Clinical efficacy of this strategy has proven to be thus far be limited. Sahm C, Schonfeld K, Wels WS. NK cells are mounted with a repertoire of inhibitory and activating surface receptors (Table 1) [25,26,27,28,29]. WebCancer immunotherapy has achieved great success in the past few years. Oyer JL, et al. 2020;111(5):147890. 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. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. All authors read and approved the final manuscript. 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. 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 Cytotherapy. 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 Han J, et al. Upon ligation, these receptors transmit either inhibitory or activating signals to control NK activation. Dhar P, Wu JD. Furthermore, NKp46-ANKET increased the number of NK cells at the tumor site, providing effective control of tumor growth in mouse models of solid and invasive WebGiven the utility of NK cells in the control of tumor cell dissemination in solid tumors, it is likely that NK cells also play a key role in the control of lung cancer cells. CAS 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. Clinical-grade generation of active NK cells from cord blood hematopoietic progenitor cells for immunotherapy using a closed-system culture process. Childs RW, Berg M. Bringing natural killer cells to the clinic: ex vivo manipulation. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Article Generation of off-the-shelf natural killer cells from peripheral blood cell-derived induced pluripotent stem cells. The broad spectrum of human natural killer cell diversity. 2012;209(13):235165. Grimm, E.A., et al., Lymphokine-activated killer cell phenomenon. So far, NK cell therapies havent shown any of the significant toxicities that plague CAR T cell therapies. CXCL16 positively correlated with M2-macrophage infiltration, enhanced angiogenesis, and poor prognosis in thyroid cancer. PubMed Beyond cytokines, other stimulants, including tumor cells, allogeneic PBMCs, antibodies, and microbiol derivatives, have been explored for enhancing ex vivo NK cell expansion. 2013;3:118. PubMed Wang et al. This method was advantageous in that it did not require magnetic cell sorting, feeder cells, or multiple cytokines, potentially lowering the cost of production. Hum Gene Ther. Anticancer Res. Koehl U, et al. Markers and function of human NK cells in normal and pathological conditions. DAP12-based activating chimeric antigen receptor for NK cell tumor immunotherapy. Zhang Q, et al. Transcription factors involved in the regulation of natural killer cell development and function: an update. 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. Clinical-scale derivation of natural killer cells from human pluripotent stem cells for cancer therapy. Donor-derived natural killer cells infused after human leukocyte antigen-haploidentical hematopoietic cell transplantation: a dose-escalation study. CD19-CAR engineered NK-92 cells are sufficient to overcome NK cell resistance in B-cell malignancies. WebFurther pharmacodynamic studies in tumor-free mice revealed superior proliferative and cytotoxic functions on NK cells after RLI treatment compared with IL-15 alone. Other methods may include transgene of suicide gene or expression of a fluorescent marker in the feeder cell. Miller et al. Dual targeting of glioblastoma with chimeric antigen receptor-engineered natural killer cells overcomes heterogeneity of target antigen expression and enhances antitumor activity and survival. Zhang P, et al. 2017;8:458. 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). Due to their innate ability to eliminate tumor cells, NK cell-based immunotherapies against cancer have been investigated for decades. 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 2017;9(6):1796812. Natural killer (NK) cell is a specialized immune effector cell type that plays a critical role in immune activation against abnormal cells. Umbilical cord blood natural killer cells, their characteristics, and potential clinical applications. Large-scale generation of natural killer lymphocytes for clinical application. Exp Hematol. As an alternative to CAR-T cell therapy, CAR-NK cell therapy not only circumvents these challenges but also presents additional major advantages: (i) the ability to use unlimited allogeneic NK source without concern of GVHD [6, 31, 32]; (ii) the potential to generate off-shelf product with NK cell line or iPSC-NK [37,38,39,40,41]; (iii) relatively shortened production time; iv) recognition and killing tumor cells through NK cell native receptors independent of the CAR engineering [42], less likely allowing disease escape through downregulation of the CAR antigens as shown with CAR-T cell therapy [37]. WebExperienced R&D leader in pharmaceutical industry focusing on biologics and cell therapy drug discovery for immuno-oncology. 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 BiKEs or TrikEs are composed of two or three linked single-chain antibody variable fragments of different antigen specificities [79]. J Immunother Cancer. 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. But what it does in the realm of cancer spread is creepier still. 1975;5(2): 1127. 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]. 2014;20(4):46373. 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]. Sci Rep. 2020;10(1):2815. 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]. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Del Zotto G, et al. 2017;8:329. Webgeneration NK cell therapies. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. PubMed Kim MJ, et al. Cancers. California Privacy Statement, Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation. Li Q, et al. Huijskens MJ, et al. 1995;1(6):60714. 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]. Wang J, et al. NK cell-based cancer immunotherapy: from basic biology to clinical development. Gao Y, et al. Over 100-fold expansion was achieved with Wilms tumor HFWT [134] and immortalized T lymphocyte Jurkat cell lines [135]. 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. 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]. J Transl Med. J Immunol Res. Knorr DA, et al. Klapdor R, et al. WebChimeric antigen receptor T cells therapy (CAR-T therapy) is a class of ACT therapy. Hu Z. Tissue factor as a new target for CAR-NK cell immunotherapy of triple-negative breast cancer. A chimeric receptor with NKG2D specificity enhances natural killer cell activation and killing of tumor cells. 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. The other important feature of iPSC-NK cell technology is the ability to manipulate the differentiation strategy, thus shaping the phenotype and functionality of the resulting product. In vivo efficacy of umbilical cord blood stem cell-derived NK cells in the treatment of metastatic colorectal cancer. Biol Blood Marrow Transpl. Cancer Immunol Immunother. Despite the immunosuppressive environment of solid tumors, NK cell activity/infiltration has been correlated with improved prognoses in humans. 2016;7:105. 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]. However, NK cell therapy directed against solid tumors is still in early development. 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]. WebThese antibodies are currently used in clinical trials in the treatment of both hematological and solid tumors. However, NK cell therapy A good manufacturing practice method to ex vivo expand natural killer cells for clinical use. Journal of Hematology & Oncology Provided by the Springer Nature SharedIt content-sharing initiative. 2017;8(68):11278396. 2006;107(1):15966. 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. Recently, the differentiation method was also established in adherent monolayer cultures [108]. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. Cancer Res. There are a number of ongoing clinical trials for cancer immunotherapy using engineered iPSC-NK cells, which are summarized in the following sections. Clin Cancer Res. Short-term (1820h) pre-activation with ALT-803 augmented cytotoxicity and ADCC of NK cells in vitro. CAR-engineered iPSC-NK cells already have demonstrated effectiveness in targeting human tumors in preclinical studies [41]. However, since 1964, only Cordyceps Heinze, A., et al. Typically, the differentiation was induced in embryoid bodies or by OP9 mouse stroma co-culture [111]. Conversely, tumorigenic cells or virally infected cells have downregulated MHC I expression but upregulated levels of ligands for NK cell activating receptors and thus trigger NK cell activation due to the lack of inhibitory signals and/or the presence of activating signals [11]. 2020;122:2006. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. Ex vivo-expanded highly purified natural killer cells in combination with temozolomide induce antitumor effects in human glioblastoma cells in vitro. Jennifer Wu helped in conception and design. 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. 2018;32(2):52031. 2016;18(1):8090. Colonna M. Innate lymphoid cells: diversity, plasticity, and unique functions in immunity. But cancer cells can make themselves invisible, making it much more difficult for NK cells to find them and do their job. Combination therapy with EpCAM-CAR-NK-92 cells and regorafenib against human colorectal cancer models. 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