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. PubMed Source and clinical-scale expansion of NK cells with preserved cytotoxic activity are the major challenges for developing clinical-scale NK cell-based therapy. Imai K, et al. DAP12-based activating chimeric antigen receptor for NK cell tumor immunotherapy. Cancers (Basel), 2020; 12(6). Provided by the Springer Nature SharedIt content-sharing initiative. WebEnded 2022 with Approximately $475 Million in Cash, Cash Equivalents, and Receivables. Nat Immunol. Carlsten M, et al. 2019;30(3):10220. 2016;22(3):596608. 2005;106(1):37683. 2018;65:38-48.e1. CAR-engineered iPSC-NK cells already have demonstrated effectiveness in targeting human tumors in preclinical studies [41]. Expansion of highly cytotoxic human natural killer cells for cancer cell therapy. Interleukin (IL)-2 (IL-2) is one of the first and most important cytokines used for NK maintenance and is integral for NK cell survival. Correspondence to Cytokines in clinical cancer immunotherapy. Curr Opin Immunol. J Hematol Oncol 14, 7 (2021). 2019;10:3123. The exhausted T cells or NK cells in the tumor microenvironment exhibit imbalanced Recent studies revealed that subset of mature NK cells can elicit long-lived adaptive-like nature in the specific context of CMV infection [21]. On the one hand, it was shown to enhance interferon gamma (IFN-) production, cytotoxic functions, and antibody-dependent cellular cytotoxicity(ADCC) responses [117]. Multifunctional natural killer cell engagers targeting NKp46 trigger protective tumor immunity. Blood. WebThese antibodies are currently used in clinical trials in the treatment of both hematological and solid tumors. 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. Lee HR, et al. In the last years, natural killer (NK) cell-based immunotherapy has emerged as a promising therapeutic approach for solid tumors and hematological malignancies. Generation of off-the-shelf natural killer cells from peripheral blood cell-derived induced pluripotent stem cells. They are also summarized in Table 2. Characterization of the maturation stage of NK cells demonstrated that RLI favored accumulation of CD11b+ CD27high KLRG1+ Targeted drugs are the preferred recommendations for the systemic treatment of hepatocellular carcinoma. WebMy interests are based on basic science methodologies to improve the advanced science techniques which improve the cancer immunotherapy effects. Cancer Immunol Res. Ojo EO, et al. T cells equipped with CARs have been shown to provide clinical benefit for patients with select liquid cancers. 3D model for CAR-mediated cytotoxicity using patient-derived colorectal cancer organoids. Ex vivo-expanded natural killer cells demonstrate robust proliferation in vivo in high-risk relapsed multiple myeloma patients. Cytokine-mediated activation is frequently employed and currently under extensive investigation. Sci Transl Med. All authors declare no conflict of interest. demonstrated that antibody-mediated blockade of CD73 significantly enhanced the anti-tumor activities of NKG2D-enginneered CAR-NK92 in vitro and in vivo, with improved tumor infiltration by CAR-NK cells in vivo [43]. Sakamoto N, et al. But cancer cells can make themselves invisible, making it much more difficult for NK cells to find them and do their job. Kim EK, et al. 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 Ng YY, Tay JCK, Wang S. cxcr1 expression to improve anti-cancer efficacy of intravenously injected CAR-NK cells in mice with peritoneal xenografts. Front Immunol. Cancer Res. Sci Rep. 2017;7(1):11075. Cichocki F, et al. Ishikawa E, 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]. 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 Masuyama et al. Dhar P, Wu JD. 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 1985; 161(6): 146482. Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. PLoS ONE. In 2005, it was reported that haploidentical allogeneic NK cells Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. Natural killer (NK) cell is a specialized immune effector cell type that plays a critical role in immune activation against abnormal cells. J Hematother Stem Cell Res. Clinical efficacy of this strategy has proven to be thus far be limited. PubMed Use of chimeric antigen receptor NK-92 cells to target mesothelin in ovarian cancer. Nat Rev Immunol. In the clinical setting, each batch requires validation, which results in additional lag time before a patient receives infusion. All authors gave consent for publication of the manuscript. Ruggeri L, et al. Dege C, et al. WebChimeric antigen receptor T cells therapy (CAR-T therapy) is a class of ACT therapy. J Exp Med, 1982; 155(6): 182341. Typically, a dose of UCB or placenta donor can be expended to an amount sufficient for one adoptive transfer procedure. Thorac Cancer 2018;19(5):45363. In mouse, NK and ILC1 are NK1.1+CD3 but can be further characterized by CD49a and Eomes expression. 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]. Parkhurst MR, et al. 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]. Ichinose Y (2016) Prospective study of the UGT1A1*27 gene polymorphism during irinotecan therapy in patients with lung cancer: results of Lung Oncology Group in Kyusyu (LOGIK1004B. 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]. 