Schonfeld K, et al. Beyond directing CAR-NK cytotoxicity against tumor cells by targeting tumor antigens, it has been proposed that CAR-NK cells can be used to eliminate immunosuppressive immune cells in the tumor microenvironment that include myeloid-derived suppressor cells (MDSCs) and M2 tumor-associated macrophages (TAMs) [77, 78]. Advances in clinical NK cell studies: donor selection, manufacturing and quality control. Blood. 2019;10:2078. Natural killer (NK) cell is a specialized immune effector cell type that plays a critical role in immune activation against abnormal cells. CAR-NK is one of the approaches in development to overcome this limitation. Liu E, et al. Zeng J, et al. 2016;1441:33346. Grimm, E.A., et al., Lymphokine-activated killer cell phenomenon. A novel source of NK cells has emerged to circumvent many of the challenges associated with NK cell therapy. Immunobiology. In vivo efficacy of umbilical cord blood stem cell-derived NK cells in the treatment of metastatic colorectal cancer. Sci Transl Med. 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]. Most NK cells in the blood are CD56dim, whereas the CD56bright subset only represents less than 15% of total circulating NK cells [17]. Pinz KG, et al. 2010;651:6177. Science. Dev Cell. Cancers (Basel), 2020; 12(6). Exposure of NK to unmodified NK cell-sensitive leukemia cells (K562) stimulates expansion and short-term proliferation [133]. For example, a subset of IL-22 secreting human ILC3s is CD56+NKp46+CD3 [14]. Int J Cancer. Nham T, et al. 2015;220(7):87688. Oyer JL, et al. Stem Cell Reports. Knorr DA, et al. 2010;59(12):17819. 2015;15:1011. Blood. Imai C, Iwamoto S, Campana D. Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells. Google Scholar. Cell Stem Cell. J Natl Cancer Inst. They patrol our bodies for abnormal cells like cancer and destroy them. Han J, et al. Google Scholar. There are a number of ongoing clinical trials for cancer immunotherapy using engineered iPSC-NK cells, which are summarized in the following sections. Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. Expansion of highly cytotoxic human natural killer cells for cancer cell therapy. 2015;13(3):46471. 2020;382(6):54553. 2018; 23(2): 181192. 2019;10:909. Galat Y, et al. The mechanism of CTV-1-mediated NK priming is unclear. 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. The anti-CD3 mAb presumably activates T cells in feeder to secret cytokines which subsequently create a milieu favorable for NK cell expansion [145]. NK Cells of the Lung Recently, the FDA has approved the investigational new drug (IND) for the use of placenta-expanded NK cells (CYNK-001) against glioblastoma (GBM). Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. WebCancer immunotherapy has achieved great success in the past few years. CAS 2019;19(1):80. 2019;7(3):36375. 2020;122:2006. 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 2015;194(7):320112. Oberschmidt O, et al. The book is a valuable resource for cancer researchers, oncologists, graduate students and those interested in learning more about novel strategies to treat cancer patients. Phillips JH, Lanier LL. It is iPSC-differentiated NK cells (iPSC-NK). Front 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. 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 Despite the immunosuppressive environment of solid tumors, NK cell activity/infiltration has been correlated with improved prognoses in humans. 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]. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. As an alternative to CAR-T cell therapy, CAR-NK cell therapy not only circumvents these challenges but also presents additional major advantages: (i) the ability to use unlimited allogeneic NK source without concern of GVHD [6, 31, 32]; (ii) the potential to generate off-shelf product with NK cell line or iPSC-NK [37,38,39,40,41]; (iii) relatively shortened production time; iv) recognition and killing tumor cells through NK cell native receptors independent of the CAR engineering [42], less likely allowing disease escape through downregulation of the CAR antigens as shown with CAR-T cell therapy [37]. Google Scholar. Characterization of the maturation stage of NK cells demonstrated that RLI favored accumulation of CD11b⁺ CD27^high KLRG1⁺ The subjects of the study were patients with high-risk solid tumors, including Ewing Sarcoma, Neuroblastoma, Rhabdomyosarcoma, Osteosarcoma, and CNS tumors. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. Recent studies revealed that subset of mature NK cells can elicit long-lived adaptive-like nature in the specific context of CMV infection [21]. Challenges in CAR NK cell therapy in solid tumors. Front Immunol. Genssler S, 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]. 2016;18(1):8090. 2015;13:277. 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. Cytotherapy. Many efforts are emerging for developing and engineering NK cell-based cancer immunotherapy. They induce short-term activation of NK cells but do not support effective expansion without feeder cells. The trial is Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes. 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). In mouse, the lack of CD3 and the presence of NK1.1 are canonical criterion for distinguishing NK cells. Ojo EO, et al. Siegler U, et al. Carlsten M, 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. 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]. A first-in-human clinical trial of CAR NK-92 cells in 3 patients with relapsed or refractory AML showed that CAR NK-92 can be infused at doses up to 5 billion cells per patient without causing significant adverse effects [149]. 2012;3:408. 7 Potent The other important feature of iPSC-NK cell technology is the ability to manipulate the differentiation strategy, thus shaping the phenotype and functionality of the resulting product. The FDA has cleared Artiva Biotherapeutics investigational new drug (IND) application for the chimeric antigen receptor NK (CAR-NK) cell therapy AB-201 for the 2020;12:324755. 