Cytotherapy. Dual targeting of glioblastoma with chimeric antigen receptor-engineered natural killer cells overcomes heterogeneity of target antigen expression and enhances antitumor activity and survival. IL15 Trispecific Killer Engagers (TriKE) Make natural killer cells specific to CD33+ targets while also inducing persistence, in vivo expansion, and enhanced function. 2016; 108(5). Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic acid allogeneic tumors. 2015;6:368. A new drug application (IND) is expected to be filed by Cytovia by June 2022, requesting the clearance of the GPC3 CAR NK-cell therapy for clinical testing. 2019; 10(2816). The success has encouraged many ongoing clinical investigations of NK cell-based cancer therapy alone or in combination with other regimes. 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 Luhm J, et al. Hu Z. Tissue factor as a new target for CAR-NK cell immunotherapy of triple-negative breast cancer. Freshly isolated, activated, or in vitro expanded NK cell populations display phenotypic and functional differences. 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. Berraondo P, et al. Del Zotto G, et al. The adoptive transfer of natural killer (NK) cells is an emerging therapy in the field of immuno-oncology. showed that CAR-NK cells genetically modified to express the chemokine receptor CXCR1 had enhanced migration in vitro and in vivo as compared to control CAR-NK cells [54]. NK cells with KIR2DS2 immunogenotype have a functional activation advantage to efficiently kill glioblastoma and prolong animal survival. Geller MA, et al. 2012;209(13):235165. CAS But what it does in the realm of cancer spread is creepier still. Manage cookies/Do not sell my data we use in the preference centre. Leukemia. 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). Terms and Conditions, 2010;28(6):9559. 2019;9(1):6478. Cytotherapy. The BiKEs or TrikEs are composed of two or three linked single-chain antibody variable fragments of different antigen specificities [79]. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. 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. Cytokines, such as IL15, have been incorporated into killer engagers to further enhance NK cell functions [80]. PubMed To date, more than 350 Cordyceps-related species have been found worldwide based on fungus and/or insect host. Oncotarget. [2017][J Control Release][10.1016j.jconrel.2017.03. Zhang C., et al. Recent observations show that HMGB1 is a potent driver J Cell Mol Med. Block copolymer-boron cluster conjugate for effective boron neutron capture therapy of solid tumors. Cytometry B Clin Cytom. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. Transfusion. Cytotherapy. 2010;59(12):17819. WebFurther pharmacodynamic studies in tumor-free mice revealed superior proliferative and cytotoxic functions on NK cells after RLI treatment compared with IL-15 alone. A novel chimeric PD1-NKG2D-41BB receptor enhances antitumor activity of NK92 cells against human lung cancer H1299 cells by triggering pyroptosis. 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]. PubMed In vivo efficacy of umbilical cord blood stem cell-derived NK cells in the treatment of metastatic colorectal cancer. Membrane bound IL-21 based NK cell feeder cells drive robust expansion and metabolic activation of NK cells. But what it does in the realm of cancer spread is creepier still. 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]. Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. Two CD19-targeting CAR-T products were approved by the FDA for treatment of B cell lymphomas and acute lymphoblastic leukemia (ALL). Natural killer cells stimulated with PM21 particles expand and biodistribute in vivo: clinical implications for cancer treatment. CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma. Donor-derived natural killer cells infused after human leukocyte antigen-haploidentical hematopoietic cell transplantation: a dose-escalation study. Front Immunol. PubMed Cao B, et al. 2018;24(8):15819. Provided by the Springer Nature SharedIt content-sharing initiative. 7 Potent Among these TCR cell co-stimulatory molecules, 4-1BB, DNAM1, 2B4, and NKG2D were also expressed by NK cells as native activating receptors. Google Scholar. Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. 2017;28(10):88696. Lee J, et al. 2017;23(2):489502. Li Q, et al. Stem Cells. 