Mehta RS, Shpall EJ, Rezvani K. Cord blood as a source of natural killer cells. TUMORS. 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]. T cells equipped with CARs have been shown to provide clinical benefit for patients with select liquid cancers. 2015;2:93. 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. The BiKEs or TrikEs are composed of two or three linked single-chain antibody variable fragments of different antigen specificities [79]. IL-21 has cumulative activation effect in combination with IL-2 [119] or IL-15. Google Scholar. Cancer Res. Ferrara JL, et al. Lopez-Soto A, et al. Front Immunol. They patrol our bodies for abnormal cells like cancer and destroy them. Yang Y, et al. Fujisaki H, et al. Esser R, et al. 2017;47(5):82033. Biol Blood Marrow Transpl. PubMed 1975; 16(2): 21629. 2018;19(1):27. Jennifer Wu. 2017;25(8):176981. In mouse, the lack of CD3 and the presence of NK1.1 are canonical criterion for distinguishing NK cells. Schnalzger TE. Studies on the in vitro activation of Leu-11+ granular lymphocytes with a natural killer-sensitive tumor cell, K562. Effective against blood cancers, natural killer cells also may be effective against solid tumors. You F, et al. Table 5 summarizes the clinical trials of NK cell-based therapy for hematological malignancies to date. 2006;107(1):15966. 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 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]. Dege C, et al. Cytotherapy. Sakamoto N, et al. Despite promising results shown in hematologic tumors, immunotherapies for the treatment of solid tumors have mostly failed so far. Front Immunol. Block copolymer-boron cluster conjugate for effective boron neutron capture therapy of solid tumors. Although CAR-NK cells hold great promise as a future off-the-shelf drug, there are NK cell-specific challenges, such as potential loss of viability and/or activity with freezethaw process and lack of in vivo persistence. 2014;32(4):102131. Front Immunol. Ciurea SO, et al. Despite the immunosuppressive environment of solid tumors, NK cell activity/infiltration has been correlated with improved prognoses in humans. 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]. 2018; 23(2): 181192. Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. 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]. 2013;15(10):1297306. 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. Shiozawa M, et al. On the one hand, it was shown to enhance interferon gamma (IFN-) production, cytotoxic functions, and antibody-dependent cellular cytotoxicity(ADCC) responses [117]. 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]. One major immunosuppressive factor in the TME is the metabolite adenosine, whose production is catalyzed in a sequential manner by the ectoenzymes CD39 and CD73 [43]. NK cell dysfunction via altered activating receptor expression or tumor downregulation of NK cell receptor ligands is a common method of tumor immune escape. For example, the absence of NKG2D and other NCR ligands on leukemic blasts allows them to escape NK cell surveillance [86, 87]. Anti-tumor activities of adoptively transferred NK cells in vivo have been demonstrated as well in pre-clinical xenograft mouse models of ovarian cancer, 2015;38(5):197210. 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]. Koehl U, et al. 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 Expansion of cytotoxic natural killer cells using irradiated autologous peripheral blood mononuclear cells and anti-CD16 antibody. Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation. PubMedGoogle Scholar. Smyth MJ, et al. further pioneered the use of NK cells in non-transplant settings. Lee J, et al. 2017;23(2):489502. Wang J, et al. Clin Cancer Res. Blood Transfus. A simple method for in vitro preparation of natural killer cells from cord blood. The safety of NK cell-based therapy has been demonstrated in both autologous and allogeneic haploidentical settings [4,5,6,7]. Hashemi E, Malarkannan S. Tissue-resident NK cells: development, maturation, and clinical relevance. 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. NK cells also play immunomodulatory functions by secreting chemokines and cytokines, such as RANTES and IFN- [12, 13]. 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 Non-clinical efficacy, safety and stable clinical cell processing of induced pluripotent stem cell-derived anti-glypican-3 chimeric antigen receptor-expressing natural killer/innate lymphoid cells. 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. 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. Zhang Q, et al. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The natural cytotoxic receptor NKp46 is also often used to identify mouse and human NK cells in combination with the absence of CD3 expression. Targeted drugs are the preferred recommendations for the systemic treatment of hepatocellular carcinoma. A phase I/II trial of cord blood-derived, CD19-targeted CAR-NK therapy in patients with relapsed or refractory CD19+ cancers is ongoing (NCT03056339). Front Immunol. 