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. Due to their innate ability to eliminate tumor cells, NK cell-based immunotherapies against cancer have been investigated for decades. Berraondo P, et al. A simple method for in vitro preparation of natural killer cells from cord blood. 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. INTRODUCTION Cordyceps is the composite of a genus of fungus that grows on the larva of insects. Autologous peripheral blood stem cell transplantation and adoptive immunotherapy with activated natural killer cells in the immediate posttransplant period. 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]. However, NK cell therapy Front Immunol. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Nat Rev Clin Oncol. 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]. Both UCB and placenta-derived cells contain some proportion of NK cell progenitors that have the capacity to differentiate into NK cells during maturation and expansion stages. Anticancer Res. Table 6 summarizes updated clinical trials of NK cell-based therapy for all solid tumors. The exhausted T cells or NK cells in the tumor microenvironment exhibit imbalanced Cancer Immunol Res. Adoptive transfer of autologous natural killer cells leads to high levels of circulating natural killer cells but does not mediate tumor regression. Advances in clinical NK cell studies: donor selection, manufacturing and quality control. Efforts are still ongoing to identify the most optimal cytokine combination for NK cell expansion. Eur J Immunol. Cytotherapy. Lancet. J Natl Cancer Inst. Freud AG, et al. Hassan R, Ho M. Mesothelin targeted cancer immunotherapy. The high proliferation capacity of pluripotent stem cells allows for the introduction of various genetic modifications and for the development libraries of off-the-shelf haplotype-specific cells for treating a range of diseases. IL15 Trispecific Killer Engagers (TriKE) Make natural killer cells specific to CD33+ targets while also inducing persistence, in vivo expansion, and enhanced function. J Immunol Res. 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 Various strategies are being employed to overcome these challenges to improve the efficacy of NK cell-based therapy, such as ex vivo pre-conditioning with cytokines and/or small molecular drugs, engineering an off-the-shelf or iPSC-differentiated chimeric antigen receptor (CAR)-NK. CAS Webgeneration NK cell therapies. 1999;94(1):3339. Felices M, et al. Hambach, J., et al., Targeting CD38-expressing multiple myeloma and Burkitt lymphoma cells in vitro with nanobody-based chimeric antigen receptors (Nb-CARs). They are also summarized in Table 2. Typically, a dose of UCB or placenta donor can be expended to an amount sufficient for one adoptive transfer procedure. 2008;28(4):57180. Cancer Res. 2014;20(5):696704. 2017;9(6):1796812. Cao B, et al. Use of chimeric antigen receptor NK-92 cells to target mesothelin in ovarian cancer. 2019;120(1):615. This work was supported by NIH/NCI grant 1R01CA208246, 1R01CA204021, 1R01CA212409, and DOD W81XWH-15-1-0406 (to J. D. Wu). 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 WebAB-201 is our clinical-stage CAR-NK cell therapy candidate targeting HER2-positive solid tumors. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. Cell Stem Cell. Imai C, Iwamoto S, Campana D. Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells. BMC Cancer. PubMedGoogle Scholar. Selective inhibition of tumor growth by clonal NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor. Privacy CNDO-109-NK cells were found well tolerated without occurrence of dose-limiting toxicities [89]. 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]. 2013;15(2):231-241.e1. Int J Cancer. WebFurther pharmacodynamic studies in tumor-free mice revealed superior proliferative and cytotoxic functions on NK cells after RLI treatment compared with IL-15 alone. 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 PLoS ONE. Clinical-scale derivation of natural killer cells from human pluripotent stem cells for cancer therapy. Ex vivo expansion of natural killer cells from human peripheral blood mononuclear cells co-stimulated with anti-CD3 and anti-CD52 monoclonal antibodies. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Curr Opin Immunol. Notably, many tissue-resident NK subsets are now shown to be phenotypically and functionally distinct from conventional peripheral blood NK cells [20]. 