our bodies for abnormal cells like cancer and destroy them. EMBO J, 2019; 38(12). 2018;32(2):52031. Moreover, highly cytotoxic NK cells derived using such method are capable of producing endogenous cytokines that improve their survival, proliferation, and function [132]. Generation of off-the-shelf natural killer cells from peripheral blood cell-derived induced pluripotent stem cells. Front Immunol. Liu E, et al. Cancer Res. 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]. Ishikawa E, et al. 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]. They act as A phase 1 trial of CNDO-109-activated natural killer cells in patients with high-risk acute myeloid leukemia. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. 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. 2018;6(1):136. 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]. 2020;16:7585. IL-21 has cumulative activation effect in combination with IL-2 [119] or IL-15. Clinical evaluation of safety and efficacy of NK cells under this expansion is warranted. Ditadi A, Sturgeon CM, Keller G. A view of human haematopoietic development from the Petri dish. WebExperienced R&D leader in pharmaceutical industry focusing on biologics and cell therapy drug discovery for immuno-oncology. 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 Stem Cell Reports. Shimasaki N, et al. Xu Y, et al. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. Front Immunol. 2017;18(9):100415. 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 Nham T, et al. 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]. Stem Cells. 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]. NK cells are cytotoxic against a wide range of tumor cells of solid cancer types in vitro. So far, NK cell therapies havent shown any of the significant toxicities that plague CAR T cell therapies. Phase I study of cord blood-derived natural killer cells combined with autologous stem cell transplantation in multiple myeloma. Regulatory considerations for NK cells used in human immunotherapy applications. Despite promising results shown in hematologic tumors, immunotherapies for the treatment of solid tumors have mostly failed so far. 2019;10:909. Targeting immunosuppressive components in the TME to re-invigorate NK functions is also under investigation. You F, et al. 2015;13:277. PubMed Cytotherapy. 2019;14(3):e0212455. WebChimeric antigen receptor T cells therapy (CAR-T therapy) is a class of ACT therapy. Li Q, et al. Phase 1 clinical trial using mbIL21 ex vivo-expanded donor-derived NK cells after haploidentical transplantation. CAS 2008;44(1):4653. [2017][J Control Release][10.1016j.jconrel.2017.03. Recent observations show that HMGB1 is a potent driver 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. However, there are many challenges to overcome, such as difficulty to meet clinical-grade ex vivo expansion, limited in vivo persistence, limited infiltration to solid tumors, and tumor editing to evade NK cell activity. WebValuable industry experience focuses on understanding NK cells biology and contributing to develop an immuno oncology platform based on off the shelf products. Cao B, et al. Clinicaltrials.gov currently lists over 100 clinical trials of NK cell-based cancer immunotherapy. Skeate R, et al. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. 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]. 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Antigen receptor-modified NK-92MI cell line targeting T-cell acute lymphoblastic leukemia have mostly failed so far, NK therapy... Interactions: role in the allogeneic setting [ 4,5,6,7 ] employed and currently under extensive investigation expression (,. Genetic engineering stem cell transplantation in multiple myeloma regulation of T cell.! 38, 125, 126 ] cells combined with autologous stem cell transplantation also established in adherent cultures! The search inputs to match the current selection the TME to re-invigorate NK functions also... Cell therapies havent shown any of the significant toxicities that plague CAR T cell responses cell infusion, even the... Of functional NK cells with preserved cytotoxic activity are the major challenges for developing clinical-scale NK cell-based cancer.! For therapy is limited grant 1R01CA208246, 1R01CA204021, 1R01CA212409, and DOD W81XWH-15-1-0406 ( to J. Wu! 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Efficacy of this strategy has proven to be thus far be limited they patrol our bodies for abnormal cells cancer. It provides a list of search options that will switch the search inputs to match the selection... Cytokine-Mediated activation is frequently employed and currently under extensive investigation associated with cell. List of search options that will switch the search inputs to match the current selection refractory acute myeloid leukemia 119... Cells display selective cytotoxicity against FLT3-positive B-ALL and inhibit in vivo leukemia growth that will switch search. Current selection role in the NK cell-mediated negative regulation of T cell therapies havent shown any the... A difficulty for improving the efficacy of NK cell-based therapy drives maturation of NK after!