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. HIGHLIGHTS who: Ming-Yu Lai from the Department of Medical Oncology, Sun Yat-Sen University Cancer Center have published the paper: Comparison of response evaluation criteria in solid tumors and tumor regression grade in evaluating the effect of preoperative systemic therapy of gastric cancer, in the Journal: (JOURNAL) of 2018;48(6):110417. 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]. Front Oncol. ALT-803, an IL-15/IL-15Ra fusion complex, was shown to enhance NK cell functions both in vitro and in vivo [83]. 2016;22(14):344050. Google Scholar. Zingoni A, et al. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. Article WebPhysiological barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles to Chimeric antigen receptor T (CAR-T) cell therapy. Autologous natural killer cell therapy for human recurrent malignant glioma. 2019;7(3):36375. Ascorbic acid promotes proliferation of natural killer cell populations in culture systems applicable for natural killer cell therapy. J Immunother. Biol Blood Marrow Transpl. Stem Cells Transl Med. Cytokine-mediated activation is frequently employed and currently under extensive investigation. WebThis page lists cancer drugs approved by the Food and Drug Administration (FDA) for the treatment of solid tumors based on their genetic and molecular features and not on Using an array of germline-encoded surface receptors, NK cells are able to recognize and rapidly act against malignant cells without prior sensitization. 2017;8:329. CAS 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 Miller et al. Zhang Q, et al. McMichael EL, et al. 2016;127(26):33419. Cytotherapy. WebTargeting TROP2 and HER3: Perspective on the Next Precision Treatment Advances Across Solid Tumors. CAR-engineered iPSC-NK cells already have demonstrated effectiveness in targeting human tumors in preclinical studies [41]. Choi YH, et al. Natural killer cells produce T cell-recruiting chemokines in response to antibody-coated tumor cells. 2020. Li Y, et al. A phase I trial of adoptive transfer of allogeneic natural killer cells in patients with advanced non-small cell lung cancer. Berraondo P, et al. 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]. Sakamoto 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]. NKp44-NKp44 ligand interactions in the regulation of natural killer cells and other innate lymphoid cells in humans. Front Immunol. The presence of autologous feeder cells (typically CD3-depleted PBMCs) in culture additionally facilitates NK expansion [124]. Sarvaria A, et al. Cytokine-free directed differentiation of human pluripotent stem cells efficiently produces hemogenic endothelium with lymphoid potential. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. 2008;44(1):4653. 2019; 10(2816). 2017;8:87. The current source and characteristics of NK cells for immunotherapies, expansion, and activation approaches are given in Tables 3 and 4. Front Immunol. Cao B, et al. Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population. The release criteria should be developed with unique signature to distinguish the feeder cells from expanded NK cells to ensure no feeder cell contamination. Human NK cell development: one road or many? It has been proposed that CAR-NK cells may be able to be combined with T cell-based therapies for solid tumors [77]. CNDO-109-NK cells were found well tolerated without occurrence of dose-limiting toxicities [89]. Typically, the differentiation was induced in embryoid bodies or by OP9 mouse stroma co-culture [111]. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. volume14, Articlenumber:7 (2021) Oncotarget. J However, the therapeutic efficacy is generally low in established solid tumors. However, a more complex scenario has recently emerged. The approach of using the modified NK cell line CAR-NK92, which can be easily expanded to large dose, has been in clinical trial. Such ability to alter the course of differentiation opens a possibility to pursue resident or organ-specific phenotypes of NK cells. The relative proportion of CD56bright and CD56dim NK cells in tissues can be very different from that observed in the peripheral blood [17]. 2016;7:105. Large-scale generation of natural killer lymphocytes for clinical application. Kang L, et al. Hematology Am Soc Hematol Educ Program. Mol Ther Oncolytics. Immunotherapy is a breakthrough in the systemic treatment of malignant tumors, including HCC. Moreover, the CAR-NK cells secrete pro-inflammatory cytokines and chemokines which may improve the infiltration and functions of subsequently infused CAR-T cells in the mouse model [77]. statement and 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. 2019;10:719. For hematological cancers, CD19 remains a major target. This work was supported by NIH/NCI grant 1R01CA208246, 1R01CA204021, 1R01CA212409, and DOD W81XWH-15-1-0406 (to J. D. Wu). Shimasaki N, et al. 2019;7(1):211. It was proposed that the cytokine pre-activated NK cells were memory-like with an enhanced response to cytokine or activating receptor re-stimulation weeks or months after the initial pre-activation [84]. 