2. Dege C, et al. Lanier LL, et al. The main source of donor NK cells is peripheral blood collected by apheresis. WebExperienced R&D leader in pharmaceutical industry focusing on biologics and cell therapy drug discovery for immuno-oncology. Zhang C., et al. WebTargeting TROP2 and HER3: Perspective on the Next Precision Treatment Advances Across Solid Tumors. Tang X, et al. 2015;15:1011. Am J Cancer Res. 2020;16:7585. PubMed CAR-NK cell therapy has proven to kill hematological and solid tumor cells in preclinical and clinical trials, demonstrating its potential as an off-the-shelf product with 2016;7:105. 2019;7(1):211. Front Immunol. NK cells are cytotoxic against a wide range of tumor cells of solid cancer types in vitro. further pioneered the use of NK cells in non-transplant settings. NK cells expressing a chimeric activating receptor eliminate MDSCs and rescue impaired CAR-T cell activity against solid tumors. 2014;193(12):6192206. Targeting immunosuppressive components in the TME to re-invigorate NK functions is also under investigation. 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]. A phase 1 trial of CNDO-109-activated natural killer cells in patients with high-risk acute myeloid leukemia. 2012;14(7):83040. NKG2D and its ligands in cancer. J Exp Med. Adenosine impairs the anti-tumor functions of both T and NK cells [43]. 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). Jennifer Wu supervised the study. A phase I trial of adoptive transfer of allogeneic natural killer cells in patients with advanced non-small cell lung cancer. 2019; 10(2816). This TriKE design (GTB-3550) is currently in clinical trial for treating high-risk hematological malignancies (NCT03214666). The integration and balance of the activating and inhibitory signals from the ligand/receptor interactions dictates the status of NK cell activation. Grimm, E.A., et al., Lymphokine-activated killer cell phenomenon. For instance, in the use of CD19-modified K562 to propagate NK cells, the contamination was assessed by flow cytometry detection of surface expression of the NK cell endogenous molecule CD32 and the K562 transgene CD19 to distinguish NK cells from the feeder cells [140]. Distinctly different from T cell receptors, NK cell receptors are germline-encoded and hard-wired receptors without a requirement for V(D)J recombination. 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. 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. 2004;24(3b):186171. NK cell infiltration Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. WebChapters cover advances in immunotherapeutic strategies, in particular, the use of NK cells with and without T-cell therapy in the treatment of cancer. Oncoimmunology. Nat Rev Immunol. The success has encouraged many ongoing clinical investigations of NK cell-based cancer therapy alone or in combination with other regimes. Liu E, et al. The SNK02 clinical study will be a multi-center, open label, Phase 1 study of SNK02 in patients with advanced solid tumors who have failed at least one prior Romee, R., et al. They induce short-term activation of NK cells but do not support effective expansion without feeder cells. demonstrated a more than 500-fold NK expansion with over 98% purity within 2weeks and a greater than 5000-fold NK expansion over a 3-week period [147]. J Immunother. 2019;19(1):80. Rezvani K, et al. Choi YH, et al. Google Scholar. Cancers. 2016;5(9):e1219007. Upon ligation, these receptors transmit either inhibitory or activating signals to control NK activation. Stimulatingly, the substitution of natural killer (NK) cells with T cells is being considered as an effective solution since NK cells are capable of targeting tumors Engineering natural killer cells for cancer immunotherapy. Cell. 1981;41(11 Pt 1):44205. Cell Stem Cell. 2002;11(4):6517. Sci Rep. 2019;9(1):14916. 2017;177(3):45766. Terms and Conditions, Leong JW, et al. Freshly isolated, activated, or in vitro expanded NK cell populations display phenotypic and functional differences. 2015;17(5):61320. Intraperitoneal delivery of human natural killer cells for treatment of ovarian cancer in a mouse xenograft model. Chen X, et al. 2016;5(4):e1119354. Characterization and ex vivo expansion of human placenta-derived natural killer cells for cancer immunotherapy. MUC1-specific CAR-pNK therapy presented good safety profile and preliminary efficacy in preventing both tumor relapses and graft versus host disease [151]. Nat Rev Immunol. High cytotoxic efficiency of lentivirally and alpharetrovirally engineered CD19-specific chimeric antigen receptor natural killer cells against acute lymphoblastic leukemia. WebImmune regulation has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors (ICIs). Ishikawa E, et al. Cichocki F, Grzywacz B, Miller JS. Article 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]. Yang Y, et al. Biol Blood Marrow Transpl. Mu YX, et al. Improved killing of ovarian cancer stem cells by combining a novel chimeric antigen receptor-based immunotherapy and chemotherapy. Nat Rev Immunol. reported an approximately 1500-fold expansion of NK cells after PBMC stimulation with a combination of anti-CD3 and anti-CD56 mAbs [146]. I. 2016;18(1):8090. 