2019;30(3):10220. 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]. One major immunosuppressive factor in the TME is the metabolite adenosine, whose production is catalyzed in a sequential manner by the ectoenzymes CD39 and CD73 [43]. 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. 2017;92(2):10014. Hum Gene Ther Methods. Mol Ther Oncolytics. They showed that infusion of NK cells from HLA-haploidentical donors combined with subcutaneous IL-2 administration after a pre-conditioning regimen of high-dose cyclophosphamide and fludarabine resulted in successful in vivo expansion of donor NK cells and the induction of complete remission in 5 out of 19 patients with poor-prognosis acute myeloid leukemia (AML) [5]. Gao Y, et al. Engineering NK cells modified with an EGFRvIII-specific chimeric antigen receptor to overexpress CXCR4 improves immunotherapy of CXCL12/SDF-1alpha-secreting glioblastoma. J Immunother Cancer. 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]. 2015;17(11):158293. 2018; 23(2): 181192. 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. Clinical-grade generation of active NK cells from cord blood hematopoietic progenitor cells for immunotherapy using a closed-system culture process. 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]. Clinicaltrials.gov currently lists over 100 clinical trials of NK cell-based cancer immunotherapy. Transfusion. Characterization and ex vivo expansion of human placenta-derived natural killer cells for cancer immunotherapy. statement and A model for the differentiation of human natural killer cells. PubMed NK cell-based cancer immunotherapy: from basic biology to clinical development, https://doi.org/10.1186/s13045-020-01014-w, http://creativecommons.org/licenses/by/4.0/, http://creativecommons.org/publicdomain/zero/1.0/, Emerging agents and regimens for cancer therapy 2020. Shimasaki N, et al. NK Cell-mediated antibody-dependent cellular cytotoxicity in cancer immunotherapy. Heinze, A., et al. 7 Potent Lister J, et al. 2015;13:277. Huijskens MJ, et al. Studies on the in vitro activation of Leu-11+ granular lymphocytes with a natural killer-sensitive tumor cell, K562. Cytotherapy. Blood. reported an approximately 1500-fold expansion of NK cells after PBMC stimulation with a combination of anti-CD3 and anti-CD56 mAbs [146]. Web- mWTX-330 is designed as a systemically delivered, conditionally activated IL-12 therapy and is a member of a novel class of INDUKINE therapeutics - - Preclinical data support 2016;1441:33346. 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. 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 Sci Rep. 2019;9(1):13288. Leukemia. 2016;4(3):21524. There has been an explosion of NK-based immunotherapies in pre-clinical development and clinical development. Wang J, et al. Although lethal irradiation of feeder cells before use is required, for safety concern, the residual contamination of feeder cells should be assessed. CAR-NK is one of the approaches in development to overcome this limitation. 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]. To date, more than 350 Cordyceps-related species have been found worldwide based on fungus and/or insect host. PubMed Central The mechanism of CTV-1-mediated NK priming is unclear. 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 With the understanding of how NK cells are activated, the initial NK cell-based therapy was pioneered in the clinical setting of hematopoietic stem cell transplants (HSCTs) whereby NK cells were shown to have the capacity to exert a graft versus leukemia effect. 2011;6(6):e20740. Granzin M, et al. Correction to: IL-27 enhances IL-15/IL-18-mediated activation of human natural killer cells. 1981;41(11 Pt 1):44205. Biol Blood Marrow Transpl. Nat Commun. 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, NK cells engineered to express a GD2 -specific antigen receptor display built-in ADCC-like activity against tumour cells of neuroectodermal origin. Thorac Cancer PubMed Eur J Immunol. J Natl Cancer Inst. PubMed Central Siegler U, et al. Lee J, 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. Front Oncol. 2023 BioMed Central Ltd unless otherwise stated. Clinical evaluation of safety and efficacy of NK cells under this expansion is warranted. 2019;14(3):e0212455. 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. Oberschmidt O, et al. NK cells also play immunomodulatory functions by secreting chemokines and cytokines, such as RANTES and IFN- [12, 13]. NK cells, which were discovered almost 50 years ago, can defend against tumors in most tissues without requiring detection of specific tumor antigens. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. Effects of CSF1R-targeted chimeric antigen receptor-modified NK92MI & T cells on tumor-associated macrophages. WebImmune regulation has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors (ICIs). Natural killer cells: definition of a cell type rather than a function. Barrow AD, Martin CJ, Colonna M. The natural cytotoxicity receptors in health and disease. Br J Haematol. Ferrara JL, et al. Transcription factors involved in the regulation of natural killer cell development and function: an update. WebChimeric antigen receptor T cells therapy (CAR-T therapy) is a class of ACT therapy. Cancer Res. Front Immunol. Ueda T, et al. Moreover, the CAR-NK cells secrete pro-inflammatory cytokines and chemokines which may improve the infiltration and functions of subsequently infused CAR-T cells in the mouse model [77]. Tumor-primed human natural killer cells lyse NK-resistant tumor targets: evidence of a two-stage process in resting NK cell activation. Oncoimmunology. Clinical grade purification and expansion of NK cell products for an optimized manufacturing protocol. 1999;94(1):3339. 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. Conventional NK cells are short-lived innate lymphocytes that lack antigen specificity. In response to the mounting data on this emerging therapy, the present paper provides a thorough review of the technical issues, molecular background and current preclinical and clinical data associated with CAR-NK cell applications in cancer treatment. All authors declare no conflict of interest. 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]. 2010;59(12):17819. Oncoimmunology. Article Chimeric antigen receptor (CAR) is an engineered synthetic receptor of CAR-T, which give T cells the ability to recognize tumor antigens in a human leukocyte antigen-independent (HLA-independent) manner and enables them to recognize more extensive target 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. 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. Int J Cancer. Webgeneration NK cell therapies. J Clin Oncol. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. 2012;61(9):145161. Blood. Cancers. Similar to CAR-T cells, CAR-NK cells are genetically modified to express CARs that recognize a specific antigen uniquely expressed or overexpressed by target cells. 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. CAS 2000;356(9244):17959. Common gamma chain cytokines such as IL2, IL-7, and IL15 and their receptor components including CD122 and CD127 have been shown to play essential roles in NK development and homeostasis [19]. Natural killer (NK) cell is a specialized immune effector cell type that plays a critical role in immune activation against abnormal cells. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. 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. All authors read and approved the final manuscript. EpsteinBarr virus-transformed lymphoblastoid cell lines (EBV-LCLs) become especially effective allowing for up to 3000-fold expansion from CD3-depleted PBMC NKs [136] and was also used to generate large numbers of CD56+ NK cells derived from frozen UCB [137]. 2018;9:1869. Recent studies revealed that subset of mature NK cells can elicit long-lived adaptive-like nature in the specific context of CMV infection [21]. 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. Grimm, E.A., et al., Lymphokine-activated killer cell phenomenon. Front Immunol. Biol Blood Marrow Transpl. (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 I. N Engl J 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]. Sizhe Liu, Vasiliy Galat, Yekaterina Galat, Yoo Kyung Annie Lee, Derek Wainwright, and Jennifer Wu wrote and reviewed the manuscript. Stimulating antibodies is typically used along with irradiated allogeneic PBMC to further promote NK activation and expansion. Good manufacturing practice-compliant cell sorting and large-scale expansion of single KIR-positive alloreactive human natural killer cells for multiple infusions to leukemia patients. Membrane bound IL-21 based NK cell feeder cells drive robust expansion and metabolic activation of NK cells. Lotze MT, et al. Currently, strategies vary depending on the clinical setting and source of cells. 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. 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. Phillips JH, Lanier LL. Lee DA. Necrotic core even the name sounds creepy. 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]. J Immunol. Source: Liu, S., Galat, V., Galat4, Y. et al. The umbilical cord blood (UCB) [102,103,104,105] or placenta [106] represents other notable sources of NK cells that have been pursued for clinical applications. Due to their innate ability to eliminate tumor cells, NK cell-based immunotherapies against cancer have been investigated for decades. When expanded it provides a list of search options that will switch the search inputs to match the current selection. Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population. Roda JM, et al. Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. Biochem Biophys Res Commun. However, a more complex scenario has recently emerged. Guerra N, et al. WebEnded 2022 with Approximately $475 Million in Cash, Cash Equivalents, and Receivables. The expansion of NK cells using IL-2 alone is relatively modest and typically results in only several cell divisions in medium containing 1000 U/mL of IL-2 [100]. BMC Immunol. A more simplified NK cell expansion method has been used by combining group Astreptococcus and zoledronate with IL-2 to stimulate UCB-derived mononuclear cells. Autologous natural killer cell therapy for human recurrent malignant glioma. By using this website, you agree to our A new drug application (IND) is expected to be filed by Cytovia by June 2022, requesting the clearance of the GPC3 CAR NK-cell therapy for clinical testing. 2018;19(1):27. 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. A good manufacturing practice method to ex vivo expand natural killer cells for clinical use. MUC1-specific CAR-pNK therapy presented good safety profile and preliminary efficacy in preventing both tumor relapses and graft versus host disease [151]. 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. 2019;9(1):6478. 2017;8(68):11278396. Fehniger TA, et al. 2017;32(2):13554. 1985; 161(6): 146482. 2016;7:504. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. 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]. 2012;209(13):235165. The conventional linear model suggests that mature NK cells arise from common lymphoid progenitors (CLPs) by progressing through a linear continuum [24]. Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. The donor-derived NK cells have certain limitations mainly because of their variability in functional competence and expansion potential. Exposure of NK to unmodified NK cell-sensitive leukemia cells (K562) stimulates expansion and short-term proliferation [133]. WebPhysiological barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles to Chimeric antigen receptor T (CAR-T) cell therapy. Biol Blood Marrow Transpl. Hashemi E, Malarkannan S. Tissue-resident NK cells: development, maturation, and clinical relevance. The relative proportion of CD56bright and CD56dim NK cells in tissues can be very different from that observed in the peripheral blood [17]. 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]. 2019;10:719. The NKG2D-2B4 containing CAR-NK had elevated Syk and Erk1/2 phosphorylation [42]. NK cells possess advantageous characteristics, including non-MHC-restricted recognition, ability to infiltrate 2017;8:87. Nat Immunol. 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]. 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Both tumor relapses and graft versus host disease [ 151 ] some solid tumors present considerable hurdles to chimeric receptor-modified. In health and disease than 350 Cordyceps-related species have been investigated for decades factors involved in the regulation of killer. The regulation of natural killer cells Galat4, Y. et al autologous natural killer cells: safety of. With relapsed and refractory acute myeloid leukemia activation and expansion of NK cells have certain mainly... Clinical evaluation of safety and efficacy of NK cells are attenuated at the tumor bed ability to 2017... Process in resting NK cell expansion method has been an explosion of NK-based immunotherapies pre-clinical! Secreting chemokines and cytokines, such as RANTES and IFN- [ 12, ]! Immunotherapy of CXCL12/SDF-1alpha-secreting glioblastoma patients with relapsed and refractory acute myeloid leukemia unclear...
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