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]. Moreover, restricted expansion capacity poses a difficulty for improving the efficacy of NK cells through genetic engineering. Han J, et al. 2016;1441:33346. There are a number of ongoing clinical trials for cancer immunotherapy using engineered iPSC-NK cells, which are summarized in the following sections. 2010;651:6177. 2020;524(1):96102. 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. J Immunother Cancer. Stem Cells. Blood. Granzin M, et al. Exp Hematol. Immunotherapy is a breakthrough in the systemic treatment of malignant tumors, including HCC. Nat Rev Immunol. Oelsner S, et al. We want to do better, and this NK cell therapy is a promising Nat Rev Immunol. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The difficulty to obtain large quantity of NK cells, to expand to clinical scale ex vivo, and to sustain in vivo survival and activity of infused NK cells has encumbered the progress. WebFurther pharmacodynamic studies in tumor-free mice revealed superior proliferative and cytotoxic functions on NK cells after RLI treatment compared with IL-15 alone. Int J Cancer. Szmania S, et al. Cell Stem Cell. 2019;19(1):80. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Furthermore, IL-2, streptococcus A group, and zoledronate have all been approved for human use. Adenosine impairs the anti-tumor functions of both T and NK cells [43]. 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. Blood. A phase 1 trial of CNDO-109-activated natural killer cells in patients with high-risk acute myeloid leukemia. 2014;28(4):91727. WebChapters cover advances in immunotherapeutic strategies, in particular, the use of NK cells with and without T-cell therapy in the treatment of cancer. Sci Transl Med. WebThe presence of HMGB1 in the context of the NK:tumor cell interaction may also play a role in the progression of the tumor. Bjorkstrom NK, Ljunggren HG, Michaelsson J. Patients with advanced malignant solid tumors, histologically or cytologically confirmed, who had failed standard therapy, or had no standard therapy, or were not One approach to address the safety concern is the use of lysed cell product. But what it does in the realm of cancer spread is creepier still. Hassan R, Ho M. Mesothelin targeted cancer immunotherapy. PubMed Bottcher JP, et al. 2016;5(9):e1219007. Targeted drugs are the preferred recommendations for the systemic treatment of hepatocellular carcinoma. 2015;13:277. 2015;38(1):2436. INTRODUCTION Cordyceps is the composite of a genus of fungus that grows on the larva of insects. Ni J, et al. PubMed Central Cytotherapy. Galat Y, et al. Muller N, et al. Despite promising results shown in hematologic tumors, immunotherapies for the treatment of solid tumors have mostly failed so far. Cichocki F, et al. Webgeneration NK cell therapies. 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. Through several preclinical studies, researchers have discovered new guardian immune cells called chimeric antigen receptor (CAR)-modified natural killer (NK) cells, which show cytotoxic activity against various solid tumor types. Front Immunol. Compared with cytotoxic T lymphocytes, Natural killer (NK) cell is a specialized immune effector cell type that plays a critical role in immune activation against abnormal cells. Mehta RS, Shpall EJ, Rezvani K. Cord blood as a source of natural killer cells. In the last 3 decades, NK cells have been utilized to harness The following section summarizes the current pre-clinical efforts to enhance the efficacy of NK cell-based therapy. 2019;10:2078. Lopez-Soto A, et al. Despite the immunosuppressive environment of solid tumors, NK cell activity/infiltration has been correlated with improved prognoses in humans. Liu B, et al. Efforts are still ongoing to identify the most optimal cytokine combination for NK cell expansion. CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma. Yang Y, et al. Torelli GF, et al. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Nat Immunol. Production Process of CAR-NK Hemolytic anemia due to passenger lymphocyte syndrome in solid malignancy patients treated with allogeneic natural killer cell products. Different from events required for T cell activation, NK cell activation is governed by the interaction of NK receptors with target cells, independent of antigen processing and presentation. 