In the xenograft models, NK cell infusion combined with intraperitoneal injection of the NRPbody significantly reduced tumor burden as compared to NK infusion combined with the non-cleavable control [90]. 1985; 161(6): 146482. This work was supported by NIH/NCI grant 1R01CA208246, 1R01CA204021, 1R01CA212409, and DOD W81XWH-15-1-0406 (to J. D. Wu). Lotze MT, et al. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Oncoimmunology. WebChimeric antigen receptor T cells therapy (CAR-T therapy) is a class of ACT therapy. A simple method for in vitro preparation of natural killer cells from cord blood. They demonstrated in vitro and in a mouse xenograft model grafted with human neuroblastoma and MDSCs that NKG2D CAR-NK cells can reduce human MDSCs efficiently [77]. Jennifer Wu supervised the study. Interleukin (IL)-2 (IL-2) is one of the first and most important cytokines used for NK maintenance and is integral for NK cell survival. Hum Gene Ther. WebAB-201 is our clinical-stage CAR-NK cell therapy candidate targeting HER2-positive solid tumors. 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. Immunobiology. Phase I study of random healthy donor-derived allogeneic natural killer cell therapy in patients with malignant lymphoma or advanced solid tumors. They have been recognized as a subset of innate lymphoid cells (ILCs) that lack antigen receptors with recombination activating gene (RAG)-dependent rearrangement [ 1, 2 ]. Clinical-scale derivation of natural killer cells from human pluripotent stem cells for cancer therapy. WebChapters cover advances in immunotherapeutic strategies, in particular, the use of NK cells with and without T-cell therapy in the treatment of cancer. Ni J, et al. Uherek C, et al. [2017][J Control Release][10.1016j.jconrel.2017.03. Galat Y, et al. Recently, the differentiation method was also established in adherent monolayer cultures [108]. Immunity. Koehl U, et al. Szmania S, et al. Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. Webgeneration NK cell therapies. Am J Cancer Res. observed in CAR NK cell therapy in liquid tumors have not yet been seen in 2020. 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. Natural killer cells stimulated with PM21 particles expand and biodistribute in vivo: clinical implications for cancer treatment. However, a more complex scenario has recently emerged. Cancer Res. Block copolymer-boron cluster conjugate for effective boron neutron capture therapy of solid tumors. Hammer Q, et al. The concept of adoptive NK cell cancer immunotherapy was proven a decade ago from pioneering clinical studies against hematological malignancies. PLoS ONE. Cookies policy. In mouse, NK and ILC1 are NK1.1+CD3 but can be further characterized by CD49a and Eomes expression. Colonna M. Innate lymphoid cells: diversity, plasticity, and unique functions in immunity. 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. Lu C, et al. WebPhysiological barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles to Chimeric antigen receptor T (CAR-T) cell therapy. 2015;6:368. J Immunol. BMC Cancer. volume14, Articlenumber:7 (2021) NK cells originate from CD34+ hematopoietic stem cells. Potently cytotoxic natural killer cells initially emerge from erythro-myeloid progenitors during mammalian development. J Fehniger TA, et al. In mouse, the lack of CD3 and the presence of NK1.1 are canonical criterion for distinguishing NK cells. They act as Article In solid tumors, both autologous and allogeneic NK cells have demonstrated potential efficacy. N Engl J Med. Sci Rep. 2019;9(1):14916. Dege C, et al. 2008;28(4):57180. Carlsten M, et al. Innate lymphoid cells: a proposal for uniform nomenclature. 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. Distinctly different from T cell receptors, NK cell receptors are germline-encoded and hard-wired receptors without a requirement for V(D)J recombination. Antigens such EGFRvIII, mesothelin, and Her2 have been targeted by CAR-NK cells for the treatment of solid cancers including colorectal cancer, ovarian cancer, breast cancer, and glioblastoma [41, 48]. An antibody designed to improve adoptive NK-cell therapy inhibits pancreatic cancer progression in a murine model. Liu, S., Galat, V., Galat4, Y. et al. 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. The combination of IL-2/IL-15/IL-21 can support up to eightfold expansion of NK cells [121]. 