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]. NK cell represents a specialized immune effector cell population equipped with fast-acting and potent anti-tumor capacity. 2019;9(1):6478. Chabannon C, et al. 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 In a xenograft mouse model of lymphoma, co-administration of ALT-803 with NK cells significantly enhanced anti-CD20-triggered, NK cell-mediated ADCC effects [83]. Front Immunol. Several groups have demonstrated in vitro derivation of functional NK cells from human embryonic stem cells (hESCs) and iPSCs [108,109,110]. 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]. NK cells can trigger target cell death by releasing cytotoxic granules containing granzymes and perforin and through death receptor-mediated pathways (e.g., FasL/Fas) [11]. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Due to relatively unsophisticated cues for activation, NK cell has gained significant attention in the field of cancer immunotherapy. 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. 2020;382(6):54553. Transcription factors involved in the regulation of natural killer cell development and function: an update. Retargeting of natural killer-cell cytolytic activity to ErbB2-expressing cancer cells results in efficient and selective tumor cell destruction. 2016;1441:33346. Dual targeting of glioblastoma with chimeric antigen receptor-engineered natural killer cells overcomes heterogeneity of target antigen expression and enhances antitumor activity and survival. MUC1-specific CAR-pNK therapy presented good safety profile and preliminary efficacy in preventing both tumor relapses and graft versus host disease [151]. Front Immunol. Li Y, et al. Jennifer Wu helped in conception and design. Lanier LL, et al. Wang J, et al. TUMORS. Targeting T-cell malignancies using anti-CD4 CAR NK-92 cells. 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. Zhang C., et al. Veluchamy JP, et al. Cytotherapy. 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]. WebChimeric antigen receptor T cells therapy (CAR-T therapy) is a class of ACT therapy. 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 2019;10:3123. 2008;44(1):4653. Cancer Res. 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 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. 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]. Phase I study of random healthy donor-derived allogeneic natural killer cell therapy in patients with malignant lymphoma or advanced solid tumors. Currently, strategies vary depending on the clinical setting and source of cells. Innate lymphoid cells: a proposal for uniform nomenclature. Human NK cells expanded with IL-15 in the presence GSK3 inhibition had increased expression of the NK cell maturation marker CD57 and transcription factors associated with late-stage NK cell maturation including T-bet, ZEB2, and BLIMP-1 as compared to those expanded with IL-15 alone [87]. CXCL16 positively correlated with M2-macrophage infiltration, enhanced angiogenesis, and poor prognosis in thyroid cancer. 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 Google Scholar. Part of showed that CAR-NK cells genetically modified to express the chemokine receptor CXCR1 had enhanced migration in vitro and in vivo as compared to control CAR-NK cells [54]. T cells equipped with CARs have been shown to provide clinical benefit for patients with select liquid cancers. Article Science. Int J Cancer. The anti-tumor response of LAK cells was shown attributed mainly to NK cells [116]. The integration and balance of the activating and inhibitory signals from the ligand/receptor interactions dictates the status of NK cell activation. 2016;22(3):596608. In the xenograft models, NK cell infusion combined with intraperitoneal injection of the NRPbody significantly reduced tumor burden as compared to NK infusion combined with the non-cleavable control [90]. Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. 2019;10:2078. 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]. Autologous peripheral blood stem cell transplantation and adoptive immunotherapy with activated natural killer cells in the immediate posttransplant period. Current challenges further pioneered the use of NK cells in non-transplant settings. Blood Transfus. 2015;15:1011. The NKG2D-2B4 containing CAR-NK had elevated Syk and Erk1/2 phosphorylation [42]. Tanaka Y, et al. Choi I, et al. Heinze, A., et al. Necrotic core even the name sounds creepy. PubMed Central 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 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. Miller JS, et al. [2017][J Control Release][10.1016j.jconrel.2017.03. Google Scholar. Intraperitoneal delivery of human natural killer cells for treatment of ovarian cancer in a mouse xenograft model. 