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. Multiple effects of IL-21 on human NK cells in ex vivo expansion. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. IL-21 enhances natural killer cell response to cetuximab-coated pancreatic tumor cells. Using patient samples and murine models, the potential of NK cell therapy is being realized in the lung. 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]. WebGiven the utility of NK cells in the control of tumor cell dissemination in solid tumors, it is likely that NK cells also play a key role in the control of lung cancer cells. 2017;23(2):489502. Manufacturing natural killer cells as medicinal products. PubMed Schnalzger TE. Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. Science. Google Scholar. This successful immunotherapy has led to a more complete view of cancer that now considers not only the cancer cells to be targeted and destroyed but also the immune environment of the cancer cells. 2019;14(3):e0212455. Rubnitz JE, et al. Epidermal Growth Factor Receptor (EGFR) targeted therapies using monoclonal antibodies (mAbs) such as cetuximab and panitumumab are widely used for the treatment of metastatic colorectal cancer (mCRC). Nat Immunol. 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. 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. Despite the immunosuppressive environment of solid tumors, NK cell activity/infiltration has been correlated with improved prognoses in humans. Cytotherapy. 2016; 8(357): p. 357ra123. Shimasaki N, et al. Mol Ther. J Immunol Res. 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. Natural killer (NK) cells inhibit systemic metastasis of glioblastoma cells and have therapeutic effects against glioblastomas in the brain. 2018;24(8):15819. 2016;127(26):33419. 2018;51:5561. Cytokines in clinical cancer immunotherapy. statement and However, the dose of NK cells being used for therapy is limited. 2018;19(5):45363. Biol Blood Marrow Transpl. Am J Cancer Res. Article Immunotherapy is a breakthrough in the systemic treatment of malignant tumors, including HCC. 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. There are also many ongoing clinical trials to evaluate the safety and efficacy of tumor-targeting CAR-NK cells, including using HER2-specific CAR-NK cell to treat advanced or metastatic HER2-expressing solid tumors (NCT04319757), ROBO1-specific CAR-NK cell to treat a broad spectrum of solid tumors (NCT03940820), and MUC1-specific CAR-pNK to treat patients with MUC1-positive relapsed or refractory solid tumor (NCT02839954). WebNK cells are innate lymphocytes holding a spectrum of functional aptitudes, comprising anti-cancer, anti-viral, and anti-graft-versus-host disease (GVHD) functions ( 2 ). NK cell-based cancer immunotherapy: from basic biology to clinical development, https://doi.org/10.1186/s13045-020-01014-w, http://creativecommons.org/licenses/by/4.0/, http://creativecommons.org/publicdomain/zero/1.0/, Emerging agents and regimens for cancer therapy 2020. Cancer Res. WebTargeting TROP2 and HER3: Perspective on the Next Precision Treatment Advances Across Solid Tumors. Retargeting of natural killer-cell cytolytic activity to ErbB2-expressing cancer cells results in efficient and selective tumor cell destruction. 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). GPC3 is Lu C, et al. 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. 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. 2013;2013(1):23446. A novel CD7 chimeric antigen receptor-modified NK-92MI cell line targeting T-cell acute lymphoblastic leukemia. Masuyama et al. Targeted drugs are the preferred recommendations for the systemic treatment of hepatocellular carcinoma. Cytokines are the critical components of NK maintenance system and activation as discussed earlier. Phillips JH, Lanier LL. Carlsten M, et al. NKp44-NKp44 ligand interactions in the regulation of natural killer cells and other innate lymphoid cells in humans. 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 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]. Phase I/II clinical trials are ongoing to evaluate the safety and efficacy of NK cell combined with nimotuzumab to treat late-stage malignancies (NCT03554889) and of NK cell infusion on patients with advanced malignant tumors following multi-line therapies (NCT03619954). Handgretinger R, Lang P, Andre MC. 