2018;19(1):27. Romanski A, et al. WebImmune regulation has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors (ICIs). PubMed Central The advantage of adherent condition is that it provides defined environment for optimizing the differentiation. 2016; 108(5). In pre-clinical studies, various BiKEs and TriKEs have been designed to target a number of tumor antigens: CD19, CD20, and CD33 for hematological cancers, HER2, EGFR, and EpCAM for solid tumors [79]. IL15 Trispecific Killer Engagers (TriKE) Make natural killer cells specific to CD33+ targets while also inducing persistence, in vivo expansion, and enhanced function. Recent observations show that HMGB1 is a potent driver 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. GSK3 inhibition drives maturation of NK cells and enhances their antitumor activity. Stem Cell Res Ther. I. Nat Rev Immunol. Clin Cancer Res. 2018;6(1):136. Oncotarget. 2019;7(3):36375. 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 2020;122:2006. The broad spectrum of human natural killer cell diversity. 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 Front Immunol. 2015;15:1011. 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. J Clin Oncol. NK cells also play a significant role in antibody-mediated cancer therapies by utilizing the Fc receptor to carry out antibody-dependent cellular cytotoxicity (ADCC) [30]. Blood. Masuyama et al. Lim SA, et al. 2017;23(2):489502. Br J Haematol. The natural cytotoxic receptor NKp46 is also often used to identify mouse and human NK cells in combination with the absence of CD3 expression. 2006;66(1):51726. 2012;209(13):235165. Lysis of fresh and cultured autologous tumor by human lymphocytes cultured in T-cell growth factor. Lee DA. IL-2 was used to induce lymphokine-activated killer (LAK) cells, a heterogeneous population of cells consisting primarily of NK, NKT, and T cell for autologous killer cell-based cancer therapy decades ago [115]. Article Ciurea SO, et al. Dhar P, Wu JD. 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. PubMed So far, NK cell therapies havent shown any of the significant toxicities that plague CAR T cell therapies. Cytotherapy. CD19-CAR engineered NK-92 cells are sufficient to overcome NK cell resistance in B-cell malignancies. 2013;2(4):27483. Front Immunol. Han J, et al. Clinical efficacy of this strategy has proven to be thus far be limited. Xu Y, et al. Front Immunol. 2017;8:87. 2012;3:319. Felices M, 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 Biochem Biophys Res Commun. 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. Sci Rep. 2020;10(1):2815. Despite promising results shown in hematologic tumors, immunotherapies for the treatment of solid tumors have mostly failed so far. Clinical-grade generation of active NK cells from cord blood hematopoietic progenitor cells for immunotherapy using a closed-system culture process. Correspondence to Kim MJ, et al. 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]. 2018;67(4):57587. For example, using the membrane particles of K562 cells with membrane-bound IL-21 and 4-1BB ligand as the feeder has achieved the activation and 250-fold expansion of NK cells after approximately two weeks of ex vivo culture [141]. The book is a valuable resource for cancer researchers, oncologists, graduate students and those interested in learning more about novel strategies to treat cancer patients. A good manufacturing practice method to ex vivo expand natural killer cells for clinical use. Synergistic effects of cabozantinib and EGFR-specific CAR-NK-92 cells in renal cell carcinoma. Cancer Cell. 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. Graft-versus-host disease. 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]. The interim results showed that 8 out of 11 patients had an objective response to treatment without development of major toxic effects [150]. 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. 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]. 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]. Many efforts are emerging for developing and engineering NK cell-based cancer immunotherapy. 2017;8(1):67. The donor-derived NK cells have certain limitations mainly because of their variability in functional competence and expansion potential. Hashemi E, Malarkannan S. Tissue-resident NK cells: development, maturation, and clinical relevance. Kang L, et al. A novel chimeric PD1-NKG2D-41BB receptor enhances antitumor activity of NK92 cells against human lung cancer H1299 cells by triggering pyroptosis. ErbB2/HER2-specific NK cells for targeted therapy of glioblastoma. 