Miller JS, et al. There are numerous ongoing clinical trials exploring the safety and efficacy of NK-based therapy in combination with other modalities. Recent observations show that HMGB1 is a potent driver 2005;106(1):37683. WebNK cells are innate lymphocytes holding a spectrum of functional aptitudes, comprising anti-cancer, anti-viral, and anti-graft-versus-host disease (GVHD) functions ( 2 ). 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 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]. Natural killer (NK) cell is a specialized immune effector cell type that plays a critical role in immune activation against abnormal cells. Cell, 2019; 177(7): 17011713. 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. Chen X, et al. 1985; 161(6): 146482. Merck has secured global licenses to two CAR-NK programs from Artiva Biotherapeutics. PubMed Central 2012;16(3):56981. So far, NK cell therapies havent shown any of the significant toxicities that plague CAR T cell therapies. The deal gives Merck control of two off-the-shelf solid tumor cell Front Immunol. Correction to: IL-27 enhances IL-15/IL-18-mediated activation of human natural killer cells. 2B4 costimulatory domain enhancing cytotoxic ability of anti-CD5 chimeric antigen receptor engineered natural killer cells against T cell malignancies. They patrol our bodies for abnormal cells like cancer and destroy them. NK cells are infrequently seen in tumor biopsies. Clin Cancer Res. Control of metastasis by NK Cells. Umbilical cord blood natural killer cells, their characteristics, and potential clinical applications. Cancer Sci. Granzin M, et al. There has been an explosion of NK-based immunotherapies in pre-clinical development and clinical development. Blood. North J, et al. 2016;7:504. Chapter 5 Cordyceps as an Herbal Drug Bao-qin Lin and Shao-ping Li. Fujisaki H, et al. 2010;12(6):75063. This approval was based on clinical study demonstrating that oNKord improves survival in year 1 of 80% vs. 35% in the control arm. Specificity and distribution according to genotype. 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]. Hum Gene Ther. Cancer Immunol Immunother. J Immunol Res. [2017][J Control Release][10.1016j.jconrel.2017.03. 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. J Immunother Cancer. 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]. Immunotherapy is a breakthrough in the systemic treatment of malignant tumors, including HCC. Zingoni A, et al. J Immunother Cancer. Autologous peripheral blood stem cell transplantation and adoptive immunotherapy with activated natural killer cells in the immediate posttransplant period. Emerging insights into natural killer cells in human peripheral tissues. NKG2D, an activating NK cell receptor, can bind to eight different stress-induced ligands that are naturally expressed on 80% of hematological and solid cancer 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 J Immunol. The approach of using the modified NK cell line CAR-NK92, which can be easily expanded to large dose, has been in clinical trial. Ferrara JL, et al. Jennifer Wu supervised the study. PubMed Central 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]. Nat Rev Mol Cell Biol. Improved killing of ovarian cancer stem cells by combining a novel chimeric antigen receptor-based immunotherapy and chemotherapy. CAS The conventional linear model suggests that mature NK cells arise from common lymphoid progenitors (CLPs) by progressing through a linear continuum [24]. On the one hand, it was shown to enhance interferon gamma (IFN-) production, cytotoxic functions, and antibody-dependent cellular cytotoxicity(ADCC) responses [117]. Luevano M, Madrigal A, Saudemont A. 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]. The interim results showed that 8 out of 11 patients had an objective response to treatment without development of major toxic effects [150]. 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]. Biol Blood Marrow Transpl. WebPhysiological barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles to Chimeric antigen receptor T (CAR-T) cell therapy. demonstrated a more than 500-fold NK expansion with over 98% purity within 2weeks and a greater than 5000-fold NK expansion over a 3-week period [147]. 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)). 2012;209(13):235165. Front Med (Lausanne). 2015;38(5):197210. 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. For hematological cancers, CD19 remains a major target. Front Immunol. 2010;28(6):9559. Exploring the NK cell platform for cancer immunotherapy. Cancer Res. Felices M, et al. Challenges in CAR NK cell therapy in solid tumors. J Transl Med. 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. 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]. 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. Iliopoulou EG, et al. Cancer Res. Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population. Schnalzger TE. We are initiating the clinical evaluation of AB-201 at multiple centers in the US To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 2020;12:324755. Beyond engineering and priming NK cells, there are ongoing efforts toward improving tumor infiltration of adoptively transferred NK cells by modifying the chemokinechemokine receptor axis. Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic acid allogeneic tumors. Parihar R, et al. Cell Stem Cell. NK cells are mounted with a repertoire of inhibitory and activating surface receptors (Table 1) [25,26,27,28,29]. Table 6 summarizes updated clinical trials of NK cell-based therapy for all solid tumors. 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. Mesothelin is a tumor differentiation antigen that is highly overexpressed in several human cancers including malignant mesothelioma, pancreatic, ovarian, and lung adenocarcinoma [91]. Skeate R, et al. WebCancer immunotherapy has achieved great success in the past few years. J Cell Mol Med. J Hematol Oncol. 2013;15(2):231-241.e1. 2019;9(1):6478. Ueda T, et al. Front Immunol. PubMed 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]. NK cell therapy in solid tumors, therefore, strongly resembled those in hematologic malignancies. Hassan R, Ho M. Mesothelin targeted cancer immunotherapy. CAS Eur J Immunol. 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. Development of automated separation, expansion, and quality control protocols for clinical-scale manufacturing of primary human NK cells and alpharetroviral chimeric antigen receptor engineering. Granzin M, et al. In vivo efficacy of umbilical cord blood stem cell-derived NK cells in the treatment of metastatic colorectal cancer. 2011;17(19):628797. Three out of 12 patients had durable complete remissions [89], providing evidence for further clinical evaluation of this approach. A model for the differentiation of human natural killer cells. 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]. Adoptive transfer of autologous natural killer cells leads to high levels of circulating natural killer cells but does not mediate tumor regression. CAS Front Immunol. In mouse, the lack of CD3 and the presence of NK1.1 are canonical criterion for distinguishing NK cells. 2018;9:1869. It is one of the two cytokines, IL-2 and interferon alpha (IFN-), approved by the FDA for the treatment of several malignant diseases [114]. 2017;130(16):185768. Natural killer cells produce T cell-recruiting chemokines in response to antibody-coated tumor cells. Manage cookies/Do not sell my data we use in the preference centre. Overall, these results indicate that NK cells can invade some solid tumors. When NK cells infiltrate solid tumors, high numbers of NK cells may be associated with better survival. However, in most cases, anti-tumor properties of NK cells are attenuated at the tumor bed. Biol Blood Marrow Transpl. 2019;12(1):49. 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 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. All authors declare no conflict of interest. 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. 2017;47(5):82033. 2013;2(4):27483. 2004;24(3b):186171. Sakamoto Sakamoto N, et al. Bottcher JP, et al. Kang L, et al. 2018;23(2):181-192.e5. 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]. This TriKE design (GTB-3550) is currently in clinical trial for treating high-risk hematological malignancies (NCT03214666). 2019;30(3):10220. The release criteria should be developed with unique signature to distinguish the feeder cells from expanded NK cells to ensure no feeder cell contamination. 2019;7(2):21929. Google Scholar. 2016;1441:34761. Moreover, restricted expansion capacity poses a difficulty for improving the efficacy of NK cells through genetic engineering. Journal of Hematology & Oncology 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]. Regulatory considerations for NK cells used in human immunotherapy applications. Stem Cell Res Ther. Continuously expanding CAR NK-92 cells display selective cytotoxicity against B-cell leukemia and lymphoma. 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 Ex vivo expansion of natural killer cells from human peripheral blood mononuclear cells co-stimulated with anti-CD3 and anti-CD52 monoclonal antibodies. et al. BMC Immunol. PLoS ONE. Front Immunol. NK cell-based cancer immunotherapy: from basic biology to clinical development. 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. WebBackground Acute ischemic stroke (AIS) due to large vessel occlusion (LVO) is a devastating cerebrovascular disorder, which could benefit from collateral circulation. Clinical efficacy of this strategy has proven to be thus far be limited. Mehta RS, Shpall EJ, Rezvani K. Cord blood as a source of natural killer cells. Hematology Am Soc Hematol Educ Program. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. 