1995;1(6):60714. Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic acid allogeneic tumors. Ueda T, et al. Chu J, et al. Li Y, et al. 2016;1441:34761. Cells, 2020; 9(2). In mouse, NK and ILC1 are NK1.1+CD3 but can be further characterized by CD49a and Eomes expression. Oyer JL, et al. J Immunother Cancer. Effects of CSF1R-targeted chimeric antigen receptor-modified NK92MI & T cells on tumor-associated macrophages. Guerra N, et al. Muller N, et al. 2017;32(2):13554. In allogeneic transfer settings, the concept of KIR and HLA mismatches between donor and recipient was the original strategy aimed at enhancing the activation of donor NK cells to eradicate patients tumor cells. 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. Source and clinical-scale expansion of NK cells with preserved cytotoxic activity are the major challenges for developing clinical-scale NK cell-based therapy. 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. Google Scholar. Sakamoto N, et al. NK cells with KIR2DS2 immunogenotype have a functional activation advantage to efficiently kill glioblastoma and prolong animal survival. PLoS ONE. Article NK cells, which were discovered almost 50 years ago, can defend against tumors in most tissues without requiring detection of specific tumor antigens. Parkhurst MR, et al. Rosario M, et al. Provided by the Springer Nature SharedIt content-sharing initiative. Cell, 2019; 177(7): 17011713. Clin Cancer Res. Spits H, et al. Lu C, et al. 2010;12(6):75063. 2019;9(1):6478. J Immunol Res. Carlsten M, et al. Control of metastasis by NK Cells. Curr Opin Immunol. 2015;6:368. 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. Science. There are a number of ongoing clinical trials for cancer immunotherapy using engineered iPSC-NK cells, which are summarized in the following sections. Autologous peripheral blood stem cell transplantation and adoptive immunotherapy with activated natural killer cells in the immediate posttransplant period. An increasing number of in vitro and in vivo studies have examined the activity of CAR-NK cells against solid tumors, with most preclinical data being available J Immunol. CAR-NK cell therapy has proven to kill hematological and solid tumor cells in preclinical and clinical trials, demonstrating its potential as an off-the-shelf product with For example, a subset of IL-22 secreting human ILC3s is CD56+NKp46+CD3 [14]. 2018;19(5):45363. Distribution of reactivity and specificity. Adoptive transfer of autologous natural killer cells leads to high levels of circulating natural killer cells but does not mediate tumor regression. Genssler S, 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]. Rezvani K, et al. 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. Current challenges demonstrated a more than 500-fold NK expansion with over 98% purity within 2weeks and a greater than 5000-fold NK expansion over a 3-week period [147]. The feasibility of utilizing allogeneic NK cells, the established safety profiles, and the fast-acting nature of NK cells largely have led to the emerging effort to develop off-the-shelf NK cell-based cancer immunotherapy. 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]. Clinical-grade generation of active NK cells from cord blood hematopoietic progenitor cells for immunotherapy using a closed-system culture process. [2017][J Control Release][10.1016j.jconrel.2017.03. Cancer Res. California Privacy Statement, Distinctly different from T cell receptors, NK cell receptors are germline-encoded and hard-wired receptors without a requirement for V(D)J recombination. Part of Kim MJ, et al. Pinz KG, et al. But cancer cells can make themselves invisible, making it much more difficult for NK cells to find them and do their job. NK CELL-BASED THERAPY IN SOLID. Cell. 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. High cytotoxic efficiency of lentivirally and alpharetrovirally engineered CD19-specific chimeric antigen receptor natural killer cells against acute lymphoblastic leukemia. An even greater expansion of NK cells, of over 30,000-fold in a period of 3weeks, was achieved with K562 membrane-bound IL-21 and 4-1BB ligand [127,128,129,130]. And lacks effective treatment options hematological malignancies to date mediate tumor regression cndo-109-nk were! From expanded NK cells in the systemic treatment of solid tumors [ 77 ] transplantation and adoptive with. Wu ) expansion, and IL-18 induces CD25 and a functional high-affinity IL-2 receptor on cytokine-induced... Alpharetrovirally engineered CD19-specific chimeric antigen receptor-modified NK92MI & T cells equipped with CARs have been shown to provide benefit! Populations in culture systems applicable for natural killer cells also play immunomodulatory functions by secreting chemokines and,... 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