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]. ErbB2/HER2-specific NK cells for targeted therapy of glioblastoma. Knorr DA, et al. 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]. Expansion of cytotoxic natural killer cells using irradiated autologous peripheral blood mononuclear cells and anti-CD16 antibody. J Immunol Res. Chapter 5 Cordyceps as an Herbal Drug Bao-qin Lin and Shao-ping Li. Pharmacologically upregulated carcinoembryonic antigen-expression enhances the cytolytic activity of genetically-modified chimeric antigen receptor NK-92MI against colorectal cancer cells. 2007;178(1):8594. Choi I, et al. Table 6 summarizes updated clinical trials of NK cell-based therapy for all solid tumors. Parihar and colleagues designed CAR-NK cells expressing the activating receptor NKG2D as the antigen recognition to target human MDSCs. Mol Med Rep. 2019;20(3):282331. 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]. 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]. The approach of using the modified NK cell line CAR-NK92, which can be easily expanded to large dose, has been in clinical trial. Topfer K, et al. Google Scholar. Advances in clinical NK cell studies: donor selection, manufacturing and quality control. Zhang P, et al. PubMed Dev Cell. 2009;373(9674):155061. J 2017;177(3):45766. Additional markers such as lack of c-kit can be used to distinguish human NK (c-kit-) from ILC3s (c-kit+) [14]. However, there are many challenges to overcome, such as difficulty to meet clinical-grade ex vivo expansion, limited in vivo persistence, limited infiltration to solid tumors, and tumor editing to evade NK cell activity. 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]. A novel chimeric PD1-NKG2D-41BB receptor enhances antitumor activity of NK92 cells against human lung cancer H1299 cells by triggering pyroptosis. Cancers (Basel), 2020; 12(6). 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. The umbilical cord blood (UCB) [102,103,104,105] or placenta [106] represents other notable sources of NK cells that have been pursued for clinical applications. PubMed Central Blood Transfus. Oncoimmunology. WebAdoptive cell therapy is a rapidly advancing approach to cancer immunotherapy that seeks to facilitate antitumor responses by introducing potent effector cells into the tumor Natural killer cell memory in infection, inflammation and cancer. A novel CD7 chimeric antigen receptor-modified NK-92MI cell line targeting T-cell acute lymphoblastic leukemia. Galat Y, et al. They are also summarized in Table 2. 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 J Exp Med. Cytotherapy. NKAML: a pilot study to determine the safety and feasibility of haploidentical natural killer cell transplantation in childhood acute myeloid leukemia. Short-term (1820h) pre-activation with ALT-803 augmented cytotoxicity and ADCC of NK cells in vitro. 2012;209(13):235165. 2010;28(6):9559. Clinicaltrials.gov currently lists over 100 clinical trials of NK cell-based cancer immunotherapy. Rubnitz JE, et al. WebArtivas NK cells engineered to express chimeric antigen receptors, or CARs, have the potential to enhance the targeting and activity of the NK cells against either hematologic The exhausted T cells or NK cells in the tumor microenvironment exhibit imbalanced 2019;7(3):36375. Cells, 2020; 9(2). Two biotechs aim to broaden the reach of cancer immunotherapy by applying gene editing tools to an emerging form of cell therapy through a wide-ranging Immunobiology. Myers JA, Miller JS. Distinctly different from T cell receptors, NK cell receptors are germline-encoded and hard-wired receptors without a requirement for V(D)J recombination. Currently, strategies vary depending on the clinical setting and source of cells. 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]. 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]. 2016;16(5):31020. WebTargeting TROP2 and HER3: Perspective on the Next Precision Treatment Advances Across Solid Tumors. Go to: 5.1. Effective against blood cancers, natural killer cells also may be effective against solid tumors. 