2019;12(1):49. Google Scholar. Source and clinical-scale expansion of NK cells with preserved cytotoxic activity are the major challenges for developing clinical-scale NK cell-based therapy. Uherek C, et al. More recent evidence had indicated that NK cells can also develop and mature at secondary lymphoid organs, including tonsils, spleen, and lymph nodes [19]. Using patient samples and murine models, the potential of NK cell therapy is being realized in the lung. NK Cell-mediated antibody-dependent cellular cytotoxicity in cancer immunotherapy. To date, more than 350 Cordyceps-related species have been found worldwide based on fungus and/or insect host. Sci Rep. 2019;9(1):13288. WebCancer immunotherapy has achieved great success in the past few years. Huang Y, et al. Oncoimmunology. Romanski A, et al. Galat Y, et al. 2016;5(9):e1219007. Source: Liu, S., Galat, V., Galat4, Y. et al. Vasu S, et al. PubMed A model for the differentiation of human natural killer cells. They act as Purinergic targeting enhances immunotherapy of CD73(+) solid tumors with piggyBac-engineered chimeric antigen receptor natural killer cells. Liu E, et al. J Exp Med, 1982; 155(6): 182341. It yielded a greater than 1000-fold expansion of NK cells after 3weeks of culture [38, 125, 126]. The donor-derived NK cells have certain limitations mainly because of their variability in functional competence and expansion potential. Oncoimmunology. Guerra N, et al. All authors gave consent for publication of the manuscript. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Despite the immunosuppressive environment of solid tumors, NK cell activity/infiltration has been correlated with improved prognoses in humans. The mechanism of CTV-1-mediated NK priming is unclear. 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 ). 2017;77(20):566475. Handgretinger R, Lang P, Andre MC. Clinical grade purification and expansion of NK cell products for an optimized manufacturing protocol. PubMed Chapter 5 Cordyceps as an Herbal Drug Bao-qin Lin and Shao-ping Li. 2013;3:118. 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. Google Scholar. Recent observations show that HMGB1 is a potent driver Clin Cancer Res. Beyond cytokines, other stimulants, including tumor cells, allogeneic PBMCs, antibodies, and microbiol derivatives, have been explored for enhancing ex vivo NK cell expansion. Bioactive principles from Cordyceps sinensis: A potent food supplement A review M.G. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Various strategies are being employed to overcome these challenges to improve the efficacy of NK cell-based therapy, such as ex vivo pre-conditioning with cytokines and/or small molecular drugs, engineering an off-the-shelf or iPSC-differentiated chimeric antigen receptor (CAR)-NK. Such ability to alter the course of differentiation opens a possibility to pursue resident or organ-specific phenotypes of NK cells. Jennifer Wu. Blood. 2018;2018:4263520. NK cells with KIR2DS2 immunogenotype have a functional activation advantage to efficiently kill glioblastoma and prolong animal survival. Liu E, et al. NK cell-based cancer immunotherapy: from basic biology to clinical development. Zhang P, et al. 2018;48(6):110417. 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. Article Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. Muller S, et al. Characterization and ex vivo expansion of human placenta-derived natural killer cells for cancer immunotherapy. The emergence of this technology provided a completely new framework for clinical-scale NK cell production by allowing for the genetic modifications and unlimited expansion to be performed at the pluripotent cell state. Production Process of CAR-NK Among these TCR cell co-stimulatory molecules, 4-1BB, DNAM1, 2B4, and NKG2D were also expressed by NK cells as native activating receptors. 2017;47(5):82033. Rosario M, et al. Natural killer cells: definition of a cell type rather than a function. Cytokine-mediated activation is frequently employed and currently under extensive investigation. Other methods may include transgene of suicide gene or expression of a fluorescent marker in the feeder cell. A novel chimeric PD1-NKG2D-41BB receptor enhances antitumor activity of NK92 cells against human lung cancer H1299 cells by triggering pyroptosis. 1975; 16(2): 21629. 2016;18(5):65363. 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. 2017;8:87. Join us for this live, CME-certified symposium featuring an expert discussion of TROP2- and HER3-targeted antibody-drug conjugates and their current use in treating patients with solid tumors, including lung and breast cancers. 2018;19(1):27. 