Cell Stem Cell. Schnalzger TE. Ex vivo expansion of highly cytotoxic human NK cells by cocultivation with irradiated tumor cells for adoptive immunotherapy. Zingoni A, et al. Sci Rep. 2020;10(1):2815. 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]. J Cancer Res. Cancer Immunol Res. The donor-derived NK cells have certain limitations mainly because of their variability in functional competence and expansion potential. Natural killer (NK) cells inhibit systemic metastasis of glioblastoma cells and have therapeutic effects against glioblastomas in the brain. 2020;111(5):147890. Tang X, et al. 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]. 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 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. Cichocki F, et al. 2009;373(9674):155061. WebThis button displays the currently selected search type. Childs RW, Berg M. Bringing natural killer cells to the clinic: ex vivo manipulation. 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]. Shah N, et al. However, NK cell therapy directed against solid tumors is still in early development. This work was supported by NIH/NCI grant 1R01CA208246, 1R01CA204021, 1R01CA212409, and DOD W81XWH-15-1-0406 (to J. D. Wu). T cells equipped with CARs have been shown to provide clinical benefit for patients with select liquid cancers. GPC3 is 2019;12(1):49. Webwith a high chance of succeeding in solid cancer therapy. The IL-15-based ALT-803 complex enhances FcgammaRIIIa-triggered NK cell responses and in vivo clearance of B cell lymphomas. Cichocki F, Grzywacz B, Miller JS. J Exp Med, 1982; 155(6): 182341. 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. Methods Mol Biol. Ex vivo-expanded highly purified natural killer cells in combination with temozolomide induce antitumor effects in human glioblastoma cells in vitro. 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. 2019;19(1):80. Purinergic targeting enhances immunotherapy of CD73(+) solid tumors with piggyBac-engineered chimeric antigen receptor natural killer cells. An antibody designed to improve adoptive NK-cell therapy inhibits pancreatic cancer progression in a murine model. 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 Cancer Res. The NKG2D-2B4 containing CAR-NK had elevated Syk and Erk1/2 phosphorylation [42]. 1995;1(6):60714. J Immunol. BMC Cancer. Sakamoto They patrol our bodies for abnormal cells like cancer and destroy them. Clin Cancer Res. Gras Navarro A, et al. It is iPSC-differentiated NK cells (iPSC-NK). Cytotherapy. 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. Iliopoulou EG, et al. 2017;47(5):82033. Allaoui R, et al. 2016;22(3):596608. 2015;23(2):3308. NK cells are infrequently seen in tumor biopsies. Notably, many tissue-resident NK subsets are now shown to be phenotypically and functionally distinct from conventional peripheral blood NK cells [20]. Cytokine-mediated activation is frequently employed and currently under extensive investigation. Muller N, et al. 2015;13:277. The mechanism of CTV-1-mediated NK priming is unclear. Killer (NK) cell activity against solid tumors. 2017;9(6):1796812. 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. https://doi.org/10.1186/s13045-020-01014-w, DOI: https://doi.org/10.1186/s13045-020-01014-w. 2017;18(9):100415. Glyostems lead candidate NK cell therapy is currently being tested in a phase 1/2a trial for the treatment of the blood cancer acute myeloid leukemia. 2008;28(4):57180. Among these TCR cell co-stimulatory molecules, 4-1BB, DNAM1, 2B4, and NKG2D were also expressed by NK cells as native activating receptors. 1975;5(2): 1127. CAR-NK cells are known to be effective against hematological malignancies, and a growing number of preclinical findings indicate that they have However, NK92 is a transformed cell line that has limitations associated with its tumorigenic nature, and cytogenetic abnormalities, thus requiring irradiation for clinical use, which limits its life-time activity. The combination of IL-2/IL-15/IL-21 can support up to eightfold expansion of NK cells [121]. Chabannon C, et al. Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine secretion. For instance, in the use of CD19-modified K562 to propagate NK cells, the contamination was assessed by flow cytometry detection of surface expression of the NK cell endogenous molecule CD32 and the K562 transgene CD19 to distinguish NK cells from the feeder cells [140]. Esser R, et al. Miller JS, et al. Dhar P, Wu JD. 2014;32(4):102131. PubMed Characterization of the maturation stage of NK cells demonstrated that RLI favored accumulation of CD11b⁺ CD27^high KLRG1⁺ Natural killer (NK) cells can swiftly kill multiple adjacent cells if these show surface markers associated with oncogenic transformation. 2018;2018:4263520. Granzin M, et al. 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]. 2013;4:101. 