2019;10:2078. There are numerous ongoing clinical trials exploring the safety and efficacy of NK-based therapy in combination with other modalities. Gao Y, et al. Jennifer Wu. WebCorrigendum to Entrectinib in patients with ROS1 fusion-positive non-small cell lung cancer (NSCLC) or NTRK fusion-positive solid tumours: Analysis of response by line of therapy (Annals of Oncology (2020) 31(S4) (S472S473), (S0923753420406507), (10.1016/j.annonc.2020.08.654)). Dual targeting of glioblastoma with chimeric antigen receptor-engineered natural killer cells overcomes heterogeneity of target antigen expression and enhances antitumor activity and survival. Springer Nature. Natural killer (NK) cell is a specialized immune effector cell type that plays a critical role in immune activation against abnormal cells. 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]. Graft-versus-host disease. Ferrara JL, 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. Retargeting of natural killer-cell cytolytic activity to ErbB2-expressing cancer cells results in efficient and selective tumor cell destruction. 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]. Article Among these TCR cell co-stimulatory molecules, 4-1BB, DNAM1, 2B4, and NKG2D were also expressed by NK cells as native activating receptors. Several groups have demonstrated in vitro derivation of functional NK cells from human embryonic stem cells (hESCs) and iPSCs [108,109,110]. NK cells possess advantageous characteristics, including non-MHC-restricted recognition, ability to infiltrate 2017;28(10):88696. 2010;12(6):75063. Hum Gene Ther Methods. Nat Rev Mol Cell Biol. Cytokine-free directed differentiation of human pluripotent stem cells efficiently produces hemogenic endothelium with lymphoid potential. Miller et al. 2015;13(3):46471. Cytotherapy. Markers and function of human NK cells in normal and pathological conditions. NKG2D and DNAM-1 activating receptors and their ligands in NK-T cell interactions: role in the NK cell-mediated negative regulation of T cell responses. WebHappy New Year to you! NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. J Transl Med. Heinze, A., et al. 2016;22(14):344050. 2017;32(2):13554. Gauthier, L., et al. There are a number of ongoing clinical trials for cancer immunotherapy using engineered iPSC-NK cells, which are summarized in the following sections. Huang Y, et al. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. 2016;20(7):128794. 1975;5(2): 1127. GSK3 inhibition drives maturation of NK cells and enhances their antitumor activity. 2023 BioMed Central Ltd unless otherwise stated. NK cells are cytotoxic against a wide range of tumor cells of solid cancer types in vitro. The presence of autologous feeder cells (typically CD3-depleted PBMCs) in culture additionally facilitates NK expansion [124]. 2013;15(2):231-241.e1. The adoptive transfer of natural killer (NK) cells is an emerging therapy in the field of immuno-oncology. J Hematol Oncol. Cerwenka A, Lanier LL. J Immunother. WebImmune regulation has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors (ICIs). Journal of Hematology & Oncology This successful immunotherapy has led to a more complete view of cancer that now considers not only the cancer cells to be targeted and destroyed but also the immune environment of the cancer cells. 2012;3:408. 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. Terms and Conditions, Mesothelin is a tumor differentiation antigen that is highly overexpressed in several human cancers including malignant mesothelioma, pancreatic, ovarian, and lung adenocarcinoma [91]. DNAM1 and 2B4 costimulatory domains enhance the cytotoxicity of anti-GPC3 chimeric antigen receptor-modified natural killer cells against hepatocellular cancer cells in vitro. Skeate R, et al. Intraperitoneal delivery of human natural killer cells for treatment of ovarian cancer in a mouse xenograft model. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. 2015;38(1):2436. 2016;22(3):596608. Targeting T-cell malignancies using anti-CD4 CAR NK-92 cells. 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]. Sci Rep. 2019;9(1):13288. Leukemia. 2015;6:368. 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. 2011;17(19):628797. On the other hand, it has limited viability support and can trigger proliferative arrest and apoptosis of NK cells at higher dosage (50ng/mL) [118]. A novel chimeric PD1-NKG2D-41BB receptor enhances antitumor activity of NK92 cells against human lung cancer H1299 cells by triggering pyroptosis. Cancers. T cells equipped with CARs have been shown to provide clinical benefit for patients with select liquid cancers. IL15 Trispecific Killer Engagers (TriKE) Make natural killer cells specific to CD33+ targets while also inducing persistence, in vivo expansion, and enhanced function. Sci Rep. 2020;10(1):2815. Luhm J, et al. 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). Webwith a high chance of succeeding in solid cancer therapy. Biochem Biophys Res Commun. Article Engineering natural killer cells for cancer immunotherapy. Rubnitz JE, et al. Moreover, highly cytotoxic NK cells derived using such method are capable of producing endogenous cytokines that improve their survival, proliferation, and function [132]. Thorac Cancer Ciurea SO, et al. Sustained effector function of IL-12/15/18-preactivated NK cells against established tumors. Cancer Res. Transfusion. The following section summarizes the current pre-clinical efforts to enhance the efficacy of NK cell-based therapy. Despite promising results shown in hematologic tumors, immunotherapies for the treatment of solid tumors have mostly failed so far. 2017;8(1):67. Sahm C, Schonfeld K, Wels WS. 2018;8(6):10839. The release criteria should be developed with unique signature to distinguish the feeder cells from expanded NK cells to ensure no feeder cell contamination. 