2020. The combination of IL-2/IL-15/IL-21 can support up to eightfold expansion of NK cells [121]. 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. 1985; 161(6): 146482. Due to their innate ability to eliminate tumor cells, NK cell-based immunotherapies against cancer have been investigated for decades. Cancer Res. 2013;2013(1):23446. Nat Immunol. Google Scholar. All authors declare no conflict of interest. WebTargeting TROP2 and HER3: Perspective on the Next Precision Treatment Advances Across Solid Tumors. Koehl U, et al. 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 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. 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]. Lim SA, et al. NKG2D and its ligands in cancer. Current preclinical development of NK cell-based therapy was largely inspired by early clinical studies. Cancer Immunol Immunother. 2013;15(2):231-241.e1. WebTargeting TROP2 and HER3: Perspective on the Next Precision Treatment Advances Across Solid Tumors. 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]. 2019;10:2078. 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]. 2020;382(6):54553. 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]. Cytokines are the critical components of NK maintenance system and activation as discussed earlier. 2018;9:1869. Targeted drugs are the preferred recommendations for the systemic treatment of hepatocellular carcinoma. Dhar P, Wu JD. 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]. 2014;20(4):46373. There are a number of ongoing clinical trials for cancer immunotherapy using engineered iPSC-NK cells, which are summarized in the following sections. For hematological cancers, CD19 remains a major target. Front Immunol. Anti-tumor activities of adoptively transferred NK cells in vivo have been demonstrated as well in pre-clinical xenograft mouse models of ovarian cancer, In the clinical setting, each batch requires validation, which results in additional lag time before a patient receives infusion. Mol Ther. Natural killer (NK) cell is a specialized immune effector cell type that plays a critical role in immune activation against abnormal cells. 2012;14(7):83040. Article In 2005, it was reported that haploidentical allogeneic NK cells Sci Rep. 2019;9(1):13288. The purification of NK cells is typically achieved by magnetic depletion of CD3-expressing cells and subsequent enrichment for CD56-expressing cells [100] or by fluorescence-activated cell sorting [101]. Dev Cell. 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 Blood. Esser R, et al. Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine secretion. 2016;7:13050. Natural killer (NK) cells are large granular lymphocytes with surface markers CD3 CD56 + NKp46 + in humans. 2019;14(3):e0212455. The interim results showed that 8 out of 11 patients had an objective response to treatment without development of major toxic effects [150]. The anti-CD3 mAb presumably activates T cells in feeder to secret cytokines which subsequently create a milieu favorable for NK cell expansion [145]. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. 2019;12(1):49. There are great numbers of clinical trials on NK cell immunotherapy to treat solid tumors. High cytotoxic efficiency of lentivirally and alpharetrovirally engineered CD19-specific chimeric antigen receptor natural killer cells against acute lymphoblastic leukemia. Mol Ther Oncolytics. A phase 1 trial of CNDO-109-activated natural killer cells in patients with high-risk acute myeloid leukemia. NK cell-based cancer immunotherapy: from basic biology to clinical development. Go to: 5.1. Continuously expanding CAR NK-92 cells display selective cytotoxicity against B-cell leukemia and lymphoma. Genetically engineered CAR NK cells display selective cytotoxicity against FLT3-positive B-ALL and inhibit in vivo leukemia growth. Cancer Immunol Res. Myers JA, Miller JS. 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]. Efficient mRNA-based genetic engineering of human NK cells with high-affinity CD16 and CCR7 augments rituximab-induced ADCC against lymphoma and targets NK cell migration toward the lymph node-associated chemokine CCL19. Sakamoto N, et al. 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)). Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation. Lysis of fresh and cultured autologous tumor by human lymphocytes cultured in T-cell growth factor. 2000;356(9244):17959. Cytotherapy. J Natl Cancer Inst. 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]. Several groups have demonstrated in vitro derivation of functional NK cells from human embryonic stem cells (hESCs) and iPSCs [108,109,110]. 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 Cancer Immunol Res. 2015;2:93. Stem Cell Res Ther. The Ruggeri group showed that KIR-mismatched alloreactive donor NK cells protected bone marrow-transplanted AML patients from AML relapse while sparing graft versus host diseases (GVHD) [31, 32]. Shiozawa M, et al. 2015;13:277. 