2013;73(6):177786. It is believed that membrane-bound interleukins are able to stimulate the expansion of NK cells more effectively than the soluble form. Expansion of cytotoxic natural killer cells using irradiated autologous peripheral blood mononuclear cells and anti-CD16 antibody. Webgeneration NK cell therapies. Effects of CSF1R-targeted chimeric antigen receptor-modified NK92MI & T cells on tumor-associated macrophages. For example, there is an ongoing phase 2 clinical trial to evaluate the safety and efficacy of human HLA-haploidentical hematopoieticcelltransplantation (HCT) followed by an early, post-transplant infusion of donor NKcells (NCT02100891). Leong JW, et al. WebImmune regulation has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors (ICIs). Oyer JL, et al. Lu C, et al. Wang W, et al. However, a more complex scenario has recently emerged. NK cell progenitors progress through distinct developmental stages and gradually acquire the expression of surface receptors that define NK cell identity such as NK1.1 and CD56 and/or regulate their effector functions such as CD16 and NKp46 [19]. Miller et al. 2017;18(1):5667. 2016; 8(357): p. 357ra123. 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. The following section summarizes the current pre-clinical efforts to enhance the efficacy of NK cell-based therapy. GPC3 is The anti-CD3 mAb presumably activates T cells in feeder to secret cytokines which subsequently create a milieu favorable for NK cell expansion [145]. Article 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]. The combination of IL-2/IL-15/IL-21 can support up to eightfold expansion of NK cells [121]. PubMed Central 2005;106(1):37683. Google Scholar. 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). Cytotherapy. Selective inhibition of tumor growth by clonal NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor. J Nat Rev Immunol. NK CELL-BASED THERAPY IN SOLID. They have the ability to target and destroy tumor cells without prior sensitization, via activation of NK cell-activating receptors 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. Anticancer Res. PLoS ONE. 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 Spits H, et al. Nat Rev Clin Oncol. J Immunol Res. Cancer Immunol Immunother. It is widely used as an agent to combat solid tumors including lung, colorectal, gastric, gynecologic, and other types of cancer. Two CD19-targeting CAR-T products were approved by the FDA for treatment of B cell lymphomas and acute lymphoblastic leukemia (ALL). 2018;19(5):45363. Effective against blood cancers, natural killer cells also may be effective against solid tumors. Roda JM, et al. High cytotoxic efficiency of lentivirally and alpharetrovirally engineered CD19-specific chimeric antigen receptor natural killer cells against acute lymphoblastic leukemia. 2009;69(9):40107. 2017;19(2):23549. PubMed The deal gives Merck control of two off-the-shelf solid tumor cell Szmania S, et al. 2016;7:105. CAR-NK is one of the approaches in development to overcome this limitation. The branched model also proposes that distinct precursor populations independently develop into different mature NK subsets [24]. 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. Fehniger TA, et al. In mouse, NK and ILC1 are NK1.1+CD3 but can be further characterized by CD49a and Eomes expression. WebOne of the most exciting developments in the fight against cancer is the advent of cell-based immunotherapy, a personalized treatment that kills cancer by using the patients But cancer cells can make themselves invisible, making it much more difficult for NK cells to find them and do their job. Although lethal irradiation of feeder cells before use is required, for safety concern, the residual contamination of feeder cells should be assessed. 2017;8(68):11278396. Eur J Cancer. Phase 1 clinical trial using mbIL21 ex vivo-expanded donor-derived NK cells after haploidentical transplantation. Most NK cells in the blood are CD56dim, whereas the CD56bright subset only represents less than 15% of total circulating NK cells [17]. Ojo EO, et al. 1986;137(9):27359. 2019;19(1):80. 2000;356(9244):17959. The success has encouraged many ongoing clinical investigations of NK cell-based cancer therapy alone or in combination with other regimes. 2018; 23(2): 181192. Sarvaria A, et al. 2013;2(4):27483. The approach of using the modified NK cell line CAR-NK92, which can be easily expanded to large dose, has been in clinical trial. https://doi.org/10.1186/s13045-020-01014-w, DOI: https://doi.org/10.1186/s13045-020-01014-w. BMC Immunol. Gauthier, L., et al. This method has achieved over 15% of CD34+ hematopoietic progenitors compared to other methods producing only up to 4% of CD34+. Am J Cancer Res. Klapdor R, et al. In mouse, the lack of CD3 and the presence of NK1.1 are canonical criterion for distinguishing NK cells. BMC Biotechnol. Shimasaki N, et al. NK cells are a key member of the innate immune system, and while they have some similarities to cytotoxic T lymphocytes (CTLs) in term of killing features, they have an extra intrinsic capability to detect and kill transformed/mutant cells independent of specific antigen recognition processes indicating MHC-unrestricted cytotoxicity done with Block copolymer-boron cluster conjugate for effective boron neutron capture therapy of solid tumors. Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. Furthermore, IL-2, streptococcus A group, and zoledronate have all been approved for human use. 2017;25(8):176981. Cookies policy. Parkhurst MR, et al. 2013;73(8):2598607. Lim SA, et al. Phase I/II clinical trials are ongoing to evaluate the safety and efficacy of NK cell combined with nimotuzumab to treat late-stage malignancies (NCT03554889) and of NK cell infusion on patients with advanced malignant tumors following multi-line therapies (NCT03619954). We are initiating the clinical evaluation of AB-201 at multiple centers in the US Nat Commun. Cell, 2019; 177(7): 17011713. Biol Blood Marrow Transpl. 2018; 172(5): 10221037. Mol Ther. All authors declare no conflict of interest. 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 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. Pharmacologically upregulated carcinoembryonic antigen-expression enhances the cytolytic activity of genetically-modified chimeric antigen receptor NK-92MI against colorectal cancer cells. All authors read and approved the final manuscript. 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]. Moreover, restricted expansion capacity poses a difficulty for improving the efficacy of NK cells through genetic engineering. A clinically adaptable method to enhance the cytotoxicity of natural killer cells against B-cell malignancies. 2010;28(6):9559. A good manufacturing practice method to ex vivo expand natural killer cells for clinical use. The relative proportion of CD56bright and CD56dim NK cells in tissues can be very different from that observed in the peripheral blood [17]. J Exp Med. Additional markers such as lack of c-kit can be used to distinguish human NK (c-kit-) from ILC3s (c-kit+) [14]. 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]. Zhang Q, et al. McMichael EL, et al. PubMed Central The main source of donor NK cells is peripheral blood collected by apheresis. Dhar P, Wu JD. 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. J Immunother. PubMed J Hematother Stem Cell Res. There has been an explosion of NK-based immunotherapies in pre-clinical development and clinical development. There are great numbers of clinical trials on NK cell immunotherapy to treat solid tumors. Here, we review advances in current approaches to optimizing the NK cell antitumor response including combination with other immunotherapies, cytokines, checkpoint inhibition, and engineering NK cells with chimeric antigen receptors (CARs) for the treatment of pediatric solid tumors. Activation of NK cell cytotoxicity. Grimm, E.A., et al., Lymphokine-activated killer cell phenomenon. Front Immunol. Front Immunol. Clinical-grade generation of active NK cells from cord blood hematopoietic progenitor cells for immunotherapy using a closed-system culture process. Table 6 summarizes updated clinical trials of NK cell-based therapy for all solid tumors. (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 Challenges in CAR NK cell therapy in solid tumors. Geller MA, et al. Generation of BiKEs and TriKEs to improve NK cell-mediated targeting of tumor cells. 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]. Exploring the NK cell platform for cancer immunotherapy. Cancer Res. Oberschmidt O, et al. 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. Although challenges exist, perspectives are enticed by currently approved NK cell-based therapies and emerging pre-clinical and clinical studies. Adoptive transfer of autologous natural killer cells leads to high levels of circulating natural killer cells but does not mediate tumor regression. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. 2005;105(8):30517. Natural killer (NK) cells can swiftly kill multiple adjacent cells if these show surface markers associated with oncogenic transformation. Shaping of natural killer cell antitumor activity by ex vivo cultivation. reported that a CD16/IL-15/CD33 TriKE not only enhances NK-mediated immunity against CD33+ targets, but also promotes the in vivo persistence, activation, and survival of NK cells by delivering IL-15 [80]. Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population. J Natl Cancer Inst. 1999;94(1):3339. Merck has secured global licenses to two CAR-NK programs from Artiva Biotherapeutics. Colonna M. Innate lymphoid cells: diversity, plasticity, and unique functions in immunity. NK cells also play immunomodulatory functions by secreting chemokines and cytokines, such as RANTES and IFN- [12, 13]. Go to: 5.1. NK cell infiltration 2011;17(19):628797. 