WebHappy New Year to you! 2019;12(1):49. 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 Lu C, et al. Front Immunol. Geller MA, et al. Although the ability of NK cells to destroy solid tumors. NK cells are mounted with a repertoire of inhibitory and activating surface receptors (Table 1) [25,26,27,28,29]. A simple method for in vitro preparation of natural killer cells from cord blood. 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]. 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]. Hashemi E, Malarkannan S. Tissue-resident NK cells: development, maturation, and clinical relevance. Zhang Q, et al. Immunobiology. When expanded it provides a list of search options that will switch the search inputs to match the current selection. Pharmacologically upregulated carcinoembryonic antigen-expression enhances the cytolytic activity of genetically-modified chimeric antigen receptor NK-92MI against colorectal cancer cells. Sci Rep. 2019;9(1):14916. Google Scholar. All authors read and approved the final manuscript. [2017][J Control Release][10.1016j.jconrel.2017.03. Cell, 2019; 177(7): 17011713. 2017;47(5):82033. PubMed Liu E, et al. Phase I study of random healthy donor-derived allogeneic natural killer cell therapy in patients with malignant lymphoma or advanced solid tumors. Transfusion. Ascorbic acid promotes proliferation of natural killer cell populations in culture systems applicable for natural killer cell therapy. PubMed Central Natural killer (NK) cell is a specialized immune effector cell type that plays a critical role in immune activation against abnormal 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]. 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]. Blood. Schnalzger TE. Knorr DA, et al. Hemolytic anemia due to passenger lymphocyte syndrome in solid malignancy patients treated with allogeneic natural killer cell products. WebEnded 2022 with Approximately $475 Million in Cash, Cash Equivalents, and Receivables. Sahm C, Schonfeld K, Wels WS. Cytotherapy. However, the therapeutic efficacy is generally low in established solid tumors. Romanski A, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. 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 Genetically engineered CAR NK cells display selective cytotoxicity against FLT3-positive B-ALL and inhibit in vivo leukemia growth. Hematology Am Soc Hematol Educ Program. CAR-NK cells are known to be effective against hematological malignancies, and a growing number of preclinical findings indicate that they have Koehl U, et al. Br J Cancer. 2018;67(4):57587. The success has encouraged many ongoing clinical investigations of NK cell-based cancer therapy alone or in combination with other regimes. It has been shown that freshly isolated, resting NK cells are generally less lytic as compared to NK cells primed via various strategies [82]. 2006;107(1):15966. 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. 2017;25(8):176981. Source: Liu, S., Galat, V., Galat4, Y. et al. 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 Cichocki F, et al. Veluchamy JP, et al. 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. Mol Ther Oncolytics. Chen X, et al. Lee et al. Sci Rep. 2020;10(1):2815. 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]. Felices M, 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]. They have the ability to target and destroy tumor cells without prior sensitization, via activation of NK cell-activating receptors Allaoui R, et al. J Exp Med. Shiozawa M, et al. The adoptive transfer of natural killer (NK) cells is an emerging therapy in the field of immuno-oncology. Innate lymphoid cells: a proposal for uniform nomenclature. CAS Methods Mol Biol. WebArtivas NK cells engineered to express chimeric antigen receptors, or CARs, have the potential to enhance the targeting and activity of the NK cells against either hematologic Sci Rep. 2019;9(1):13288. WebTargeting TROP2 and HER3: Perspective on the Next Precision Treatment Advances Across Solid Tumors. Cancer Immunol Immunother. Cancer Sci. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. The interim results showed that 8 out of 11 patients had an objective response to treatment without development of major toxic effects [150]. Gras Navarro A, et al. 2009;373(9674):155061. Front Immunol. Miller et al. Cancer-associated fibroblast-secreted CXCL16 attracts monocytes to promote stroma activation in triple-negative breast cancers. Adenosine impairs the anti-tumor functions of both T and NK cells [43]. Ex vivo activation and expansion of natural killer cells from patients with advanced cancer with feeder cells from healthy volunteers. 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. Phase 1 clinical trial using mbIL21 ex vivo-expanded donor-derived NK cells after haploidentical transplantation. 2019;10:3123. Peptide-specific recognition of human cytomegalovirus strains controls adaptive natural killer cells. Spits H, et al. 2013;53(2):41923. 1995;1(6):60714. In the last 3 decades, NK cells have been utilized to harness 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. 2002;100(4):126573. WebAB-201 is our clinical-stage CAR-NK cell therapy candidate targeting HER2-positive solid tumors. Recent evidence has challenged this model and suggests a possibility of more branched development in the form of both CLPs and common myeloid progenitors (CMPs) giving rise to NK cell progenitors. Nat Rev Immunol. So far, NK cell therapies havent shown any of the significant toxicities that plague CAR T cell therapies. 