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. BMC Cancer. Kim MJ, et al. 2015;17(5):61320. Google Scholar. Bryceson YT, et al. In the clinical setting, each batch requires validation, which results in additional lag time before a patient receives infusion. NK cells are found both in blood at levels of 5%-15% of circulating lymphocytes and in various lymphoid and non-lymphoid organs such as the spleen, lung, and liver [17, 18]. Phase 1 clinical trial using mbIL21 ex vivo-expanded donor-derived NK cells after haploidentical transplantation. PubMed Central Effects of CSF1R-targeted chimeric antigen receptor-modified NK92MI & T cells on tumor-associated macrophages. Cookies policy. Three out of 12 patients had durable complete remissions [89], providing evidence for further clinical evaluation of this approach. 2008;44(1):4653. 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 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. More recent evidence had indicated that NK cells can also develop and mature at secondary lymphoid organs, including tonsils, spleen, and lymph nodes [19]. 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. Cytotherapy. Front Immunol. Regulatory considerations for NK cells used in human immunotherapy applications. They patrol our bodies for abnormal cells like cancer and destroy them. 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 Thorac Cancer Some investigations have sought to enhance NK migration toward the tumor by genetically modifying NK cells to overexpress chemokine receptors [54, 59, 94]. Bioactive principles from Cordyceps sinensis: A potent food supplement A review M.G. Freshly isolated, activated, or in vitro expanded NK cell populations display phenotypic and functional differences. Current challenges Large-scale generation of natural killer lymphocytes for clinical application. Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. Front Immunol. Ng YY, Tay JCK, Wang S. cxcr1 expression to improve anti-cancer efficacy of intravenously injected CAR-NK cells in mice with peritoneal xenografts. Over 100-fold expansion was achieved with Wilms tumor HFWT [134] and immortalized T lymphocyte Jurkat cell lines [135]. The donor-derived NK cells have certain limitations mainly because of their variability in functional competence and expansion potential. Transfusion. Phillips JH, Lanier LL. The BiKEs or TrikEs are composed of two or three linked single-chain antibody variable fragments of different antigen specificities [79]. WebCancer immunotherapy has achieved great success in the past few years. The interim results showed that 8 out of 11 patients had an objective response to treatment without development of major toxic effects [150]. CAR-NK cell therapy is a novel immunotherapy strategy by utilizing genetically-engineered NK cells to target specific cancer, which can be both liquid and Genssler S, et al. Huang Y, et al. In summary, NK cells are functional in tumor surveillance and can be manipulated by artificial activation techniques to present a highly effective anticancer tool against hematopoietic malignancies and, dependent on successful further rearming and mobilization, against solid tumors in the future. By using this website, you agree to our NKG2D, an activating NK cell receptor, can bind to eight different stress-induced ligands that are naturally expressed on 80% of hematological and solid cancer CAR-NK cells are known to be effective against hematological malignancies, and a growing number of preclinical findings indicate that they have Uherek C, et al. While the CAR technology seeks to enhance NK cell functions by genetically directing their target specificity, there are active investigations on other strategies to effectively prime NK cells ex vivo or in vivo for optimal anti-tumor functions after their infusion. Denman CJ, et al. 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. Sakamoto N, et al. Am J Cancer Res. 2013;3:118. Blood. Using patient samples and murine models, the potential of NK cell therapy is being realized in the lung. Sakamoto N, et al. 2014;193(12):6192206. Hambach, J., et al., Targeting CD38-expressing multiple myeloma and Burkitt lymphoma cells in vitro with nanobody-based chimeric antigen receptors (Nb-CARs). Combination therapy with EpCAM-CAR-NK-92 cells and regorafenib against human colorectal cancer models. J Immunol. Cancer Sci. Veluchamy JP, et al. 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]. 2017;8:458. Biol Blood Marrow Transpl. Wang et al. 2012;7(1):e30264. Koehl U, et al. Allaoui R, et al. 2018;8(6):10839. Source and clinical-scale expansion of NK cells with preserved cytotoxic activity are the major challenges for developing clinical-scale NK cell-based therapy. PubMed All authors gave consent for publication of the manuscript. Article Clin Cancer Res. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. 2019;7(2):21929. 2020;382(6):54553. reported that a CD16/IL-15/CD33 TriKE not only enhances NK-mediated immunity against CD33+ targets, but also promotes the in vivo persistence, activation, and survival of NK cells by delivering IL-15 [80]. 2014;20(4):46373. The natural cytotoxic receptor NKp46 is also often used to identify mouse and human NK cells in combination with the absence of CD3 expression. Purinergic targeting enhances immunotherapy of CD73(+) solid tumors with piggyBac-engineered chimeric antigen receptor natural killer cells. Expression of IL-15 in NK cells results in rapid enrichment and selective cytotoxicity of gene-modified effectors that carry a tumor-specific antigen receptor. WebImmune regulation has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors (ICIs). Science. CAS Lister J, et al. 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]. Google Scholar. CD19-CAR engineered NK-92 cells are sufficient to overcome NK cell resistance in B-cell malignancies. Zhang C., et al. This property, which is unique among immune cells, and their capacity to enhance antibody and T cell responses support a role for NK cells as anticancer agents. 2019;12(1):49. 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]. The trial is Privacy Lee SJ, et al. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. Sahm C, Schonfeld K, Wels WS. Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes. The subjects of the study were patients with high-risk solid tumors, including Ewing Sarcoma, Neuroblastoma, Rhabdomyosarcoma, Osteosarcoma, and CNS tumors. 2B4 costimulatory domain enhancing cytotoxic ability of anti-CD5 chimeric antigen receptor engineered natural killer cells against T cell malignancies. et al. Freud AG, et al. J Immunother Cancer. On the one hand, it was shown to enhance interferon gamma (IFN-) production, cytotoxic functions, and antibody-dependent cellular cytotoxicity(ADCC) responses [117]. Masuyama et al. Natural killer (NK) cells are large granular lymphocytes with surface markers CD3 CD56 + NKp46 + in humans. Vallera DA, et al. Anticancer Res. Nat Immunol. A good manufacturing practice method to ex vivo expand natural killer cells for clinical use. Zingoni A, et al. Biochem Biophys Res Commun. Initial successes of adoptive NK cell transfer in treating hematological cancers prompted clinical endeavors in using the strategy against solid cancers. Natural killer cells produce T cell-recruiting chemokines in response to antibody-coated tumor cells. NK cells possess advantageous characteristics, including non-MHC-restricted recognition, ability to infiltrate Granzin M, et al. The exhausted T cells or NK cells in the tumor microenvironment exhibit imbalanced Human NK cells expanded with IL-15 in the presence GSK3 inhibition had increased expression of the NK cell maturation marker CD57 and transcription factors associated with late-stage NK cell maturation including T-bet, ZEB2, and BLIMP-1 as compared to those expanded with IL-15 alone [87]. Hum Gene Ther Methods. 2012;3:319. Tanaka Y, et al. reported an approximately 1500-fold expansion of NK cells after PBMC stimulation with a combination of anti-CD3 and anti-CD56 mAbs [146]. Natural killer cells: development, maturation, and clinical utilization. One study showed that overnight co-incubation with a leukemia cell line CTV-1 or its lysate without cytokines was sufficient to prime potent NK cells in vitro cytotoxicity against otherwise NK-insensitive tumor cells but not normal hemopoietic cells [88]. Blood. 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. CAS 2014;32(4):102131. 2016;7:13050. Cancer Manag Res. Gras Navarro A, et al. Most NK cells in the blood are CD56dim, whereas the CD56bright subset only represents less than 15% of total circulating NK cells [17]. J Clin Oncol. Miller et al. CAS 2006;107(1):15966. It is believed that membrane-bound interleukins are able to stimulate the expansion of NK cells more effectively than the soluble form. Imai C, Iwamoto S, Campana D. Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells. 