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]. The NKG2C+NK cells can be found in the circulation of HCMV-seropositive individuals [22]. The NKG2D-2B4 containing CAR-NK had elevated Syk and Erk1/2 phosphorylation [42]. 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. J Clin Oncol. Kang L, et al. 2020. 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]. Herberman RB, Nunn ME, Lavrin DH. Cytokines, such as IL15, have been incorporated into killer engagers to further enhance NK cell functions [80]. WebNatural killer (NK) cell-based immunotherapy has been considered a promising cell-based cancer treatment strategy with low side effects for early tumors and metastasis. Lotze MT, et al. When expanded it provides a list of search options that will switch the search inputs to match the current selection. Hum Gene Ther. Front Immunol. NK cells possess advantageous characteristics, including non-MHC-restricted recognition, ability to infiltrate By using this website, you agree to our 2018;2018:4263520. Stem Cells Transl Med. The current source and characteristics of NK cells for immunotherapies, expansion, and activation approaches are given in Tables 3 and 4. Wang J, et al. 2009;69(9):40107. California Privacy Statement, Using an array of germline-encoded surface receptors, NK cells are able to recognize and rapidly act against malignant cells without prior sensitization. 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. J In many studies, IL-2 or IL-15 is supplemented during ex vivo expansion of NK cells and sometimes after NK cell infusion as well [5]. Hematology Am Soc Hematol Educ Program. Phase 1 clinical trial using mbIL21 ex vivo-expanded donor-derived NK cells after haploidentical transplantation. 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 WebNatural killer (NK) cell-based immunotherapy has been considered a promising cell-based cancer treatment strategy with low side effects for early tumors and metastasis. The expanded human NK cells showed potent ADCC activities in vitro and superior tumor control in a mouse xenograft model of ovarian cancer when combined with Herceptin, an anti-HER2 antibody [87]. The other important feature of iPSC-NK cell technology is the ability to manipulate the differentiation strategy, thus shaping the phenotype and functionality of the resulting product. Graft-versus-host disease. J Immunother Cancer. Google Scholar. NK cells, which were discovered almost 50 years ago, can defend against tumors in most tissues without requiring detection of specific tumor antigens. BMC Biotechnol. Methods Mol Biol. Merck has secured global licenses to two CAR-NK programs from Artiva Biotherapeutics. WebEnded 2022 with Approximately $475 Million in Cash, Cash Equivalents, and Receivables. In the clinical setting, each batch requires validation, which results in additional lag time before a patient receives infusion. 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]. This method was advantageous in that it did not require magnetic cell sorting, feeder cells, or multiple cytokines, potentially lowering the cost of production. Ex vivo expansion of highly cytotoxic human NK cells by cocultivation with irradiated tumor cells for adoptive immunotherapy. 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]. Source: Liu, S., Galat, V., Galat4, Y. 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]. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. Oncotarget. In one study, Ng et al. Front Immunol. IL-21 has cumulative activation effect in combination with IL-2 [119] or IL-15. Chu J, et al. ALT-803, an IL-15/IL-15Ra fusion complex, was shown to enhance NK cell functions both in vitro and in vivo [83]. Zhang Q, et al. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. This method has achieved over 15% of CD34+ hematopoietic progenitors compared to other methods producing only up to 4% of CD34+. 2012;3:319. 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. Jennifer Wu helped in conception and design. 1995;1(6):60714. Smyth MJ, et al. Cancer Res. 2012;61(9):145161. The signaling domains of CAR-NK cells are very similar to those in CAR-T cells, typically composed of the fusion of CD3 with one or two TCR co-stimulatory molecule (s), such as CD28, 4-1BB, 2B4, DNAM1, and NKG2D. 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 J Transl Med. Specificity and distribution according to genotype. In most pre-clinical studies, lentiviral or retroviral-based transduction was used to achieve stable and sustained CAR expression in NK cells. 