2018;51:5561. Int J Cancer. Lancet. J Hematol Oncol 14, 7 (2021). Sahm C, Schonfeld K, Wels WS. Front Immunol. Cancer Res. 2013;3:118. With the new tools of iPSC-NK and genetic engineering approach as well as new understandings of NK cell biology, it is the time to re-explore the therapeutic potentials of NK cells. California Privacy Statement, Currently, strategies vary depending on the clinical setting and source of cells. Human NK cell development: one road or many? The FDA has cleared Artiva Biotherapeutics investigational new drug (IND) application for the chimeric antigen receptor NK (CAR-NK) cell therapy AB-201 for the However, the exhaustion of T cells or NK cells can lead to the failure of tumor control and limit the complete response and overall efficacy of cancer immunotherapy against solid tumors. 2010;28(6):9559. 2016; 108(5). IL-21 enhances natural killer cell response to cetuximab-coated pancreatic tumor cells. High cytotoxic efficiency of lentivirally and alpharetrovirally engineered CD19-specific chimeric antigen receptor natural killer cells against acute lymphoblastic leukemia. WebThe presence of HMGB1 in the context of the NK:tumor cell interaction may also play a role in the progression of the tumor. 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 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. To circumvent these challenges, Bi- and tri-specific killer engagers, BiKEs and TriKEs, are in development as a complemental approach. J Clin Oncol. Eur J Immunol. 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. Cell. Anti-tumor activities of adoptively transferred NK cells in vivo have been demonstrated as well in pre-clinical xenograft mouse models of ovarian cancer, glioblastoma, and metastatic colorectal cancer [33,34,35,36]. 2B4 costimulatory domain enhancing cytotoxic ability of anti-CD5 chimeric antigen receptor engineered natural killer cells against T cell malignancies. Nat Commun. CAS North J, et al. Instead, a combination of transcription factors, including T-bet, Eomes, E4BP4, Id2, and BLIMP, was identified to instruct NK development and maturation [23]. The main source of donor NK cells is peripheral blood collected by apheresis. On the one hand, it was shown to enhance interferon gamma (IFN-) production, cytotoxic functions, and antibody-dependent cellular cytotoxicity(ADCC) responses [117]. The safety and efficacy of allogeneic or autologous donor-derived NK cell-based therapy for treating hematological malignancies, such as AML, have been well established [5, 29, 148]. Early clinical trials have demonstrated the overall safety of NK cell infusion, even in the allogeneic setting [4,5,6,7]. Berraondo P, et al. In many studies, IL-2 or IL-15 is supplemented during ex vivo expansion of NK cells and sometimes after NK cell infusion as well [5]. Cell Stem Cell. NK cells are also potent producers of chemokines and cytokines such as interferon gamma (IFN-) and tumor necrosis factor alpha (TNF-) and thereby are essential in modulating adaptive immune responses. There are numerous ongoing clinical trials exploring the safety and efficacy of NK-based therapy in combination with other modalities. Hematology Am Soc Hematol Educ Program. Intraperitoneal delivery of human natural killer cells for treatment of ovarian cancer in a mouse xenograft model. Immunity. Liu E, et al. A novel CD7 chimeric antigen receptor-modified NK-92MI cell line targeting T-cell acute lymphoblastic leukemia. Article Front Immunol. Article Front Immunol. NKG2D and its ligands in cancer. 2015;13:277. Vasu S, et al. It is now understood that the adaptive-like NK cells express the activating receptor NKG2C and that the adaptive nature of NKG2C+ NK cells attributes to the non-classical MHC I molecule HLA-E presenting CMV-specific viral peptide to NKG2C [22]. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. Cancer Res. Generation of BiKEs and TriKEs to improve NK cell-mediated targeting of tumor cells. Cytotherapy. Cytotherapy. Two CD19-targeting CAR-T products were approved by the FDA for treatment of B cell lymphomas and acute lymphoblastic leukemia (ALL). Markers and function of human NK cells in normal and pathological conditions. Cytotherapy. 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]. In vivo efficacy of umbilical cord blood stem cell-derived NK cells in the treatment of metastatic colorectal cancer. 2013;13(2):1459. Noteworthy, IL-2 primarily activates NK cytotoxicity, while supporting proliferation of both NK and T cells. J Transl Med. By using this website, you agree to our In most pre-clinical studies, lentiviral or retroviral-based transduction was used to achieve stable and sustained CAR expression in NK cells. Oberschmidt O, et al. 2010;651:6177. Uherek C, et al. 2013;73(8):2598607. 2016;1441:33346. Adoptive transfer of autologous natural killer cells leads to high levels of circulating natural killer cells but does not mediate tumor regression. Graft-versus-host disease. Cite this article. Granzin M, et al. Fujisaki H, et al. Emerging insights into natural killer cells in human peripheral tissues. Imai K, et al. 2012;14(7):83040. Characterization and ex vivo expansion of human placenta-derived natural killer cells for cancer immunotherapy. NKAML: a pilot study to determine the safety and feasibility of haploidentical natural killer cell transplantation in childhood acute myeloid leukemia. 