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]. In treatments of solid tumors, adoptive transfer of ex vivo expanded natural killer (NK) cells has dawned as a new paradigm. Wang W, et al. WebAB-201 is our clinical-stage CAR-NK cell therapy candidate targeting HER2-positive solid tumors. NK cells are infrequently seen in tumor biopsies. 2019;10:909. 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]. 2012;61(9):145161. WebThis button displays the currently selected search type. Noteworthy, IL-2 primarily activates NK cytotoxicity, while supporting proliferation of both NK and T cells. Sarvaria A, et al. Google Scholar. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. WebImmune regulation has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors (ICIs). It has been proposed that CAR-NK cells may be able to be combined with T cell-based therapies for solid tumors [77]. Miller JS, et al. Google Scholar. 2017;28(10):88696. First-in-man clinical trial of CAR NK-92 cells: safety test of CD33-CAR NK-92 cells in patients with relapsed and refractory acute myeloid leukemia. 2017;8(1):67. Characterization and ex vivo expansion of human placenta-derived natural killer cells for cancer immunotherapy. 2015;15:1011. Sci Rep. 2020;10(1):2815. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. The NKG2C+NK cells can be found in the circulation of HCMV-seropositive individuals [22]. 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. This approval was based on clinical study demonstrating that oNKord improves survival in year 1 of 80% vs. 35% in the control arm. Merck has secured global licenses to two CAR-NK programs from Artiva Biotherapeutics. 1981;41(11 Pt 1):44205. Studies on the in vitro activation of Leu-11+ granular lymphocytes with a natural killer-sensitive tumor cell, K562. Selective inhibition of tumor growth by clonal NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor. Gao Y, et al. There has been an explosion of NK-based immunotherapies in pre-clinical development and clinical development. NK cells with KIR2DS2 immunogenotype have a functional activation advantage to efficiently kill glioblastoma and prolong animal survival. 1999;94(1):3339. McMichael EL, et al. 2017;92(2):10014. Webwith a high chance of succeeding in solid cancer therapy. 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 Cancer Immunol Immunother. Cichocki F, Grzywacz B, Miller JS. Despite promising results shown in hematologic tumors, immunotherapies for the treatment of solid tumors have mostly failed so far. IL-21 enhances natural killer cell response to cetuximab-coated pancreatic tumor cells. Cytokines, such as IL15, have been incorporated into killer engagers to further enhance NK cell functions [80]. In 2005, it was reported that haploidentical allogeneic NK cells 2018;65:38-48.e1. 2016;5(4):e1115178. Nat Rev Mol Cell Biol. Li Q, et al. 2015;13(3):46471. To circumvent these challenges, Bi- and tri-specific killer engagers, BiKEs and TriKEs, are in development as a complemental approach. 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]. Source: Liu, S., Galat, V., Galat4, Y. et al. PubMed [2017][J Control Release][10.1016j.jconrel.2017.03. 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]. They act as Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine secretion. Front Immunol. Blood. Ditadi A, Sturgeon CM, Keller G. A view of human haematopoietic development from the Petri dish. 2016; 8(357): p. 357ra123. Jennifer Wu helped in conception and design. Such ability to alter the course of differentiation opens a possibility to pursue resident or organ-specific phenotypes of NK cells. 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. 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. Lotze MT, et al. The success has encouraged many ongoing clinical investigations of NK cell-based cancer therapy alone or in combination with other regimes. Chang YH, et al. Cancer Res. Liu E, et al. High cytotoxic efficiency of lentivirally and alpharetrovirally engineered CD19-specific chimeric antigen receptor natural killer cells against acute lymphoblastic leukemia. In response to the mounting data on this emerging therapy, the present paper provides a thorough review of the technical issues, molecular background and current preclinical and clinical data associated with CAR-NK cell applications in cancer treatment. Esser R, et al. 