2020;122:2006. Targeting immunosuppressive components in the TME to re-invigorate NK functions is also under investigation. Zingoni A, et al. The cleavable CXCL16 containing NRPbody was shown to promote NK cell migration in vitro and infiltration into the tumor sites in vivo in xenografted mouse models of orthotopic and metastatic pancreatic cancer [90]. Front Immunol. Sarvaria A, et al. Berraondo P, et al. Phase I study of cord blood-derived natural killer cells combined with autologous stem cell transplantation in multiple myeloma. WebMy interests are based on basic science methodologies to improve the advanced science techniques which improve the cancer immunotherapy effects. The concept of adoptive NK cell cancer immunotherapy was proven a decade ago from pioneering clinical studies against hematological malignancies. Although the ability of NK cells to destroy solid tumors. Parodi M, et al. Bjorkstrom NK, Ljunggren HG, Michaelsson J. 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, Clinical-grade generation of active NK cells from cord blood hematopoietic progenitor cells for immunotherapy using a closed-system culture process. Google Scholar. One approach to address the safety concern is the use of lysed cell product. Noteworthy, IL-2 primarily activates NK cytotoxicity, while supporting proliferation of both NK and T cells. Google Scholar. 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). 2018; 172(5): 10221037. 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. 2013;53(2):41923. Liu E, et al. Luhm J, et al. Int J Cancer. The BiKEs or TrikEs are composed of two or three linked single-chain antibody variable fragments of different antigen specificities [79]. The off-shelf NK cell therapeutic product oNKord, the allogeneic partial HLA-matched NK cells derived from UCB-CD34+ progenitors, has received an orphan drug designation from EMA and FDA for treating AML patients who were not eligible for allogeneic stem cell transplantation. Hum Gene Ther. Article 2016; 108(5). Nham T, et al. Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. Zhang Q, et al. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. The approach of using the modified NK cell line CAR-NK92, which can be easily expanded to large dose, has been in clinical trial. Huijskens MJ, et al. J Immunol. 2015;17(11):158293. 2019;30(3):10220. BMC Immunol. 2015;194(7):320112. 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. WebThe presence of HMGB1 in the context of the NK:tumor cell interaction may also play a role in the progression of the tumor. 2016;16(5):31020. Freshly isolated, activated, or in vitro expanded NK cell populations display phenotypic and functional differences. 2016;127(26):33419. Yang Y, et al. The success has encouraged many ongoing clinical investigations of NK cell-based cancer therapy alone or in combination with other regimes. J Immunother. J Immunol. Choi I, et al. Exp Hematol. This protocol created a possibility to generate a substantially higher number of NK cells from a single dose of peripheral blood [131] and is currently in phase I/II clinical trial (NCT01787474) with expanded haploid-identical NK cells for treating relapsed or refractory AML. Hemolytic anemia due to passenger lymphocyte syndrome in solid malignancy patients treated with allogeneic natural killer cell products. 2017;28(10):88696. 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. 2016;16(2):11223. 2002;295(5562):2097100. WebImmune regulation has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors (ICIs). 2013;4:101. Recently, the differentiation method was also established in adherent monolayer cultures [108]. 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]. Natural killer (NK) cells have potential as a cellular anticancer therapy that could be significantly safer, cheaper, and faster, researchers say. For instance, healthy cells express no or minimal level of ligands for NK cell activating receptors, but express high levels of the major histocompatibility complex class I molecules (MHC I), also known as human leukocyte antigen (HLA), that ligates to the killer immunoglobulin-like (KIR) family inhibitory receptors on NK cells to protect them from NK attack [29]. Immunotherapy is a breakthrough in the systemic treatment of malignant tumors, including HCC. Leukemia. Membrane bound IL-21 based NK cell feeder cells drive robust expansion and metabolic activation of NK cells. Natural killer cells: definition of a cell type rather than a function. Moreover, highly cytotoxic NK cells derived using such method are capable of producing endogenous cytokines that improve their survival, proliferation, and function [132]. 2017;18(1):5667. 2012;3:319. Despite the immunosuppressive environment of solid tumors, NK cell activity/infiltration has been correlated with improved prognoses in humans. 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