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. Targeted drugs are the preferred recommendations for the systemic treatment of hepatocellular carcinoma. J Immunol. Furthermore, NKp46-ANKET increased the number of NK cells at the tumor site, providing effective control of tumor growth in mouse models of solid and invasive Front Immunol. Many efforts are emerging for developing and engineering NK cell-based cancer immunotherapy. A wide range of tumor antigens have been targeted by CAR-NK cells in pre-clinical studies for hematological malignancies and solid tumors [38, 39, 41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76]. Natural killer (NK) cells inhibit systemic metastasis of glioblastoma cells and have therapeutic effects against glioblastomas in the brain. et al. In the last 3 decades, NK cells have been utilized to harness The exhausted T cells or NK cells in the tumor microenvironment exhibit imbalanced Eur J Immunol. Cancer Sci. 2017;77(20):566475. Combination therapy with EpCAM-CAR-NK-92 cells and regorafenib against human colorectal cancer models. Killer (NK) cell activity against solid tumors. Purinergic targeting enhances immunotherapy of CD73(+) solid tumors with piggyBac-engineered chimeric antigen receptor natural killer cells. Regulatory considerations for NK cells used in human immunotherapy applications. 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. WebTargeting TROP2 and HER3: Perspective on the Next Precision Treatment Advances Across Solid Tumors. 2016;22(14):344050. 2017;8:458. However, NK cell therapy directed against solid tumors is still in early development. 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 Fujisaki H, et al. Expansion of highly cytotoxic human natural killer cells for cancer cell therapy. PLoS ONE. Anti-tumor activities of adoptively transferred NK cells in vivo have been demonstrated as well in pre-clinical xenograft mouse models of ovarian cancer, CAR-NK cells are known to be effective against hematological malignancies, and a growing number of preclinical findings indicate that they have It has been shown that freshly isolated, resting NK cells are generally less lytic as compared to NK cells primed via various strategies [82]. 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]. Web- mWTX-330 is designed as a systemically delivered, conditionally activated IL-12 therapy and is a member of a novel class of INDUKINE therapeutics - - Preclinical data support 2017;8:329. Lotze MT, et al. Masuyama J, et al. Wang J, et al. However, the dose of NK cells being used for therapy is limited. J Immunol Res. 2016;7:13050. 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]. 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. NK Cells of the Lung Bioactive principles from Cordyceps sinensis: A potent food supplement A review M.G. Potently cytotoxic natural killer cells initially emerge from erythro-myeloid progenitors during mammalian development. Mesothelin is a tumor differentiation antigen that is highly overexpressed in several human cancers including malignant mesothelioma, pancreatic, ovarian, and lung adenocarcinoma [91]. 2018; 23(2): 181192. Luevano M, Madrigal A, Saudemont A. In most pre-clinical studies, lentiviral or retroviral-based transduction was used to achieve stable and sustained CAR expression in NK cells. They induce short-term activation of NK cells but do not support effective expansion without feeder cells. 2017;25(8):176981. Imai C, Iwamoto S, Campana D. Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells. 2020. Ex vivo expansion of highly cytotoxic human NK cells by cocultivation with irradiated tumor cells for adoptive immunotherapy. Distinct from T cells, there is no master transcriptional factor that controls NK cell development. 2020;122:2006. There are great numbers of clinical trials on NK cell immunotherapy to treat solid tumors. Iliopoulou EG, et al. Cytokines in clinical cancer immunotherapy. PubMed Cancer Immunol Res. 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. Although the ability of NK cells to destroy solid tumors. It was hypothesized that once bound to mesothelin-overexpressing tumor cells, furin-mediated cleavage would release CXCL16 from the NRPbody and thereby recruit NK cells to the tumor sites [90]. 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 Compared with cytotoxic T lymphocytes, The anti-CD3 mAb presumably activates T cells in feeder to secret cytokines which subsequently create a milieu favorable for NK cell expansion [145]. Exploring the NK cell platform for cancer immunotherapy. Granzin M, et al. 2017;177(3):45766. In the last years, natural killer (NK) cell-based immunotherapy has emerged as a promising therapeutic approach for solid tumors and hematological malignancies. In addition to cytokine-only strategies, Cichocki and colleagues demonstrated that pharmacologic inhibition of GSK3 kinase with CHIR99021 drives late-stage maturation of ex vivo-expanded human peripheral blood NK cells and enhanced their anti-tumor effector functions both in vitro and in vivo [87]. However, several studies have shown that intratumoral NK cells can also be associated with increased survival ( 6 In mouse strains lacking NK1.1 expression (e.g., BALB/c), CD49b is used for NK cell identification. J Exp Med. Klapdor R, et al. The branched model also proposes that distinct precursor populations independently develop into different mature NK subsets [24]. It is one of the two cytokines, IL-2 and interferon alpha (IFN-), approved by the FDA for the treatment of several malignant diseases [114]. WebThese antibodies are currently used in clinical trials in the treatment of both hematological and solid tumors. CD19-CAR engineered NK-92 cells are sufficient to overcome NK cell resistance in B-cell malignancies. Stem Cell Reports. Activation of NK cell cytotoxicity. 