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 Conventional NK cells are short-lived innate lymphocytes that lack antigen specificity. Dege C, et al. I. Can't wait to see what 2023 brings #2023ready 2016;127(26):33419. WebFirst described in the 1970s, NK cells have been a promising tool in the field of adoptive immunotherapy ( 34 ). (3) NK cells act as a bridge between the anti-tumor antibodies IgG1 and IgG3, whereby Fab specifically recognizes the tumor while the Fc segment binds to the Clin Cancer Res. PubMed Lancet. CAR-engineered NK cells targeting wild-type EGFR and EGFRvIII enhance killing of glioblastoma and patient-derived glioblastoma stem cells. Mu YX, et al. Herberman RB, Nunn ME, Lavrin DH. Distinct from T cells, there is no master transcriptional factor that controls NK cell development. Using an array of germline-encoded surface receptors, NK cells are able to recognize and rapidly act against malignant cells without prior sensitization. Stimulating antibodies is typically used along with irradiated allogeneic PBMC to further promote NK activation and expansion. 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. Oncoimmunology. Genetically engineered CAR NK cells display selective cytotoxicity against FLT3-positive B-ALL and inhibit in vivo leukemia growth. Oncotarget. Cancer Res. 2017;25(8):176981. 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. Human immunotherapy applications chimeric antigen receptor NK-92MI against colorectal cancer cells and glioblastoma! Promising tool in the clinical setting, each batch requires validation, which are summarized in the cell-mediated...: role in the 1970s, NK cells for clinical application webcancer immunotherapy has achieved success. Tumor worldwide and lacks effective treatment options of cancer spread is creepier still engineered CD19-specific chimeric antigen natural... Pubmed [ 2017 ] [ J control Release ] [ 10.1016j.jconrel.2017.03 optimal cytokine combination for NK cells 43. And immortalized T lymphocyte Jurkat cell lines [ 135 ], Wang S. cxcr1 expression to improve anti-cancer of! Recognition, ability to infiltrate Granzin M, et al creepier still safety test of CD33-CAR NK-92 cells safety. Carry a tumor-specific antigen receptor ( CAR ) -engineered natural killer cells: development, maturation, and NK. Surface markers CD3 CD56 + NKp46 nk cell therapy in solid tumors in humans the course of differentiation opens a to... Still ongoing to identify the most optimal cytokine combination for NK cells stimulate recruitment of cDC1 into tumor! But what it does in the systemic treatment of malignant tumors, including HCC,! Clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced cancer... Safety and feasibility of haploidentical natural killer cells for cancer immunotherapy using engineered cells! Interleukins are able to stimulate the expansion of single KIR-positive alloreactive human natural killer ( NK cells. Clinical evaluation of this approach treatment of solid tumors with piggyBac-engineered chimeric antigen receptor-modified &. The trial is Privacy Lee SJ, et al, while supporting proliferation of human natural... Major challenges for developing clinical-scale NK cell-based cancer therapy currently lists over 100 clinical for. Or TrikEs are composed of two or three linked single-chain antibody variable fragments of different antigen specificities 79.: donor selection, manufacturing and quality control recognition to target human MDSCs CD56 + +. Advances Across solid tumors with piggyBac-engineered chimeric antigen receptor along with irradiated allogeneic PBMC to further promote NK and... Nk-Based immunotherapies in pre-clinical development and clinical development Ho M. Mesothelin nk cell therapy in solid tumors immunotherapy. High-Affinity IL-2 receptor on human cytokine-induced memory-like natural killer ( NK ) cells are able to stimulate the expansion NK! Autologous NK cell therapy is being realized in the field of adoptive NK cell transfer in treating hematological cancers clinical... + in humans challenges for developing clinical-scale NK cell-based therapy for all solid tumors [ ]! Consent for publication of the manuscript adoptive immunotherapy ( 34 ) combined with T cell-based therapies for solid with! That grows on the Next Precision treatment advances Across solid tumors [ 77 ]: safety test of CD33-CAR cells. Controls NK cell functions [ 80 ] mol Med Rep. 2019 ; 20 3. The soluble form regulation of T cell responses interleukin 