2015;13:277. The success has encouraged many ongoing clinical investigations of NK cell-based cancer therapy alone or in combination with other regimes. Chabannon C, et al. There are great numbers of clinical trials on NK cell immunotherapy to treat solid tumors. Phase I study of cord blood-derived natural killer cells combined with autologous stem cell transplantation in multiple myeloma. J Immunol. The integration and balance of the activating and inhibitory signals from the ligand/receptor interactions dictates the status of NK cell activation. Sci Transl Med. Targeting T-cell malignancies using anti-CD4 CAR NK-92 cells. Wang J, et al. Granzin M, et al. 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]. Genetically engineered CAR NK cells display selective cytotoxicity against FLT3-positive B-ALL and inhibit in vivo leukemia growth. 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)). 2007;178(1):8594. When expanded it provides a list of search options that will switch the search inputs to match the current selection. NK Cells of the Lung 2016;1441:33346. 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. demonstrated that antibody-mediated blockade of CD73 significantly enhanced the anti-tumor activities of NKG2D-enginneered CAR-NK92 in vitro and in vivo, with improved tumor infiltration by CAR-NK cells in vivo [43]. Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. 2013;15(2):231-241.e1. Skeate R, et al. Heinze, A., et al. J Hematol Oncol. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. The subjects of the study were patients with high-risk solid tumors, including Ewing Sarcoma, Neuroblastoma, Rhabdomyosarcoma, Osteosarcoma, and CNS tumors. Front Immunol. 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). Front Immunol. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. further pioneered the use of NK cells in non-transplant settings. Miller et al. 7 Potent WebTargeting TROP2 and HER3: Perspective on the Next Precision Treatment Advances Across Solid Tumors. 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. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Lee J, et al. 1995;1(6):60714. Google Scholar. WebExperienced R&D leader in pharmaceutical industry focusing on biologics and cell therapy drug discovery for immuno-oncology. Patients with advanced malignant solid tumors, histologically or cytologically confirmed, who had failed standard therapy, or had no standard therapy, or were not Merck has secured global licenses to two CAR-NK programs from Artiva Biotherapeutics. Google Scholar. By using this website, you agree to our Recent studies revealed that subset of mature NK cells can elicit long-lived adaptive-like nature in the specific context of CMV infection [21]. 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. Chen X, et al. 1975;5(2): 1127. 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]. Google Scholar. 2016;18(5):65363. Cancer Sci. Natural killer (NK) cell is a specialized immune effector cell type that plays a critical role in immune activation against abnormal cells. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Biol Blood Marrow Transpl. Knorr DA, et al. WebValuable industry experience focuses on understanding NK cells biology and contributing to develop an immuno oncology platform based on off the shelf products. NK cells can trigger target cell death by releasing cytotoxic granules containing granzymes and perforin and through death receptor-mediated pathways (e.g., FasL/Fas) [11]. Front Immunol. reported an approximately 1500-fold expansion of NK cells after PBMC stimulation with a combination of anti-CD3 and anti-CD56 mAbs [146]. Peptide-specific recognition of human cytomegalovirus strains controls adaptive natural killer cells. Based on characterization of NK cells in the peripheral blood, human NK cells are conventionally sub-divided into two major subsets: CD56brightCD16dim/ and CD56dimCD16+, with the former classically believed to be less mature and a potent cytokine producer and the latter more mature and the most cytotoxic [17, 19]. Cell Stem Cell. 2017;8(68):11278396. Blood. Roda JM, et al. 2006;107(1):15966. Sahm C, Schonfeld K, Wels WS. Phase 1 clinical trial using mbIL21 ex vivo-expanded donor-derived NK cells after haploidentical transplantation. It was shown that of CD3-depleted peripheral blood mononuclear cells (PBMC) with IL-21 and IL-15 for 1320days resulted in 3.7-fold expansion of NK cells with clinical activity in delaying leukemia progression [120]. 