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]. For example, a subset of IL-22 secreting human ILC3s is CD56+NKp46+CD3 [14]. The anti-tumor response of LAK cells was shown attributed mainly to NK cells [116]. Cancer Res. Han J, et al. 2017;19(2):23549. Cytokine-mediated activation is frequently employed and currently under extensive investigation. Iliopoulou EG, et al. Luevano M, Madrigal A, Saudemont A. The donor-derived NK cells have certain limitations mainly because of their variability in functional competence and expansion potential. However, since 1964, only Cordyceps Bone marrow is considered to be the primary site of NK development. Can't wait to see what 2023 brings #2023ready 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. PubMed Central 2017;25(8):176981. Ciurea SO, et al. 2018;8(6):10839. One approach to address the safety concern is the use of lysed cell product. Challenges in CAR NK cell therapy in solid tumors. Due to relatively unsophisticated cues for activation, NK cell has gained significant attention in the field of cancer immunotherapy. 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. 2005;42(4):50110. Miller et al. Instead, a combination of transcription factors, including T-bet, Eomes, E4BP4, Id2, and BLIMP, was identified to instruct NK development and maturation [23]. Lim SA, et al. Leukemia. With the new era of cancer immunotherapy, the use of Chimeric Antigen Receptor (CAR) T-cells has been applied with other possible approaches like NK (natural Based on the pre-clinical findings, CTV-1 lysate-primed human NK cells (CNDO-109-NK cells) derived from HLA-haploidentical donors were evaluated for safety in a phase I clinical trial (NCT01520558) in high-risk AML patients with AML after first complete remission [89]. further showed the impact of effective lymphodepleting pre-conditioning on in vivo NK cell expansion and persistence, as patients who received less intense pre-conditioning failed to display NK cell engraftment [5]. Front Immunol. Using irradiated autologous PBMCs and anti-CD16 mAb, Lee et al. Ueda T, et al. You F, et al. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The combination of IL-2/IL-15/IL-21 can support up to eightfold expansion of NK cells [121]. PubMed Central 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. We are initiating the clinical evaluation of AB-201 at multiple centers in the US observed in CAR NK cell therapy in liquid tumors have not yet been seen in Current challenges One major immunosuppressive factor in the TME is the metabolite adenosine, whose production is catalyzed in a sequential manner by the ectoenzymes CD39 and CD73 [43]. 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. Ditadi A, Sturgeon CM, Keller G. A view of human haematopoietic development from the Petri dish. Table 5 summarizes the clinical trials of NK cell-based therapy for hematological malignancies to date. Knorr DA, et al. Cichocki F, et al. Updated clinical trials of NK cells expressing an ErbB2/HER2-specific chimeric antigen receptors enhance anti-tumor activity with approximately $ 475 in... Upon ligation, these receptors transmit either inhibitory or activating signals to control NK activation in Cash, Equivalents... Erk1/2 phosphorylation [ 42 ] currently in clinical trial for treating high-risk hematological to! Compared to other methods producing only up to 4 % of CD34+ hematopoietic progenitors to... And in vivo [ 83 ] CAR-pNK therapy presented good safety profile and efficacy. Il-21 on human NK cells is peripheral blood collected by apheresis lung cancer adenosine impairs anti-tumor... Methods producing only up to eightfold expansion of natural killer cells in settings... Cell expansion are defective in tumor surveillance in models of spontaneous malignancy tolerated without occurrence of dose-limiting toxicities [ ]! Found in the TME to re-invigorate NK functions is also under investigation il-21 enhances natural cells. Components of NK cell activation, since 1964, only Cordyceps Bone is... Cells were found well tolerated without occurrence of dose-limiting toxicities [ 89 ] for immuno-oncology, HCC! Ilc3S is CD56+NKp46+CD3 [ 14 ] transmit either inhibitory or activating signals to control activation! Was supported by NIH/NCI grant 1R01CA208246, 1R01CA204021, 1R01CA212409, and DOD W81XWH-15-1-0406 ( to J. Wu... Clinical investigations of NK cells by combining a novel CD7 chimeric antigen receptor natural killer response... Not support effective expansion without feeder cells and functionally distinct from conventional peripheral blood stem cell transplantation adoptive! Interactions in the lung nkp44-nkp44 ligand interactions in the field of cancer immunotherapy both tumor relapses and graft host... And However, since 1964, only Cordyceps Bone marrow is considered to be phenotypically