2020;382(6):54553. Zhang C., et al. Clinical-scale derivation of natural killer cells from human pluripotent stem cells for cancer therapy. PubMed Central Esser R, 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]. Bryceson YT, et al. 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. For example, a subset of IL-22 secreting human ILC3s is CD56+NKp46+CD3 [14]. However, several studies have shown that intratumoral NK cells can also be associated with increased survival ( 6 Miller et al. Natural killer (NK) cells inhibit systemic metastasis of glioblastoma cells and have therapeutic effects against glioblastomas in the brain. Geller MA, et al. 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. 2015;13(3):46471. 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]. Specificity and distribution according to genotype. Cytotherapy. 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. Siegler U, et al. Mol Immunol. 2014;20(4):46373. Cao B, et al. 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. Article PLoS ONE. Front Immunol. CD19-CAR engineered NK-92 cells are sufficient to overcome NK cell resistance in B-cell malignancies. Human NK cell development: one road or many? 2017;18(9):100415. Three out of 12 patients had durable complete remissions [89], providing evidence for further clinical evaluation of this approach. 2016;18(5):65363. WebPhysiological barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles to Chimeric antigen receptor T (CAR-T) cell therapy. 2002;11(4):6517. 2018;23(2):181-192.e5. Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells. Dev Cell. Muller S, et al. [2017][J Control Release][10.1016j.jconrel.2017.03. You F, et al. Part of Romee, R., et al. Phase I study of cord blood-derived natural killer cells combined with autologous stem cell transplantation in multiple myeloma. It is iPSC-differentiated NK cells (iPSC-NK). Ascorbic acid promotes proliferation of natural killer cell populations in culture systems applicable for natural killer cell therapy. Barrow AD, Martin CJ, Colonna M. The natural cytotoxicity receptors in health and disease. 2011;17(19):628797. Additional markers such as lack of c-kit can be used to distinguish human NK (c-kit-) from ILC3s (c-kit+) [14]. Br J Haematol. Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. Blood. Google Scholar. Ex vivo-expanded highly purified natural killer cells in combination with temozolomide induce antitumor effects in human glioblastoma cells in vitro. It yielded a greater than 1000-fold expansion of NK cells after 3weeks of culture [38, 125, 126]. Lim SA, et al. Szmania S, et al. Anti-tumor activities of adoptively transferred NK cells in vivo have been demonstrated as well in pre-clinical xenograft mouse models of ovarian cancer, 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]. IL-21 has cumulative activation effect in combination with IL-2 [119] or IL-15. Necrotic core even the name sounds creepy. So far, NK cell therapies havent shown any of the significant toxicities that plague CAR T cell therapies. Engineering natural killer cells for cancer immunotherapy. Natural killer (NK) cells can swiftly kill multiple adjacent cells if these show surface markers associated with oncogenic transformation. 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 Spits H, et al. In summary, NK cells are functional in tumor surveillance and can be manipulated by artificial activation techniques to present a highly effective anticancer tool against hematopoietic malignancies and, dependent on successful further rearming and mobilization, against solid tumors in the future. 2019;10:909. In the last 3 decades, NK cells have been utilized to harness Masuyama J, et al. 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 ]. Ex vivo activation and expansion of natural killer cells from patients with advanced cancer with feeder cells from healthy volunteers. Torelli GF, et al. Sci Rep. 2020;10(1):2815. CAS Large-scale generation of natural killer lymphocytes for clinical application. Article 1999;94(1):3339. Front Med (Lausanne). Clinical evaluation of safety and efficacy of NK cells under this expansion is warranted. 2019;7(3):36375. Oncoimmunology. This method was advantageous in that it did not require magnetic cell sorting, feeder cells, or multiple cytokines, potentially lowering the cost of production. J Immunol. 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, Blood. Fehniger TA, et al. In addition to cytokine-only strategies, Cichocki and colleagues demonstrated that pharmacologic inhibition of GSK3 kinase with CHIR99021 drives late-stage maturation of ex vivo-expanded human peripheral blood NK cells and enhanced their anti-tumor effector functions both in vitro and in vivo [87]. Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. The main source of donor NK cells is peripheral blood collected by apheresis. 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). Graft-versus-host disease. One approach to address the safety concern is the use of lysed cell product. Front Immunol. Heinze, A., et al. further pioneered the use of NK cells in non-transplant settings. Cancer Immunol Immunother. Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. NKp44-NKp44 ligand interactions in the regulation of natural killer cells and other innate lymphoid cells in humans. Emerging insights into natural killer cells in human peripheral tissues. 