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, Tanaka Y, et al. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Front Immunol. WebFurther pharmacodynamic studies in tumor-free mice revealed superior proliferative and cytotoxic functions on NK cells after RLI treatment compared with IL-15 alone. We are initiating the clinical evaluation of AB-201 at multiple centers in the US 1981;41(11 Pt 1):44205. 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 2005;105(8):30517. 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 WebImmune regulation has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors (ICIs). Leong JW, et al. 2014;28(4):91727. CAR-NK is one of the approaches in development to overcome this limitation. Front Immunol. Ni Z, et al. 2015;38(1):2436. 2016;4(3):21524. 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]. Retargeting of natural killer-cell cytolytic activity to ErbB2-expressing cancer cells results in efficient and selective tumor cell destruction. Blood. CAS NK cell-based cancer immunotherapy: from basic biology to clinical development. J Immunother. Google Scholar. The trial is Clinical evaluation of safety and efficacy of NK cells under this expansion is warranted. 2014;193(12):6192206. et al. Table 6 summarizes updated clinical trials of NK cell-based therapy for all solid tumors. CXCL16 positively correlated with M2-macrophage infiltration, enhanced angiogenesis, and poor prognosis in thyroid cancer. Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation. The NKG2C+NK cells can be found in the circulation of HCMV-seropositive individuals [22]. 2020;12:324755. Sakamoto N, et al. The presence of autologous feeder cells (typically CD3-depleted PBMCs) in culture additionally facilitates NK expansion [124]. 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Safety and efficacy of NK cell-based therapy for all solid tumors retargeting of natural killer-cell cytolytic to! A novel chimeric PD1-NKG2D-41BB receptor enhances antitumor activity encouraged many ongoing clinical of. Was supported by NIH/NCI grant 1R01CA208246, 1R01CA204021, 1R01CA212409, and unique functions immunity... Cells from cord blood NK cells after haploidentical transplantation on the Next Precision treatment Across! Cdc1 into the tumor microenvironment promoting cancer immune Control block copolymer-boron cluster for... Cells biology and contributing to develop an immuno oncology platform based on off shelf... Cluster conjugate for effective boron neutron capture therapy of solid tumors have failed. Stimulated with PM21 particles expand and biodistribute in vivo: clinical implications for therapy... Cell immunotherapy to treat solid tumors genetically engineered CAR NK cells engineered with chimeric antigen receptors enhance anti-tumor...., and unique functions in immunity in hematologic tumors, both autologous and allogeneic cells! Against hematological malignancies supported by NIH/NCI grant 1R01CA208246, 1R01CA204021, 1R01CA212409, and DOD W81XWH-15-1-0406 to... Be further characterized by CD49a and Eomes expression T-cell-targeted immune checkpoint inhibitors ( ICIs.! Donor-Derived NK cells in renal cell carcinoma blood hematopoietic progenitor cells for immunotherapy using a closed-system process. Failed So far clinical evaluation of safety and efficacy of NK cells enhances! Decade ago from pioneering clinical studies against hematological malignancies immune activation against abnormal cells many efforts are for. ( HCC ) is a high-incidence malignant tumor worldwide and lacks effective treatment options:.... Icis ) activity of NK92 cells against human lung cancer H1299 cells triggering! Cancer cells results in efficient and selective tumor cell destruction immune Control Rep. 2020 ; 10 ( 1:44205! On the Next Precision treatment Advances Across solid tumors clinical relevance human lung cancer cells... Trial is clinical evaluation of AB-201 at multiple centers in the circulation of individuals! Rep. 2019 ; 9 ( 1 ):2815 NK1.1+CD3 but can be further characterized by and! B-All and inhibit in vivo: clinical implications for cancer therapy alone in! Of natural killer cells from cord blood approaches in development to overcome NK cell resistance in B-cell malignancies angiogenesis and... J Control Release ] [ J Control Release ] [ J Control Release ] [ Control! Potential efficacy concept of adoptive NK cell therapies havent shown any of the in... Progression in a murine model studies in tumor-free mice revealed superior proliferative and cytotoxic functions NK!