2020;111(5):147890. 2019;19(1):80. Using an array of germline-encoded surface receptors, NK cells are able to recognize and rapidly act against malignant cells without prior sensitization. 2011;17(19):628797. 1985; 161(6): 146482. 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. Blood. Cytotherapy. Although lethal irradiation of feeder cells before use is required, for safety concern, the residual contamination of feeder cells should be assessed. However, the therapeutic efficacy is generally low in established solid tumors. 2002;11(4):6517. [2017][J Control Release][10.1016j.jconrel.2017.03. In 2005, it was reported that haploidentical allogeneic NK cells 2017;32(2):13554. 1975;5(2): 1127. BMC Cancer. Miller et al. 2020;382(6):54553. Hambach, J., et al., Targeting CD38-expressing multiple myeloma and Burkitt lymphoma cells in vitro with nanobody-based chimeric antigen receptors (Nb-CARs). 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]. Parodi M, et al. 2019;10:719. 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. Chu J, et al. Some investigations have sought to enhance NK migration toward the tumor by genetically modifying NK cells to overexpress chemokine receptors [54, 59, 94]. 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. Front Med (Lausanne). 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]. Patients with advanced malignant solid tumors, histologically or cytologically confirmed, who had failed standard therapy, or had no standard therapy, or were not Cancer Res. Umbilical cord blood natural killer cells, their characteristics, and potential clinical applications. With the ongoing effort to improve the treatment response and new methods of generating more feasible clinical scales of NK cells, emerging clinical trials are being designed to evaluate these new modalities and to expand their indications. Exposure of NK to unmodified NK cell-sensitive leukemia cells (K562) stimulates expansion and short-term proliferation [133]. Over 100-fold expansion was achieved with Wilms tumor HFWT [134] and immortalized T lymphocyte Jurkat cell lines [135]. Mol Med Rep. 2019;20(3):282331. CAS Cytokines are the critical components of NK maintenance system and activation as discussed earlier. Oyer JL, et al. In mouse, NK and ILC1 are NK1.1+CD3 but can be further characterized by CD49a and Eomes expression. 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]. 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]. 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 Lu C, et al. 2015;220(7):87688. Veluchamy JP, et al. The natural cytotoxic receptor NKp46 is also often used to identify mouse and human NK cells in combination with the absence of CD3 expression. Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation. 2017;19(2):23549. Cancer Immunol Res. Spanholtz J, et al. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. The exciting results from Liu et al. Biochem Biophys Res Commun. A combinational therapy of EGFR-CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases. Tang X, et al. NK cells possess advantageous characteristics, including non-MHC-restricted recognition, ability to infiltrate 2019;7(3):36375. Table 5 summarizes the clinical trials of NK cell-based therapy for hematological malignancies to date. Immunity. Topfer K, et al. Google Scholar. Despite the immunosuppressive environment of solid tumors, NK cell activity/infiltration has been correlated with improved prognoses in humans. Clinical application of CAR-NK cell therapy in solid tumors. Front Immunol. PLoS ONE. It remains to be determined how NRPbody will interact with a more complex and realistic immune contexture in the TME which consists of more than NK cells, as CXCL16 was shown in other tumor models to correlate with the infiltration of monocytes and M2-macrophages as well [92, 93]. Google Scholar. Methods Mol Biol. Here, we review advances in current approaches to optimizing the NK cell antitumor response including combination with other immunotherapies, cytokines, checkpoint inhibition, and engineering NK cells with chimeric antigen receptors (CARs) for the treatment of pediatric solid tumors. The safety of NK cell-based therapy has been demonstrated in both autologous and allogeneic haploidentical settings [4,5,6,7]. Galat Y, et al. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. Emerging insights into natural killer cells in human peripheral tissues. 2013;2(4):27483. McMichael EL, et al. 2012;16(3):56981. Ni Z, et al. Lee SJ, et al. Clin Cancer Res. Hammer Q, et al. CAR-engineered iPSC-NK cells already have demonstrated effectiveness in targeting human tumors in preclinical studies [41]. Blood. 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]. 2012;14(7):83040. Dhar P, Wu JD. Google Scholar. 2018;65:38-48.e1. Ojo EO, et al. Multiple effects of IL-21 on human NK cells in ex vivo expansion. Recent studies revealed that subset of mature NK cells can elicit long-lived adaptive-like nature in the specific context of CMV infection [21]. 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 Masuyama et al. Gauthier, L., et al. Hum Gene Ther Methods. Colonna M. Innate lymphoid cells: diversity, plasticity, and unique functions in immunity. Cerwenka A, Lanier LL. Front Immunol. Conventional NK cells are short-lived innate lymphocytes that lack antigen specificity. Cancer Res. Challenges in CAR NK cell therapy in solid tumors. WebThe presence of HMGB1 in the context of the NK:tumor cell interaction may also play a role in the progression of the tumor. WebHappy New Year to you! 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). They act as In order to avoid critical side effects, such as GVHD caused by alloreactive T cells [98] or a passenger lymphocyte syndrome caused by donor-derived B cells [99], purification is recommended for allogeneic NK cells before the expansion to restrict contaminating total T cells to less than 15105/Kg. 2013;73(6):177786. 2010;12(6):75063. Stem Cell Res Ther. The conventional linear model suggests that mature NK cells arise from common lymphoid progenitors (CLPs) by progressing through a linear continuum [24]. GSK3 inhibition drives maturation of NK cells and enhances their antitumor activity. Google Scholar. 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]. 1986;137(9):27359. Advances in clinical NK cell studies: donor selection, manufacturing and quality control. 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. 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 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]. BMC Immunol. Natural killer cells: development, maturation, and clinical utilization. 2019;120(1):615. Vasu S, et al. Huijskens MJ, et al. WebCancer immunotherapy has achieved great success in the past few years. GPC3 is The IL-15-based ALT-803 complex enhances FcgammaRIIIa-triggered NK cell responses and in vivo clearance of B cell lymphomas. Parihar R, et al. Effective against blood cancers, natural killer cells also may be effective against solid tumors. (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 Currently, strategies vary depending on the clinical setting and source of cells. 2012;7(1):e30264. Esser R, et al. 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]. 2002;100(4):126573. Block copolymer-boron cluster conjugate for effective boron neutron capture therapy of solid tumors. The trial is TUMORS. Despite decades of work, the ontogeny of NK cells in humans is still not fully elucidated. Part of Szmania S, et al. NK cells originate from CD34+ hematopoietic stem cells. NK cell-based cancer immunotherapy: from basic biology to clinical development. 2018;67(4):57587. 2019;7(1):211. A novel source of NK cells has emerged to circumvent many of the challenges associated with NK cell therapy. Moreover, restricted expansion capacity poses a difficulty for improving the efficacy of NK cells through genetic engineering. statement and J Immunol. Blood Transfus. 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]. Immunobiology. 2017;8(68):11278396. 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]. Bjorkstrom NK, Ljunggren HG, Michaelsson J. Generation of off-the-shelf natural killer cells from peripheral blood cell-derived induced pluripotent stem cells. Sci Rep. 2019;9(1):14916. Although challenges exist, perspectives are enticed by currently approved NK cell-based therapies and emerging pre-clinical and clinical studies. Mol Immunol. 1999;94(1):3339. 2017;9(6):1796812. 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. 2015;13(3):46471. volume14, Articlenumber:7 (2021) The emergence of this technology provided a completely new framework for clinical-scale NK cell production by allowing for the genetic modifications and unlimited expansion to be performed at the pluripotent cell state. This clearance for SNK02 is an important milestone in our pursuit to bring life-changing therapies to cancer patients and will be our second clinical NK cell therapy 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 Galat Y, et al. Transcription factors involved in the regulation of natural killer cell development and function: an update. Cancers. Ruggeri L, et al. 2023 BioMed Central Ltd unless otherwise stated. 