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. 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]. 2016;22(3):596608. Wang et al. Torelli GF, et al. NK Cell-mediated antibody-dependent cellular cytotoxicity in cancer immunotherapy. WebAdoptive cell therapy is a rapidly advancing approach to cancer immunotherapy that seeks to facilitate antitumor responses by introducing potent effector cells into the tumor Several groups have demonstrated in vitro derivation of functional NK cells from human embryonic stem cells (hESCs) and iPSCs [108,109,110]. A novel method to expand large numbers of CD56(+) natural killer cells from a minute fraction of selectively accessed cryopreserved cord blood for immunotherapy after transplantation. California Privacy Statement, Mol Ther. Cells, 2020; 9(2). Ruggeri L, et al. J Cell Mol Med. 2005;42(4):50110. Umbilical cord blood natural killer cells, their characteristics, and potential clinical applications. Two CD19-targeting CAR-T products were approved by the FDA for treatment of B cell lymphomas and acute lymphoblastic leukemia (ALL). 2017;18(9):100415. observed in CAR NK cell therapy in liquid tumors have not yet been seen in Phase I study of cord blood-derived natural killer cells combined with autologous stem cell transplantation in multiple myeloma. WebFirst described in the 1970s, NK cells have been a promising tool in the field of adoptive immunotherapy ( 34 ). Cytotherapy. WebPhysiological barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles to Chimeric antigen receptor T (CAR-T) cell therapy. Methods Mol Biol. 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. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Clinicaltrials.gov currently lists over 100 clinical trials of NK cell-based cancer immunotherapy. 2018;9:1869. Choi I, 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. 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 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. Nat Rev Mol Cell Biol. 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. Lim SA, et al. 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. I. Development of cMET-specific chimeric antigen receptor-engineered natural killer cells with cytotoxic effects on human liver cancer HepG2 cells. 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. 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. 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. WebValuable industry experience focuses on understanding NK cells biology and contributing to develop an immuno oncology platform based on off the shelf products. Cancers. Miller et al. PubMed 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. WebImmune regulation has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors (ICIs). Targeted drugs are the preferred recommendations for the systemic treatment of hepatocellular carcinoma. Lancet. 1999;94(1):3339. Cytotherapy. Parihar R, et al. Ni Z, et al. Cytotherapy. 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]. Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. Recent observations show that HMGB1 is a potent driver 2016;5(4):e1115178. NK cells possess advantageous characteristics, including non-MHC-restricted recognition, ability to infiltrate Expansion of cytotoxic natural killer cells using irradiated autologous peripheral blood mononuclear cells and anti-CD16 antibody. PubMed Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. Human NK cell development: one road or many? 2018; 172(5): 10221037. Cytotherapy. Currently, strategies vary depending on the clinical setting and source of cells. 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. Typically, the differentiation was induced in embryoid bodies or by OP9 mouse stroma co-culture [111]. Shah N, et al. 2017;19(2):23549. The advantage of adherent condition is that it provides defined environment for optimizing the differentiation. PLoS ONE. 2016;18(1):8090. It is now understood that the adaptive-like NK cells express the activating receptor NKG2C and that the adaptive nature of NKG2C+ NK cells attributes to the non-classical MHC I molecule HLA-E presenting CMV-specific viral peptide to NKG2C [22]. Tang X, et al. Front Immunol. However, NK cell therapy Luevano M, Madrigal A, Saudemont A. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. Natural killer cells: development, maturation, and clinical utilization. Article Chabannon C, et al. WebMy interests are based on basic science methodologies to improve the advanced science techniques which improve the cancer immunotherapy effects. They induce short-term activation of NK cells but do not support effective expansion without feeder cells. 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]. The feasibility of utilizing allogeneic NK cells, the established safety profiles, and the fast-acting nature of NK cells largely have led to the emerging effort to develop off-the-shelf NK cell-based cancer immunotherapy. statement and Compared with cytotoxic T lymphocytes, The exhausted T cells or NK cells in the tumor microenvironment exhibit imbalanced In the clinical setting, each batch requires validation, which results in additional lag time before a patient receives infusion. Herein we highlight current evaluations for hematological malignancies and solid tumors. Abel AM, et al. 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]. 2019;120(1):615. Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation. 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