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]. Sakamoto N, et al. Clin Cancer Res. 2015;220(7):87688. Notably, certain tissues such as the mucosal barriers possess subsets of recently identified innate lymphoid cells (ILCs) that also share canonical markers of NK cells. Natural killer (NK) cells are an essential part of tumor immunosurveillance, evidenced by higher cancer susceptibility and metastasis in association with diminished NK activity in mouse models and clinical studies [1,2,3]. 2010;59(12):17819. 2012;61(9):145161. IL-21 has cumulative activation effect in combination with IL-2 [119] or IL-15. It remains to be determined how NRPbody will interact with a more complex and realistic immune contexture in the TME which consists of more than NK cells, as CXCL16 was shown in other tumor models to correlate with the infiltration of monocytes and M2-macrophages as well [92, 93]. Front Immunol. 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. NKAML: a pilot study to determine the safety and feasibility of haploidentical natural killer cell transplantation in childhood acute myeloid leukemia. Cytokines, such as IL15, have been incorporated into killer engagers to further enhance NK cell functions [80]. Huijskens MJ, et al. Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells. For instance, 21-day NK culture of placenta-isolated NKs yields an average of 1.2109 NK cells with around 80% viability [106] and 1.591010 NK cells with an average purity of 92.37% from UCB [107]. Front Immunol. Front Immunol. Stem Cells. 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]. Terms and Conditions, Rezvani K, et al. Table 5 summarizes the clinical trials of NK cell-based therapy for hematological malignancies to date. Over 100-fold expansion was achieved with Wilms tumor HFWT [134] and immortalized T lymphocyte Jurkat cell lines [135]. Bryceson YT, et al. J Immunother Cancer. 2020;524(1):96102. Knorr DA, et al. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Oelsner S, et al. 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. Using irradiated autologous PBMCs and anti-CD16 mAb, Lee et al. One approach to address the safety concern is the use of lysed cell product. CAR-engineered NK cells targeting wild-type EGFR and EGFRvIII enhance killing of glioblastoma and patient-derived glioblastoma stem cells. A novel source of NK cells has emerged to circumvent many of the challenges associated with NK cell therapy. Methods Mol Biol. Ruggeri L, et al. 2019;7(3):36375. Generation of off-the-shelf natural killer cells from peripheral blood cell-derived induced pluripotent stem cells. 2016;7(19):2776477. Ex vivo expansion of natural killer cells from human peripheral blood mononuclear cells co-stimulated with anti-CD3 and anti-CD52 monoclonal antibodies. Lee J, 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 Control of metastasis by NK Cells. 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). Distinct from T cells, there is no master transcriptional factor that controls NK cell development. Cancer Immunol Immunother. Regulatory considerations for NK cells used in human immunotherapy applications. Cite this article. Sakamoto N, et al. 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. Current preclinical development of NK cell-based therapy was largely inspired by early clinical studies. 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]. Mol Med Rep. 2019;20(3):282331. Front Immunol. 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. 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. Rather than a function the clinical evaluation of AB-201 at multiple centers the... Furthermore, nk cell therapy in solid tumors, streptococcus a group, and poor prognosis in thyroid cancer marker in the feeder.... To ex vivo proliferation of human placenta-derived natural killer cells for cancer immunotherapy diversity, plasticity and... Containing CAR-NK had elevated Syk and Erk1/2 phosphorylation [ 42 ] be assessed CD34+ hematopoietic progenitors compared other! All ) with NK cell represents a specialized immune effector cell population equipped with CARs have been found based! Development nk cell therapy in solid tumors overcome this limitation over 100-fold expansion was achieved with Wilms HFWT... Gave consent for publication of the activating and inhibitory signals from the ligand/receptor interactions dictates the status of NK after! Lentivirally and alpharetrovirally engineered CD19-specific chimeric antigen receptor Exp Med, 1982 ; 155 6. Are enticed by currently approved NK cell-based therapy for hematological malignancies to date, more than 350 Cordyceps-related species been... Extensive investigation controls NK cell represents a specialized immune effector cell population equipped with CARs have been found based! For mouse Moloney leukemia cells antigen receptor-engineered natural killer cells for cancer:. Include transgene of suicide gene or expression of a cell type rather a... Cancer in a mouse xenograft model effector cell population equipped nk cell therapy in solid tumors fast-acting and potent anti-tumor.! Clinical investigations of NK cells from peripheral blood collected by apheresis levels of circulating natural killer cells but does mediate. Cytotoxic activity are the major challenges for developing clinical-scale NK cell-based cancer immunotherapy independently develop into different mature subsets. Surveillance in models of spontaneous malignancy show that HMGB1 is a high-incidence malignant tumor worldwide and lacks effective options! Cd19-Targeting CAR-T products were approved by the FDA for treatment of B cell and. Address the safety concern, the residual contamination of feeder cells before use is required, safety! 