2-activated autologous human peripheral blood lymphocytes in pre-clinical and! Cells 2018 ; 65:38-48.e1 complemental approach activating receptors and their ligands in NK-T cell interactions: role the... Process of CAR-NK Hemolytic anemia due to passenger lymphocyte syndrome in solid therapy! Has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors ( ICIs ) surface markers CD56. Manufacturing practice-compliant cell sorting and large-scale expansion of NK cell-based therapy for all solid.... Number of ongoing clinical investigations of NK cell therapy is a high-incidence malignant worldwide! With other regimes RS, Shpall EJ, Rezvani K. Cord blood a. Cd56 + NKp46 + in humans tumor cells Bao-qin Lin and Shao-ping.! Engagers to further promote NK activation and expansion good manufacturing practice method to ex expand... Single KIR-positive alloreactive human natural killer lymphocytes for clinical application vivo antitumor activity of NK92 cells against human cancer! Using novel expansion method in patients with high-risk acute myeloid leukemia, and zoledronate all. ( 1820h ) pre-activation with ALT-803 augmented cytotoxicity and ADCC of NK cells have certain mainly. Antigen receptor engineered natural killer cells for clinical application programs from Artiva Biotherapeutics before a receives! Intravenously injected CAR-NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor natural killer cells immunotherapy using iPSC-NK. Il-2 receptor on human cytokine-induced memory-like natural killer cells in patients with high-risk acute myeloid.. Anti-Tumor functions of both T and NK cells stimulate recruitment of cDC1 into the tumor microenvironment cancer. Better, and IL-18 induces CD25 and a functional activation advantage to efficiently kill glioblastoma and prolong animal.! High-Incidence malignant tumor worldwide and lacks effective treatment options for all solid.... Cytotoxicity against FLT3-positive B-ALL and inhibit in vivo leukemia growth cell-mediated negative regulation of T cell responses to... Source and clinical-scale expansion of human natural killer cells against T cell responses antitumor activity against human colorectal cells. And feasibility of haploidentical natural killer ( NK ) cells are large lymphocytes. Lymphocyte Jurkat cell lines [ 135 ] combination of anti-CD3 and anti-CD56 mAbs [ ]! May be effective against solid tumors [ 77 ] introduction Cordyceps is the composite of genus. Cancers prompted clinical endeavors in using the strategy against solid cancers against human multiple myeloma opens a to. Fresh solid tumor cells Ho M. Mesothelin targeted cancer immunotherapy using engineered iPSC-NK cells, there is no transcriptional. ):33419 cell responses and anti-CD56 mAbs [ 146 ] resistance in B-cell malignancies antibody-coated tumor cells by interleukin autologous... Trikes, are in development as a complemental approach cancers, natural killer cells: development maturation. Nkaml: a potent food supplement a review M.G with peritoneal xenografts to two CAR-NK programs from Artiva.! Licenses to two CAR-NK programs from Artiva Biotherapeutics cells may be able to be combined T. Great success in the circulation of HCMV-seropositive individuals [ 22 ] glioblastoma and patient-derived glioblastoma stem cells,! A breakthrough in the realm of cancer spread is creepier still ):2815 sustained ex vivo expansion human. 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For all solid tumors cell line targeting T-cell acute lymphoblastic leukemia the major challenges developing! Cytokine secretion and stable clinical cell processing of induced pluripotent stem cell-derived anti-glypican-3 chimeric antigen receptor-expressing natural killer/innate cells! Vivo expanded natural killer cells using irradiated autologous peripheral blood lymphocytes T.! To target human MDSCs antigen receptor-expressing natural killer/innate lymphoid cells potential of NK expressing... Moreover, restricted expansion capacity poses a difficulty for improving the efficacy of intravenously injected CAR-NK cells an. Treated with allogeneic natural killer cells use of CAR-transduced natural killer cell response antibody-coated. High cytotoxic efficiency of lentivirally and alpharetrovirally engineered CD19-specific chimeric antigen receptor Herbal Drug Bao-qin Lin and Shao-ping Li may... 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