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. Bryceson YT, et al. 2016;20(7):128794. Engineering NK cells modified with an EGFRvIII-specific chimeric antigen receptor to overexpress CXCR4 improves immunotherapy of CXCL12/SDF-1alpha-secreting glioblastoma. 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 Huang Y, et al. NK cell-based cancer immunotherapy: from basic biology to clinical development. Phase I study of random healthy donor-derived allogeneic natural killer cell therapy in patients with malignant lymphoma or advanced solid tumors. Denman CJ, et al. For instance, the enhancement of the Wnt signaling pathway with GSK3b inhibitor induces definitive hematopoiesis [112, 113] NK cells developed in such conditions had more pronounced inflammatory cytokine production phenotype, whereas Wnt independent NK subsets, similar to primary fetal NK cells, formed a bias for increased cytotoxicity [110]. J Clin Oncol. Cookies policy. Transcription factors involved in the regulation of natural killer cell development and function: an update. Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine secretion. Intraperitoneal delivery of human natural killer cells for treatment of ovarian cancer in a mouse xenograft model. Veluchamy JP, et al. 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. Ishikawa E, et al. Google Scholar. Int J Cancer. 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 ]. The ability of Natural Killer (NK) cells to kill tumor targets has been extensively studied in various hematological malignancies. 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. Oelsner S, et al. Stem Cell Res Ther. NKp44-NKp44 ligand interactions in the regulation of natural killer cells and other innate lymphoid cells in humans. Early clinical trials have demonstrated the overall safety of NK cell infusion, even in the allogeneic setting [4,5,6,7]. NK CELL-BASED THERAPY IN SOLID. Pharmacologically upregulated carcinoembryonic antigen-expression enhances the cytolytic activity of genetically-modified chimeric antigen receptor NK-92MI against colorectal cancer cells. 2012;14(7):83040. Using irradiated autologous PBMCs and anti-CD16 mAb, Lee et al. Targeting immunosuppressive components in the TME to re-invigorate NK functions is also under investigation. 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]. 2008;44(1):4653. Front Immunol. J Cell Mol Med. WebChimeric antigen receptor T cells therapy (CAR-T therapy) is a class of ACT therapy. NK cell-based cancer immunotherapy: from basic biology to clinical development. Sci Rep. 2017;7(1):11075. 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. Ni Z, et al. Application of small molecule CHIR99021 leads to the loss of hemangioblast progenitor and increased hematopoiesis of human pluripotent stem cells. WebPhysiological barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles to Chimeric antigen receptor T (CAR-T) cell therapy. 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. Natural killer (NK) cells have potential as a cellular anticancer therapy that could be significantly safer, cheaper, and faster, researchers say. Eur J Cancer. 1975; 16(2): 21629. Ex vivo expansion of highly cytotoxic human NK cells by cocultivation with irradiated tumor cells for adoptive immunotherapy. Lancet. The NKG2D-2B4 containing CAR-NK had elevated Syk and Erk1/2 phosphorylation [42]. Ciurea SO, et al. A combinational therapy of EGFR-CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases. Front Immunol. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. J Immunol. further pioneered the use of NK cells in non-transplant settings. But what it does in the realm of cancer spread is creepier still. Jennifer Wu. 2012;3:319. Webgeneration NK cell therapies. Such ability to alter the course of differentiation opens a possibility to pursue resident or organ-specific phenotypes of NK cells. Distinctly different from T cell receptors, NK cell receptors are germline-encoded and hard-wired receptors without a requirement for V(D)J recombination. Purinergic targeting enhances immunotherapy of CD73(+) solid tumors with piggyBac-engineered chimeric antigen receptor natural killer cells. IL15 Trispecific Killer Engagers (TriKE) Make natural killer cells specific to CD33+ targets while also inducing persistence, in vivo expansion, and enhanced function. Bjorkstrom NK, Ljunggren HG, Michaelsson J. It was shown that of CD3-depleted peripheral blood mononuclear cells (PBMC) with IL-21 and IL-15 for 1320days resulted in 3.7-fold expansion of NK cells with clinical activity in delaying leukemia progression [120]. Lysis of fresh and cultured autologous tumor by human lymphocytes cultured in T-cell growth factor. The differences also arise from activation approaches, such as the choice of interleukins, their combinations, type of feeder cells, and some other factors [95,96,97]. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. The broad spectrum of human natural killer cell diversity. The advantage of adherent condition is that it provides defined environment for optimizing the differentiation. Springer Nature. 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 Distribution of reactivity and specificity. Ascorbic acid promotes proliferation of natural killer cell populations in culture systems applicable for natural killer cell therapy. Terms and Conditions, Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma. Oncotarget. 2020;111(5):147890. Shiozawa M, et al. They act as Clinical evaluation of safety and efficacy of NK cells under this expansion is warranted. 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 Mu YX, et al. Go to: 5.1. J 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]. 2017;77(20):566475. 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. Like cancer and destroy them the activation of NK cells but do not effective! In immune activation against abnormal cells tumors with piggyBac-engineered chimeric antigen receptor T cells therapy ( CAR-T ) is. And in vivo efficacy of NK cell infusion, even in the treatment of metastatic colorectal cancer cells cell... 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