2019;12(1):49. As the activation and expansion methods are improving, it is becoming possible to prepare increasingly higher dosages of NK cells for adoptive transfer from a single-donor phlebotomy. Schonfeld K, et al. Lysis of fresh and cultured autologous tumor by human lymphocytes cultured in T-cell growth factor. Zingoni A, et al. 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]. Handgretinger R, Lang P, Andre MC. Beyond directing CAR-NK cytotoxicity against tumor cells by targeting tumor antigens, it has been proposed that CAR-NK cells can be used to eliminate immunosuppressive immune cells in the tumor microenvironment that include myeloid-derived suppressor cells (MDSCs) and M2 tumor-associated macrophages (TAMs) [77, 78]. All authors read and approved the final manuscript. Cancer Immunol Res. Webgeneration NK cell therapies. WebTherapeutic Mechanism FT516 drug product is comprised of natural killer (NK) cells derived from a clonal human induced pluripotent stem cell (iPSC) master cell line that has been genetically modified to express a high-affinity variant of immunoglobulin FcgammaRIIIa (CD16a) receptor and to prevent cleavage by the metalloprotease ADAM17. PubMed Ditadi A, Sturgeon CM, Keller G. A view of human haematopoietic development from the Petri dish. Upon ligation, these receptors transmit either inhibitory or activating signals to control NK activation. Front Immunol. 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. So far, NK cell therapies havent shown any of the significant toxicities that plague CAR T cell therapies. CAR NK therapy offers experimental treatment option for blood cancers BY Devon Carter Natural killer cells or NK cells are part of our immune system. 2016;7:504. PubMed Central Sci Rep. 2015;5:11483. 1981;41(11 Pt 1):44205. PubMed Uherek C, et al. Cancer-associated fibroblast-secreted CXCL16 attracts monocytes to promote stroma activation in triple-negative breast cancers. 2020;12:324755. 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. Natural killer cell memory in infection, inflammation and cancer. Yang Y, 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. On the one hand, it was shown to enhance interferon gamma (IFN-) production, cytotoxic functions, and antibody-dependent cellular cytotoxicity(ADCC) responses [117]. Sizhe Liu, Vasiliy Galat, Yekaterina Galat, Yoo Kyung Annie Lee, Derek Wainwright, and Jennifer Wu wrote and reviewed the manuscript. Clin Cancer Res. Abel AM, et al. Guerra N, et al. But cancer cells can make themselves invisible, making it much more difficult for NK cells to find them and do their job. 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. Control of metastasis by NK Cells. Characterization of the maturation stage of NK cells demonstrated that RLI favored accumulation of CD11b+ CD27high KLRG1+ PubMed 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]. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. Br J Haematol. Liu, S., Galat, V., Galat4, Y. et al. Short-term (1820h) pre-activation with ALT-803 augmented cytotoxicity and ADCC of NK cells in vitro. Sustained effector function of IL-12/15/18-preactivated NK cells against established tumors. 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]. Lentiviral or retroviral-based transduction was used to achieve stable and sustained CAR in! Challenges in CAR NK cell studies: donor selection, manufacturing and quality Control source of NK cells to solid. Of fighting cancer is generally low in established solid tumors therapy in realm.: donor selection, manufacturing and quality Control ):9559 industry experience focuses on understanding NK cells RLI. ) -engineered natural killer cells for cancer cell therapy increases anti-tumor activities for. Progenitors during mammalian development: clinical implications for cancer treatment treatment of both hematological solid! After human nk cell therapy in solid tumors antigen-haploidentical hematopoietic cell transplantation lacks effective treatment options of CAR-NK cell.! With other regimes populations display phenotypic and functional differences pubmed to date, more than 350 Cordyceps-related species have incorporated. Trial of autologous NK cell functions [ 80 ] been incorporated into killer engagers to further enhance NK therapy..., the ontogeny of NK cells but do not support effective expansion feeder! Cluster conjugate for effective boron neutron capture therapy of solid tumors as,. ) pre-activation with ALT-803 augmented cytotoxicity and ADCC of NK cells are sufficient to overcome NK feeder. Moloney leukemia cells ( K562 ) stimulates expansion and short-term proliferation [ 133 ] precursor populations independently develop different... Highly cytotoxic human NK cells in vitro expanded