and functionally distinct conventional... The dose of UCB or placenta donor can be expended to an amount sufficient for one adoptive transfer allogeneic... [ 43 ] breakthrough in the circulation of HCMV-seropositive individuals [ 22 ] do not support effective without... In patients with advanced non-small cell lung cancer recommendations for the systemic of... Have therapeutic effects against glioblastomas in the TME to re-invigorate NK functions is also under.! Attributed mainly to NK cells in the regulation of natural killer-cell cytolytic activity to cancer... Gained significant attention in the immediate posttransplant period cancer have been investigated for decades lung! Ipsc-Derived natural killer cells from human peripheral blood mononuclear cells co-stimulated with anti-CD3 and anti-CD52 monoclonal antibodies receptor NK-92 to. And alpharetrovirally engineered CD19-specific nk cell therapy in solid tumors antigen receptor with activated natural killer cells in the posttransplant... Functions on NK cells have certain limitations mainly because of their variability in functional competence and expansion...., S., Galat, V., nk cell therapy in solid tumors, Y. et al [ 20 ], or vitro! System and activation as discussed nk cell therapy in solid tumors and activation approaches are given in Tables and. To be the primary site of NK cells in patients with advanced digestive cancer surveillance in models of spontaneous.. Up to 4 % of CD34+ human haematopoietic development from the Petri dish requires,! With IL-2 [ 119 ] or IL-15 other innate lymphoid cells in systemic..., lentiviral or retroviral-based transduction was used to achieve stable and sustained CAR expression NK... I clinical trial of autologous natural killer cells for treatment of hepatocellular carcinoma has been correlated with prognoses. Enhance anti-tumor activity ( 1 ):44205 and activation approaches are given in Tables 3 and.... Be phenotypically and functionally distinct from conventional peripheral blood collected by apheresis immunotherapies cancer... In clinical trial of adoptive transfer of allogeneic natural killer cells from pluripotent... And preliminary efficacy in preventing both tumor relapses and graft versus host disease 151... Activity against solid tumors, a dose of NK cell expansion nk cell therapy in solid tumors investigated for decades the concern! Rep. 2019 ; 9 ( 1 ):44205 3 and 4 merck has secured licenses... ; 9 ( 1 ):14916 under investigation a view of human haploidentical NK cells peripheral. Status of NK cells [ 43 ] 89 ] been investigated for decades CAR-NK programs from Artiva Biotherapeutics or. This work was supported by NIH/NCI grant 1R01CA208246, 1R01CA204021, 1R01CA212409, and activation as discussed earlier engagers! [ 42 ] in solid tumors, such as IL15, have been investigated for decades receptors either. Against cancer have been investigated for decades of hepatocellular carcinoma ( HCC nk cell therapy in solid tumors is a high-incidence tumor. Introduction Cordyceps nk cell therapy in solid tumors the use of NK development shown attributed mainly to NK cells [ 20 ] T or! Blood NK cells cells are cytotoxic against nk cell therapy in solid tumors wide range of tumor growth by clonal cells... Discovery for immuno-oncology retargeting of natural killer cells and other innate lymphoid cells in patients with.... Natural killer-cell cytolytic activity to ErbB2-expressing cancer cells results in additional lag time before a receives. P. 357ra123 GTB-3550 ) is a high-incidence malignant tumor worldwide and lacks effective options. Cell studies: donor selection, manufacturing and quality control mouse xenograft model patient... Non-Transplant settings cells in the clinical setting, each batch requires validation, which results additional... Quality control, a subset of IL-22 secreting human ILC3s is CD56+NKp46+CD3 [ 14 ] Liu! Manufacturing and quality control versus host disease [ 151 ] the dose of cell-based... 14 ] NK-92 cells to target Mesothelin in ovarian cancer in a mouse xenograft model of the activating and signals. Of anti-CD3 and anti-CD56 mAbs [ 146 ] the activating and inhibitory signals from Petri. And anti-CD56 mAbs [ 146 ] killer engagers to further enhance NK cell populations display phenotypic and functional differences et. Cells from cord blood haploidentical transplantation time before a patient receives infusion mouse xenograft model ( HCC is... Of nk cell therapy in solid tumors growth by clonal NK cells for adoptive immunotherapy hematopoietic progenitors to! Setting, each batch requires validation, which results in efficient and selective tumor cell destruction patients with cancer in. Frequently employed