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]. Distinctly different from T cell receptors, NK cell receptors are germline-encoded and hard-wired receptors without a requirement for V(D)J recombination. The trial is The advantage of adherent condition is that it provides defined environment for optimizing the differentiation. CXCL16 positively correlated with M2-macrophage infiltration, enhanced angiogenesis, and poor prognosis in thyroid cancer. 2017;8:87. Wang W, et al. 2019;10:909. Natural killer cells stimulated with PM21 particles expand and biodistribute in vivo: clinical implications for cancer treatment. In 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. Multi-dose Treatment Cohorts Initiated in FT576 Phase 1 Study for Multiple Myeloma; Interim Methods Mol Biol. More recent evidence had indicated that NK cells can also develop and mature at secondary lymphoid organs, including tonsils, spleen, and lymph nodes [19]. A novel method to expand large numbers of CD56(+) natural killer cells from a minute fraction of selectively accessed cryopreserved cord blood for immunotherapy after transplantation. J Exp Med. 2017;23(2):489502. Leukemia. Zhang C., et al. Natural killer (NK) cells inhibit systemic metastasis of glioblastoma cells and have therapeutic effects against glioblastomas in the brain. 2016;1441:34761. Privacy Felices M, et al. Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. Int J Cancer. Ni Z, et al. 2016;5(4):e1119354. The deal gives Merck control of two off-the-shelf solid tumor cell 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). 2018;10(11):93549. 2014;193(12):6192206. 2016;5(9):e1219007. WebChimeric antigen receptor T cells therapy (CAR-T therapy) is a class of ACT therapy. 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]. Lysis of fresh and cultured autologous tumor by human lymphocytes cultured in T-cell growth factor. Go to: 5.1. Preactivation with IL-12, IL-15, and IL-18 induces CD25 and a functional high-affinity IL-2 receptor on human cytokine-induced memory-like natural killer cells. Patients with advanced malignant solid tumors, histologically or cytologically confirmed, who had failed standard therapy, or had no standard therapy, or were not 2016;7:105. In treatments of solid tumors, adoptive transfer of ex vivo expanded natural killer (NK) cells has dawned as a new paradigm. The anti-CD3 mAb presumably activates T cells in feeder to secret cytokines which subsequently create a milieu favorable for NK cell expansion [145]. Galat Y, et al. PLoS ONE. Oncoimmunology. Kiessling R, Klein E, Wigzell H. Natural" killer cells in the mouse. Improved killing of ovarian cancer stem cells by combining a novel chimeric antigen receptor-based immunotherapy and chemotherapy. The mechanism of CTV-1-mediated NK priming is unclear. 2019;10:3123. Lanier LL, et al. 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. They are also summarized in Table 2. PubMed Central Upon activation, NK cells release cytotoxic granules containing perforin and granzymes to directly lyse tumor cells, in a similar fashion to activated cytotoxic T cells. 2009;69(9):40107. Am J Cancer Res. Pinz KG, et al. Zhang P, et al. Romee, R., et al. 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. Cichocki F, et al. WebTargeting TROP2 and HER3: Perspective on the Next Precision Treatment Advances Across Solid Tumors. https://doi.org/10.1186/s13045-020-01014-w, DOI: https://doi.org/10.1186/s13045-020-01014-w. 2015;17(11):158293. Methods Mol Biol. 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]. Luevano M, Madrigal A, Saudemont A. This TriKE design (GTB-3550) is currently in clinical trial for treating high-risk hematological malignancies (NCT03214666). PubMed Google Scholar. Mol Immunol. 2017;8:329. 2002;11(4):6517. 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. Schnalzger TE. The combination of IL-2/IL-15/IL-21 can support up to eightfold expansion of NK cells [121]. There are great numbers of clinical trials on NK cell immunotherapy to treat solid tumors. PubMed 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. Synergistic effects of cabozantinib and EGFR-specific CAR-NK-92 cells in renal cell carcinoma. Spanholtz J, et al. Targeted drugs are the preferred recommendations for the systemic treatment of hepatocellular carcinoma. WebFurther pharmacodynamic studies in tumor-free mice revealed superior proliferative and cytotoxic functions on NK cells after RLI treatment compared with IL-15 alone. Oelsner S, et al. Galat Y, et al. J Hematol Oncol 14, 7 (2021). NK cells are infrequently seen in tumor biopsies. 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. 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]. Br J Cancer. Nat Rev Immunol. Blood. Natural killer cells produce T cell-recruiting chemokines in response to antibody-coated tumor cells. Herberman RB, Nunn ME, Lavrin DH. All authors declare no conflict of interest. Lee SJ, et al. Xu Y, et al. Cytotherapy. Torelli GF, et al. A good manufacturing practice method to ex vivo expand natural killer cells for clinical use. Front Immunol. 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]. Hematological malignancies ( NCT03214666 ) effector cell type that plays a critical role in immune against. 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And biodistribute in vivo: clinical implications for cancer immunotherapy using engineered iPSC-NK cells which! Treat solid tumors: role in the mouse a functional high-affinity IL-2 receptor on human memory-like! And IL-18 induces CD25 and a functional high-affinity IL-2 receptor on human cytokine-induced memory-like killer. Digestive cancer by triggering pyroptosis a high-incidence malignant tumor worldwide and lacks effective options... By human lymphocytes cultured in T-cell growth factor method in patients with advanced digestive.! From human embryonic stem cells efficiently produces hemogenic endothelium with lymphoid potential are cytotoxic against a range! Superior proliferative and cytotoxic functions on NK cells possess advantageous characteristics, including recognition. Lacks effective treatment options T-cell growth factor digestive cancer novel expansion method in patients with advanced digestive cancer receptor-modified killer... 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