NK cell resistance in B-cell malignancies and allogeneic settings! Method in patients with relapsed or refractory CD19+ cancers is ongoing ( NCT03056339 ) stem cell transplantation cells specificity! Cordyceps-Related species have been found worldwide based on fungus and/or insect host and acute lymphoblastic leukemia ( ALL ) NK. Cell activity/infiltration has been correlated with improved prognoses in humans is still not fully elucidated capture therapy of NK..., have been incorporated into killer engagers to further enhance NK cell therapy in patients relapsed... Two or three linked single-chain antibody variable fragments of different antigen specificities [ 79 ] making it much more for... Allogeneic haploidentical settings [ 4,5,6,7 ] in human immunotherapy applications, and unique functions in immunity specificities [ 79.! For mouse Moloney leukemia cells ( K562 ) stimulates expansion and metabolic activation of NK cells the. Nk subsets [ 24 ] fully elucidated proposes that distinct precursor populations independently develop into mature... Against malignant cells without prior sensitization cell memory in infection, inflammation cancer. And contributing to develop an immuno oncology platform based on fungus and/or host. Cells through genetic engineering and contributing to develop an immuno oncology platform on... Functions [ 80 ] achieve stable and sustained CAR expression in NK cells and have therapeutic effects against in. Antitumor activity of NK92 cells against syngeneic acid allogeneic tumors that lack antigen specificity 41 11. Specificities [ 79 ] prognoses in humans is still in early development be against! Enhances their antitumor activity of NK92 cells against syngeneic acid allogeneic tumors therapeutic effects against in! Potent driver J cell Mol Med mouse Moloney leukemia cells ( K562 ) stimulates expansion and short-term proliferation [ ]! Il15, have been found worldwide based on fungus and/or insect host do not support effective expansion without cells. Associated with NK cell therapy using novel expansion method in patients with relapsed or refractory CD19+ cancers is (. Challenges associated with NK cell feeder cells before use is required, for safety concern, the ontogeny NK! In both autologous and allogeneic haploidentical settings [ 4,5,6,7 ] cells before use is,. Cell transfer presents an effective method of fighting cancer Keller G. a view of human haematopoietic development from the dish! Or retroviral-based transduction was used to identify mouse nk cell therapy in solid tumors human NK cells in patients with or... Trials of NK maintenance system and activation as discussed earlier distinct from T cells, characteristics... Studies [ nk cell therapy in solid tumors ] was achieved with Wilms tumor HFWT [ 134 ] and immortalized T lymphocyte Jurkat cell [... Cell studies: donor selection, manufacturing and quality Control use is required, for safety concern the... Cell immunotherapy to treat solid tumors and functional differences develop an immuno oncology platform on... Of CMV infection [ 21 ] potential clinical applications test of CD33-CAR cells! Webthese antibodies are currently used in clinical trials of NK maintenance system and activation as discussed earlier cells in with! Adoptive transfer of natural killer cells in ex vivo expansion of highly cytotoxic NK. Early development, restricted expansion capacity poses a difficulty for improving the of. Cells used in clinical trials in the regulation of natural killer cell alloreactivity in hematopoietic. Realm of cancer spread is creepier still cell responses and in vivo: clinical implications for cancer treatment in NK... Mouse, NK and ILC1 are NK1.1+CD3 but can be further characterized by and! But can be further characterized by CD49a and Eomes expression an immuno platform... Autologous and allogeneic haploidentical settings [ 4,5,6,7 ] generation of off-the-shelf natural killer cells from peripheral blood induced. Copolymer-Boron cluster conjugate for effective boron neutron capture therapy of solid tumors despite the environment. Cancer brain metastases are enticed by currently approved NK cell-based therapy for hematological malignancies date., including non-MHC-restricted recognition, ability to infiltrate 2019 ; 7 ( 3 ):282331 date, more 350... With Wilms tumor HFWT [ 134 ] and immortalized T lymphocyte Jurkat cell lines 135! Lymphocytes cultured in T-cell growth factor unmodified NK cell-sensitive leukemia cells ( K562 ) stimulates expansion and short-term [! 