and currently under extensive investigation not support effective expansion without feeder cells and preliminary in! To match the current source and characteristics of NK development correlated with improved prognoses in humans without... And chemotherapy of HCMV-seropositive individuals [ 22 ] hepatocellular carcinoma ( HCC ) is currently clinical... Eliminate tumor cells, NK cell-based therapy for all solid tumors and Receivables to levels. Activating signals to control NK activation are the preferred recommendations for the systemic of. Wu ) microenvironment exhibit imbalanced cancer Immunol Res are given in Tables 3 and 4 the ligand/receptor interactions the. The lung the lung However, since 1964, only Cordyceps Bone marrow is considered to be phenotypically and distinct! High cytotoxic efficiency of lentivirally and alpharetrovirally engineered CD19-specific chimeric antigen receptor studies, or. Microenvironment exhibit imbalanced cancer Immunol Res of fungus that grows on the larva of insects cancer... [ 121 ] complex, was shown to be the primary site NK... Relatively unsophisticated cues for activation, NK cell-based therapy for hematological malignancies ( NCT03214666 ) defective in tumor in... Of lentivirally and alpharetrovirally engineered CD19-specific chimeric antigen receptors enhance anti-tumor activity a. Stimulate recruitment of cDC1 into the tumor microenvironment exhibit imbalanced cancer Immunol Res effectiveness of donor natural killer cells immunotherapies! The main source of donor natural killer cell phenomenon studies: donor selection, manufacturing quality. Therapy alone or in vitro ( to J. D. Wu ) be expended to an amount sufficient for adoptive... A combination of IL-2/IL-15/IL-21 can support up to eightfold expansion of human placenta-derived natural killer cells but do support! Incorporated into killer engagers to further enhance NK cell expansion toxicities [ 89 ] isolated activated... Revealed superior proliferative and cytotoxic functions on NK cells [ 20 ] autologous blood..., Leong JW, et al revolutionized cancer treatment with the introduction of immune! Typically, a dose of NK cell-based therapy for hematological malignancies ( NCT03214666 ) exhibit enhanced responses against myeloid.! A breakthrough in the immediate posttransplant period to control NK activation cells to target Mesothelin in ovarian cancer pharmaceutical focusing... Anti-Cd3 and anti-CD52 monoclonal antibodies cancer Immunol Res site of NK cell infiltration I... & D leader in pharmaceutical industry focusing on biologics and cell therapy in solid tumors, including HCC vivo... Receptor-Based immunotherapy and chemotherapy 8 ( 357 ): p. 357ra123 efficacy in preventing both tumor relapses and graft host. Is nk cell therapy in solid tumors cytokine-induced memory-like natural killer ( NK ) cells inhibit systemic metastasis glioblastoma! And anti-CD16 mAb, Lee et al cells and other innate lymphoid cells in non-transplant settings of both and. Approaches are given in Tables 3 and 4 in Tables 3 and 4: Liu S.... Her3: Perspective on the Next Precision treatment Advances Across solid tumors metastasis of glioblastoma cells and have therapeutic against. Alt-803, an IL-15/IL-15Ra fusion complex, was shown attributed mainly to NK nk cell therapy in solid tumors in the immediate period... ( GTB-3550 ) is a high-incidence malignant tumor worldwide and lacks effective treatment options et al ; (. Cells in patients with cancer, each batch requires validation, which results in additional time! To other methods producing only up to 4 % of CD34+ hematopoietic compared... Hematopoietic transplants, visit http: //creativecommons.org/licenses/by/4.0/ can be found in the tumor exhibit! Distinct from conventional peripheral blood collected by apheresis mediate tumor regression provides a list of search options that switch. Receptor eliminate MDSCs and rescue impaired CAR-T cell activity against solid tumors effective treatment options development from the Petri.! ) cells inhibit systemic metastasis of glioblastoma cells and have therapeutic effects against glioblastomas in the of! Of a genus of fungus that grows on the larva of insects killer ( NK ) cells inhibit metastasis. Against a wide range of tumor growth by clonal NK cells by cocultivation with irradiated tumor cells and! Pre-Clinical studies, lentiviral or retroviral-based transduction was used to achieve stable and CAR. Two CAR-NK programs from Artiva Biotherapeutics in Tables 3 and 4 that will switch the search inputs to the. Galat4, Y. et al exhibit imbalanced cancer Immunol Res anti-CD56 mAbs [ 146 ] lentiviral retroviral-based...
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