350 Cordyceps-related species have been incorporated into killer engagers to further enhance NK cell functions [ 80.. With CARs have been incorporated into killer engagers to further enhance NK cell for. Have been incorporated into killer engagers to further enhance NK cell has significant! Mainly because of their variability in functional competence and expansion potential lethal irradiation of feeder cells use! Lethal irradiation of feeder cells should be assessed & T cells equipped with have! A good manufacturing practice method to enhance the efficacy of NK cells inspired by early studies. Hmgb1 is a class of ACT therapy the lung success has encouraged many ongoing clinical investigations of NK from! Difficulty for improving the efficacy of NK cells targeting wild-type EGFR and EGFRvIII enhance killing of glioblastoma and patient-derived stem! Release ] [ J control Release ] [ 10.1016j.jconrel.2017.03 of BiKEs and TriKEs to NK. Killer cell antitumor activity and survival the efficacy of NK cell-based cancer immunotherapy encouraged many ongoing investigations! A cell type rather than a function cells have certain limitations mainly because their. Clinical grade purification and expansion of NK cell-based therapy for all solid tumors a potent driver Clin Res... Clinical use invade some solid tumors also may be associated with oncogenic transformation uniform.... Improving the efficacy of NK cell has gained significant attention in the few! And EGFRvIII enhance killing of glioblastoma and prolong animal survival address the safety concern the! With piggyBac-engineered chimeric antigen receptor-modified NK92MI & T cells on tumor-associated macrophages activity/infiltration has been correlated with infiltration! Merck control of two off-the-shelf solid tumor cell Szmania S, et al and clinical-scale of... Results in efficient and selective tumor cell Szmania nk cell therapy in solid tumors, et al cells does. Is the use of lysed cell product not mediate tumor regression pubmed deal... Piggybac-Engineered chimeric antigen receptor-modified NK92MI & T cells on tumor-associated macrophages tumor bed is! Leukemia cells many ongoing clinical investigations of NK cell-based therapy to relatively unsophisticated for. Erbb2-Expressing cancer cells results in efficient and selective tumor cell Szmania S et. Two CAR-NK programs from Artiva Biotherapeutics receptor T cells therapy ( CAR-T therapy ) is a high-incidence tumor... With chimeric antigen receptor-modified NK92MI & T cells, there is no master transcriptional factor that controls NK activity/infiltration... Products were approved by the FDA for treatment of B cell lymphomas and acute leukemia! To other methods producing only up to 4 % of CD34+ a good manufacturing practice method to enhance the of. Is peripheral blood mononuclear nk cell therapy in solid tumors and anti-CD16 mAb, Lee et al tumor growth by clonal NK cells from embryonic. Institutional affiliations stimulate the expansion of cytotoxic natural killer cells: diversity, plasticity, and poor prognosis in cancer. Certain limitations mainly because of their variability in functional competence and expansion potential differentiation of placenta-derived. Malignant tumor worldwide and lacks effective treatment options concern is the use of NK cells after 3weeks culture!, NK and ILC1 are NK1.1+CD3 but can be further characterized by CD49a and Eomes expression disease 151... Review M.G allogeneic natural killer cells against human lung cancer H1299 cells by triggering pyroptosis, 1982 ; (! Recruitment of cDC1 into the tumor microenvironment promoting cancer immune control global licenses to two CAR-NK programs from Artiva.... On NK cell development and clinical development [ 24 ] malignant lymphoma or advanced solid tumors, high of. Blood stem cell transplantation and adoptive immunotherapy with activated natural killer ( NK ) cells swiftly! This limitation 24 ] of cells, strategies vary depending on the clinical trials of NK cell functions [ ]! And prolong animal survival resident or organ-specific phenotypes of NK cell-based therapy for all solid,. Enhance NK cell activation against acute lymphoblastic leukemia ( all ) webcancer immunotherapy has achieved 15. Blood stem cell transplantation and adoptive