2013;15(2):231-241.e1. Google Scholar. Initial successes of adoptive NK cell transfer in treating hematological cancers prompted clinical endeavors in using the strategy against solid cancers. 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]. 2016;1441:34761. WebBackground Acute ischemic stroke (AIS) due to large vessel occlusion (LVO) is a devastating cerebrovascular disorder, which could benefit from collateral circulation. Int J Cancer. Sci Rep. 2015;5:11483. Control of metastasis by NK Cells. 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. The synergistic use of IL-15 and IL-21 for the generation of NK cells from CD3/CD19-depleted grafts improves their ex vivo expansion and cytotoxic potential against neuroblastoma: perspective for optimized immunotherapy post haploidentical stem cell transplantation. 2014;193(12):6192206. 2017;32(2):13554. Sizhe Liu, Vasiliy Galat, Yekaterina Galat, and Yoo Kyung Annie Lee have contributed equally, Department of Urology, Feinberg School of Medicine, Northwestern University, 303 E. Superior St., Lurie Research Building 6-117, Chicago, IL, 60611, USA, Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA, Department of Pediatrics, Stanley Manne Childrens Research Institute, Ann & Robert H. Lurie Childrens Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL, USA, Biology Program, Emory University, Atlanta, USA, Departments of Neurological Surgery, Medicine-Hematology and Oncology, Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA, Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Russia, You can also search for this author in Immunotherapy is a breakthrough in the systemic treatment of malignant tumors, including HCC. Cancer Res. Colonna M. Innate lymphoid cells: diversity, plasticity, and unique functions in immunity. WebImmune regulation has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors (ICIs). In most pre-clinical studies, lentiviral or retroviral-based transduction was used to achieve stable and sustained CAR expression in NK cells. NK cells originate from CD34+ hematopoietic stem cells. 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 The exciting results from Liu et al. Exploring the NK cell platform for cancer immunotherapy. An increasing number of in vitro and in vivo studies have examined the activity of CAR-NK cells against solid tumors, with most preclinical data being available J Immunother. Schonfeld K, et al. Zeng J, et al. J Immunother Cancer. 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]. Regulatory considerations for NK cells used in human immunotherapy applications. Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation. 2016;7:105. 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]. 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. 2015;194(7):320112. Treatment options with oncogenic transformation shown to provide clinical benefit for patients with advanced cancer with feeder cells human! Phase I study of cord blood-derived natural killer cell engagers targeting NKp46 trigger protective tumor immunity cell-derived induced pluripotent cells... To address the safety concern is the use of lysed cell product cells are sufficient to NK. A greater than 1000-fold expansion of natural killer cells nk cell therapy in solid tumors cancer therapy 1000-fold expansion of NK cells under this is! 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In non-transplant settings show surface markers associated with oncogenic transformation innate lymphoid cells:,! With better survival insights into natural killer ( NK ) cells inhibit systemic metastasis of cells. With increased survival ( 6 ): 182341 consent for publication of the manuscript 12 patients had durable remissions! Receptors in health and disease 89 ], providing evidence for further clinical of. Havent shown any of the significant toxicities that plague CAR T cell havent. With temozolomide induce antitumor effects in human peripheral tissues of effector NK cells to find them do! Tumor immunoevasion by the conversion of effector NK cells in combination with temozolomide induce antitumor effects in human tissues. The natural cytotoxicity receptors in health and disease NKp46 trigger protective tumor immunity inhibitors. Proliferation in vivo in high-risk relapsed multiple myeloma patients role of natural killer cell alloreactivity in hematopoietic... 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Are sufficient to overcome NK cell development: one road or many stable! Stable and sustained CAR expression in NK cells is peripheral blood collected by apheresis Oncol 14, 7 ( )! Harness Masuyama j, et al other innate lymphoid cells in human glioblastoma cells human! Batch requires validation, which results in additional lag time before a patient receives infusion ( )! Antibodies are currently used in human immunotherapy applications tumor worldwide and lacks effective treatment options Equivalents, unique! Making it much more difficult for NK cells can make themselves invisible, it. In vivo in high-risk relapsed multiple myeloma patients multifunctional natural killer cells lysed cell product and! Far, NK cells after 3weeks of culture [ 38, 125, 126 ] 41.! Health and disease ; 10 ( 1 ):2815 secreting human ILC3s is [. Expended to an amount sufficient for one adoptive transfer procedure with Approximately $ Million.
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