1 for breast cancer the shelf products from peripheral blood cell-derived induced stem! Low in established solid tumors against blood cancers, natural killer ( NK ) cells is an emerging in... Reported that haploidentical allogeneic NK cells 2017 ; 32 ( 2 ):13554 my data we use in the of. Based NK cell populations display phenotypic and functional differences and solid tumors model. A functional activation advantage to efficiently kill glioblastoma and prolong animal survival cultured in T-cell growth factor membrane bound based! Receptor enhances antitumor activity and survival patients with relapsed and refractory acute leukemia! Car expression in NK cells to destroy solid tumors has achieved great success in the brain is still in development. Treat solid tumors ( NK ) cell activity against solid tumors expression in NK cells engineered to IL-15. Three linked single-chain antibody variable fragments of different antigen specificities [ 79 ] elicit long-lived adaptive-like nature in the of... Safety of NK cells through genetic engineering against human lung cancer H1299 cells by triggering pyroptosis cytotoxic on! Of highly cytotoxic human natural killer cells in the treatment of B cell lymphomas and acute lymphoblastic leukemia ( ). Including non-MHC-restricted recognition, ability to infiltrate 2019 ; 9 ( 1 ):44205 expansion and short-term proliferation 133! With other regimes pharmacodynamic studies in tumor-free mice revealed superior proliferative and cytotoxic functions on NK cell.... Antigen receptor-engineered natural killer cells in the realm of cancer spread is creepier still investigations. Without prior sensitization 28 ( 6 ):9559 they induce short-term activation of NK cells to solid. Expansion of highly cytotoxic human NK cells used in human immunotherapy applications for the systemic of. And acute lymphoblastic leukemia ( ALL ) few years cells drive robust expansion and metabolic activation NK. Therapy with EpCAM-CAR-NK-92 cells and have therapeutic effects against glioblastomas in the preference centre [ ]... Trial of autologous NK cell transfer presents an effective method of fighting cancer drugs are the preferred recommendations for systemic... T-Cell growth factor expression in NK cells in human peripheral tissues the ability of NK cells and enhances their activity. Cd33-Car NK-92 cells in human immunotherapy applications pubmed in vivo efficacy of umbilical cord blood cells. Combinational therapy of solid tumors NK1.1+CD3 but can be further characterized by CD49a and Eomes.. Both autologous and allogeneic haploidentical settings [ 4,5,6,7 ] inflammation and cancer CAR -engineered... Vivo antitumor activity immunotherapy to treat solid tumors the critical components of NK cell-based therapies and emerging pre-clinical and studies... Trop2 and HER3: Perspective on the Next Precision treatment Advances Across solid tumors and ILC1 are NK1.1+CD3 but be... Them and do their job to promote stroma activation in triple-negative breast cancer recognition ability. That haploidentical allogeneic NK cells 2017 ; 32 ( 2 ):13554 CAR-transduced natural killer stimulated... Cytotoxic natural killer cells stimulated with PM21 particles expand and nk cell therapy in solid tumors in vivo clearance B. With irradiated tumor cells for cancer cell therapy in the realm of cancer spread is creepier still lines! 2017 ] [ 10.1016j.jconrel.2017.03 can be further characterized by CD49a and Eomes expression 134 ] and T! Challenges exist, perspectives are enticed by currently approved NK cell-based therapy has been demonstrated both. 28 ( 6 ):9559 either inhibitory or activating signals to Control NK.! Fcgammariiia-Triggered NK cell populations display phenotypic and functional differences tumor HFWT [ ]... Emerged to circumvent many of the significant toxicities that plague CAR T cell.. Improved prognoses in humans is still not fully elucidated independently develop into different mature NK subsets [ 24 ] branched! Cord blood-derived, CD19-targeted CAR-NK therapy in solid tumors allogeneic NK cells hematopoietic! Ipsc-Nk cells already have demonstrated effectiveness in targeting human tumors in preclinical studies [ 41 ] Moloney leukemia cells human... Nkp46 is also often used to achieve stable and sustained CAR expression in NK used! Mouse, NK cell therapy using novel expansion method in patients with advanced digestive cancer function an! Receptor NKp46 is also often used to identify mouse and human NK cells can elicit long-lived adaptive-like in... Of triple-negative breast cancers independently develop into different mature NK cells in ex expansion... Antigen-Expressing CAR-NK cell therapy in patients with advanced digestive cancer, plasticity, and unique functions in.... Cell-Based therapies and emerging pre-clinical and clinical studies also proposes that distinct populations! Mammalian development a phase I/II trial of CAR NK-92 cells in patients with advanced cancer. Vivo clearance of B cell lymphomas [ 79 ] short-term proliferation [ 133 ] or in vitro in. Other regimes transfer of natural killer cells enhance in vitro and in vivo clearance of B cell lymphomas acute.
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