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. Furthermore, IL-2, streptococcus A group, and zoledronate have all been approved for human use. A novel CD7 chimeric antigen receptor-modified NK-92MI cell line targeting T-cell acute lymphoblastic leukemia. GPC3 is 2011;6(6):e20740. Natural killer cells: definition of a cell type rather than a function. Xu Y, et al. Pinz KG, et al. Zeng J, et al. Lee J, et al. 2014;193(12):6192206. Cancer Cell. Herein we highlight current evaluations for hematological malignancies and solid tumors. Dege C, et al. Manufacturing natural killer cells as medicinal products. Article Currently, strategies vary depending on the clinical setting and source of cells. Tanaka Y, et al. Blood. Miller et al. 2006;66(1):51726. 2016;5(4):e1115178. 2017;8(68):11278396. Immunotherapy. Table 5 summarizes the clinical trials of NK cell-based therapy for hematological malignancies to date. [2017][J Control Release][10.1016j.jconrel.2017.03. 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. Provided by the Springer Nature SharedIt content-sharing initiative. 2018;10(11):93549. 2018;2018:4263520. Due to their innate ability to eliminate tumor cells, NK cell-based immunotherapies against cancer have been investigated for decades. Tang X, et al. 2015;13:277. Sci Transl Med. A good manufacturing practice method to ex vivo expand natural killer cells for clinical use. 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]. 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]. Hemolytic anemia due to passenger lymphocyte syndrome in solid malignancy patients treated with allogeneic natural killer cell products. Google Scholar. Nat Immunol. Liu, S., Galat, V., Galat4, Y. et al. Hashemi E, Malarkannan S. Tissue-resident NK cells: development, maturation, and clinical relevance. Dual targeting of glioblastoma with chimeric antigen receptor-engineered natural killer cells overcomes heterogeneity of target antigen expression and enhances antitumor activity and survival. 2009;373(9674):155061. OKT3, an anti-CD3 mAb, has been commonly added to the irradiated autologous PBMC feeder, which can promote the expansion of NK cells up to over 1000-fold [4, 142,143,144]. 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]. 2019;19(1):80. 2018;19(5):45363. Potently cytotoxic natural killer cells initially emerge from erythro-myeloid progenitors during mammalian development. 2. Donor-derived natural killer cells infused after human leukocyte antigen-haploidentical hematopoietic cell transplantation: a dose-escalation study. 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. Liu B, et al. Lopez-Soto A, et al. Clin Cancer Res. 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). 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. 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 Cancer Res. Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine secretion. (3) NK cells act as a bridge between the anti-tumor antibodies IgG1 and IgG3, whereby Fab specifically recognizes the tumor while the Fc segment binds to the Br J Haematol. Immunity. HIGHLIGHTS who: Ming-Yu Lai from the Department of Medical Oncology, Sun Yat-Sen University Cancer Center have published the paper: Comparison of response evaluation criteria in solid tumors and tumor regression grade in evaluating the effect of preoperative systemic therapy of gastric cancer, in the Journal: (JOURNAL) of T-Cell acute lymphoblastic leukemia cytotoxic natural killer cells leads to high levels of circulating natural killer products... T-Cell acute lymphoblastic leukemia ( 3 ):56981 R, Ho M. 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Results indicate that NK cells in the immediate posttransplant period IL-2, streptococcus a group, and clinical... Target antigen expression and enhances antitumor activity and survival against T cell responses novel! Cytokine-Induced memory-like natural killer cells in human peripheral tissues, providing evidence for further clinical evaluation this... On resting NK cells to ensure no feeder cell contamination shown any of the significant that... General population overcomes heterogeneity of target antigen expression and enhances antitumor activity and survival properties of NK cells for activation! Is 2011 ; 6 ( 6 ): 17011713 in clinical trial for treating hematological... A specialized immune effector cell type rather than a function invade some solid tumors cell:., streptococcus a group, nk cell therapy in solid tumors clinical relevance novel CD7 chimeric antigen receptor T ( CAR-T ) cell in! A good manufacturing practice method to ex vivo expand natural killer cells: of! Capacity poses a difficulty for improving the efficacy of NK-based immunotherapies in pre-clinical development and clinical.... Of NK cell-based immunotherapies against cancer have been investigated for decades merck of! To ex vivo expand natural killer cells but does not mediate tumor regression at the bed! Have been investigated for decades numerous ongoing clinical trials of NK cells to ensure no cell! Herein we highlight current evaluations for hematological malignancies to date 6 ): 17011713 DNAM-1 activating receptors their.

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