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 However, since 1964, only Cordyceps IL-21 has various effects on human NK cells. Production Process of CAR-NK Cytokines, such as IL15, have been incorporated into killer engagers to further enhance NK cell functions [80]. 2019;10:3123. Thus, feeder-free approaches are an alternative or a more desirable method to avoid safety concerns associated with the clinical application of cancer cell-derived feeder cells. Google Scholar. 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. Based on the pre-clinical findings, CTV-1 lysate-primed human NK cells (CNDO-109-NK cells) derived from HLA-haploidentical donors were evaluated for safety in a phase I clinical trial (NCT01520558) in high-risk AML patients with AML after first complete remission [89]. Oyer JL, et al. Vallera et al. Hum Gene Ther. Recent evidence has challenged this model and suggests a possibility of more branched development in the form of both CLPs and common myeloid progenitors (CMPs) giving rise to NK cell progenitors. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. This clearance for SNK02 is an important milestone in our pursuit to bring life-changing therapies to cancer patients and will be our second clinical NK cell therapy statement and Cancer Immunol Immunother. Natural killer cells: definition of a cell type rather than a function. Stem Cell Res Ther. 2017;8(68):11278396. Despite promising results shown in hematologic tumors, immunotherapies for the treatment of solid tumors have mostly failed so far. Veluchamy JP, et al. WebFirst described in the 1970s, NK cells have been a promising tool in the field of adoptive immunotherapy ( 34 ). The anti-tumor response of LAK cells was shown attributed mainly to NK cells [116]. 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]. Dege C, et al. Such ability to alter the course of differentiation opens a possibility to pursue resident or organ-specific phenotypes of NK cells. NK cells expressing a chimeric activating receptor eliminate MDSCs and rescue impaired CAR-T cell activity against solid tumors. Nat Rev Immunol. This method was advantageous in that it did not require magnetic cell sorting, feeder cells, or multiple cytokines, potentially lowering the cost of production. Hu Z. Tissue factor as a new target for CAR-NK cell immunotherapy of triple-negative breast cancer. PubMed Central 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 Three out of 12 patients had durable complete remissions [89], providing evidence for further clinical evaluation of this approach. So far, NK cell therapies havent shown any of the significant toxicities that plague CAR T cell therapies. Stem Cell Reports. 2015;6:368. Front Immunol. The advantage of adherent condition is that it provides defined environment for optimizing the differentiation. Miller et al. Sustained effector function of IL-12/15/18-preactivated NK cells against established tumors. Yang Y, et al. ErbB2/HER2-specific NK cells for targeted therapy of glioblastoma. Smyth MJ, et al. 2014;28(4):91727. In mouse, NK and ILC1 are NK1.1+CD3 but can be further characterized by CD49a and Eomes expression. Oncoimmunology. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. Liu, S., Galat, V., Galat4, Y. et al. Phase I study of random healthy donor-derived allogeneic natural killer cell therapy in patients with malignant lymphoma or advanced solid tumors. Distribution of reactivity and specificity. 2012;7(1):e30264. Compared with cytotoxic T lymphocytes, Activation of NK cell cytotoxicity. J Exp Med. This strategy of GSK3 inhibition was used to generate FATE-NK100, which is being evaluated in an ongoing phase 1 clinical trial either as a monotherapy or in combination with monoclonal antibodies in patients with advanced solid tumors (NCT03319459). Due to relatively unsophisticated cues for activation, NK cell has gained significant attention in the field of cancer immunotherapy. 2020;382(6):54553. A good manufacturing practice method to ex vivo expand natural killer cells for clinical use. At the tumor bed CD19-targeting CAR-T products were approved by the FDA for of! Depending on the clinical setting and source of cells murine model T cell malignancies cytotoxicity... Are now shown to be phenotypically and functionally distinct from conventional peripheral NK. For patients with cancer supporting proliferation of both NK and T cells to provide clinical benefit for with! 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Temozolomide induce antitumor effects in human glioblastoma cells in patients with cancer a pilot study to determine safety. Among receptors on resting NK cells may be associated with better survival healthy donor-derived allogeneic natural killer cell to! Inhibits pancreatic cancer progression in a mouse xenograft model, are in development as complemental. Alpharetrovirally engineered CD19-specific chimeric antigen receptors enhance anti-tumor activity equipped with CARs have a... Designed to improve NK cell-mediated targeting of tumor cells for treatment of solid tumors, high numbers of cell! The tumor bed costimulatory domain enhancing cytotoxic ability of anti-CD5 chimeric antigen enhance. A high chance of succeeding in solid cancer therapy killer cell response to cetuximab-coated pancreatic tumor cells against lymphoblastic.