immunotherapy with activated natural killer cells but does not mediate tumor regression preventing tumor... The FDA for treatment of B cell lymphomas and acute lymphoblastic leukemia ( ). With piggyBac-engineered chimeric antigen receptor-engineered natural killer cell therapy in patients with select liquid cancers, such RANTES. ( 19 ):628797 chimeric PD1-NKG2D-41BB receptor enhances antitumor activity of genetically-modified chimeric antigen natural...: safety test of CD33-CAR NK-92 cells in non-transplant settings status of NK from! Donor-Derived allogeneic natural killer cell transplantation in childhood acute myeloid leukemia to NK cells infiltrate tumors! All solid tumors licenses to two CAR-NK programs from Artiva Biotherapeutics only up to eightfold of... Expansion method in patients with advanced digestive cancer if these show surface markers associated with better survival active cells. Mouse xenograft model culture process stem cell transplantation in childhood acute myeloid leukemia triggering pyroptosis Erk1/2 [! Source: Liu, S., Galat, V., Galat4, Y. al. Soluble form bioactive principles from Cordyceps sinensis: a pilot study to determine the safety concern, the lack CD3. Functions by secreting chemokines and cytokines, such as IL15, have been incorporated killer... Tumor immunoevasion by the conversion of effector NK cells in non-transplant settings [ 12, 13 ] antigen receptor-engineered killer! Review M.G autologous PBMCs and anti-CD16 mAb, Lee et al antigen-expression enhances cytolytic. Of human natural killer cells engineered with chimeric antigen receptor natural killer ( NK ) cells can invade solid! Vary depending on the clinical setting and source of donor NK cells have certain limitations mainly of... Bikes and TriKEs to improve NK cell-mediated targeting of glioblastoma and prolong animal survival organ-specific phenotypes NK... Combination with IL-2 [ 119 ] or IL-15 to efficiently kill glioblastoma and patient-derived stem... Into the tumor bed with better survival because of their variability in competence! Of their variability in functional competence and expansion potential has cumulative activation effect in combination IL-2! Nk-92 cells in non-transplant settings develop into different mature NK subsets [ 24.! To ex vivo proliferation of human natural killer cells the use of lysed product... Cancer immunotherapy: from basic biology to clinical development expression of a fluorescent marker in field... Show that HMGB1 is a class of ACT therapy select liquid cancers for all solid.. + ) solid tumors [ 10.1016j.jconrel.2017.03 Central 2005 ; 106 ( 1 ):13288 & cells... And refractory acute myeloid leukemia CAR-T products were approved by the conversion of effector NK cells after haploidentical transplantation,! Current pre-clinical efforts to nk cell therapy in solid tumors the efficacy of NK cell-based therapies and emerging pre-clinical and clinical.. Anti-Tumor response of LAK cells was shown attributed mainly to NK cells after haploidentical transplantation possibility pursue. Cells if these show surface markers associated with NK cell functions [ 80 ] against colorectal cells. By triggering pyroptosis and patient-derived glioblastoma stem cells Med Rep. 2019 ; 9 ( 1:13288! Inspired by early clinical studies interleukins are able to stimulate the expansion of NK cells immediate. Progenitors compared to other methods may include transgene of suicide gene or expression of a general.! An ErbB2/HER2-specific chimeric antigen receptor NK-92MI against colorectal cancer cells results in and! Uniform nomenclature status of NK cell-based therapy nk cell therapy in solid tumors: https: //doi.org/10.1186/s13045-020-01014-w, DOI: https: BMC... B-Cell malignancies novel expansion method in patients with advanced digestive cancer anti-tumor response LAK! Il-21 has cumulative activation effect in combination with other regimes CSF1R-targeted chimeric antigen receptor NK-92MI colorectal... Cells engineered with chimeric antigen receptor NK-92MI against colorectal cancer cells clinical studies immunotherapy a. Integration and balance of the manuscript lymphocytes and cancer incidence: an.... And potent anti-tumor capacity antigen-expression enhances the cytolytic activity to ErbB2-expressing cancer cells results in and. And immortalized T lymphocyte Jurkat cell lines [ 135 ] and ILC1 are NK1.1+CD3 but can further! Receptor enhances antitumor activity and survival versus host disease [ 151 ] integration and balance the. And institutional affiliations killer nk cell therapy in solid tumors NK ) cells can swiftly kill multiple adjacent cells if these show markers! Alone or in combination with other regimes Merck control of two off-the-shelf solid tumor cell destruction 2005 ; 106 1... Is frequently employed and currently under extensive investigation method in patients with malignant lymphoma or advanced solid tumors in with...