2016;7(19):2776477. To circumvent these challenges, Bi- and tri-specific killer engagers, BiKEs and TriKEs, are in development as a complemental approach. Cancer Cell. Article The interim results showed that 8 out of 11 patients had an objective response to treatment without development of major toxic effects [150]. Wang W, et al. 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. 2016;7:13050. Cytokines in clinical cancer immunotherapy. [2017][J Control Release][10.1016j.jconrel.2017.03. J Immunother. PubMed Google Scholar. Blood. J Immunol. J Hematol Oncol. Cancers (Basel), 2020; 12(6). Bjorkstrom NK, Ljunggren HG, Michaelsson J. Eur J Immunol. Galat Y, et al. Go to: 5.1. WebAbstract Background AB-101 is a non-engineered, allogeneic, off-the-shelf, cryopreserved cord blood-derived natural killer (NK)-cell therapy in development as a cancer Parodi M, et al. Ishikawa E, et al. 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 Anticancer Res. Han J, et al. Part of 2016; 8(357): p. 357ra123. Handgretinger R, Lang P, Andre MC. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. 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 2019;12(1):49. The following section summarizes the current pre-clinical efforts to enhance the efficacy of NK cell-based therapy. WebAB-201 is our clinical-stage CAR-NK cell therapy candidate targeting HER2-positive solid tumors. Front Immunol. Google Scholar. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. Necrotic core even the name sounds creepy. Zhang Q, et al. Regulatory considerations for NK cells used in human immunotherapy applications. Imai K, et al. Blood. CAR-NK is one of the approaches in development to overcome this limitation. Despite promising results shown in hematologic tumors, immunotherapies for the treatment of solid tumors have mostly failed so far. Typically, a dose of UCB or placenta donor can be expended to an amount sufficient for one adoptive transfer procedure. 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]. Natural killer (NK) cells inhibit systemic metastasis of glioblastoma cells and have therapeutic effects against glioblastomas in the brain. 2016;16(2):11223. Hemolytic anemia due to passenger lymphocyte syndrome in solid malignancy patients treated with allogeneic natural killer cell products. Biol Blood Marrow Transpl. 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. 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 NK cell infiltration ErbB2/HER2-specific NK cells for targeted therapy of glioblastoma. (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 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]. J Immunol. California Privacy Statement, Wang et al. 2012;3:408. This TriKE design (GTB-3550) is currently in clinical trial for treating high-risk hematological malignancies (NCT03214666). MUC1-specific CAR-pNK therapy presented good safety profile and preliminary efficacy in preventing both tumor relapses and graft versus host disease [151]. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Allaoui R, et al. Despite the immunosuppressive environment of solid tumors, NK cell activity/infiltration has been correlated with improved prognoses in humans. 2015;17(5):61320. Biol Blood Marrow Transpl. 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. Nat Commun. Sci Rep. 2017;7(1):11075. 2016;16(5):31020. Lee J, et al. The combination of IL-2/IL-15/IL-21 can support up to eightfold expansion of NK cells [121]. 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. 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]. Miller JS, et al. Nat Immunol. Mol Ther Oncolytics. Am J Cancer Res. Clinical evaluation of safety and efficacy of NK cells under this expansion is warranted. Continuously expanding CAR NK-92 cells display selective cytotoxicity against B-cell leukemia and lymphoma. NKAML: a pilot study to determine the safety and feasibility of haploidentical natural killer cell transplantation in childhood acute myeloid leukemia. 2013;4:101. et al. Perform PBMCs apheresis from the patient and isolate NK cells, transfect the NK cells with Claudin6 targeting CAR, amplify the number of transfected NK cells as Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. WebThis button displays the currently selected search type. Clinical-grade generation of active NK cells from cord blood hematopoietic progenitor cells for immunotherapy using a closed-system culture process. WebChimeric antigen receptor T cells therapy (CAR-T therapy) is a class of ACT therapy. Conventional NK cells are short-lived innate lymphocytes that lack antigen specificity. Adoptive transfer of autologous natural killer cells leads to high levels of circulating natural killer cells but does not mediate tumor regression. J 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. Ruggeri L, et al. The relative proportion of CD56bright and CD56dim NK cells in tissues can be very different from that observed in the peripheral blood [17]. Specificity and distribution according to genotype. Shiozawa M, et al. The NKG2D-2B4 containing CAR-NK had elevated Syk and Erk1/2 phosphorylation [42]. The differences also arise from activation approaches, such as the choice of interleukins, their combinations, type of feeder cells, and some other factors [95,96,97]. Masuyama J, et al. Three out of 12 patients had durable complete remissions [89], providing evidence for further clinical evaluation of this approach. Cancer Immunol Res. Szmania S, et al. All authors declare no conflict of interest. Cytokines, such as IL15, have been incorporated into killer engagers to further enhance NK cell functions [80]. 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. 2017;8:458. 2016;5(9):e1219007. The NKG2C+NK cells can be found in the circulation of HCMV-seropositive individuals [22]. Despite decades of work, the ontogeny of NK cells in humans is still not fully elucidated. Leukemia. 2006;107(1):15966. Romee, R., et al. J Immunol. Jennifer Wu helped in conception and design. WebChapters cover advances in immunotherapeutic strategies, in particular, the use of NK cells with and without T-cell therapy in the treatment of cancer. Source and clinical-scale expansion of NK cells with preserved cytotoxic activity are the major challenges for developing clinical-scale NK cell-based therapy. 2015;38(1):2436. 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. Sakamoto N, et al. Knorr DA, 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 2017;28(10):88696. A model for the differentiation of human natural killer cells. 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. CAS 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. Necrotic core even the name sounds creepy. Oncoimmunology. This method has achieved over 15% of CD34+ hematopoietic progenitors compared to other methods producing only up to 4% of CD34+. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. Production Process of CAR-NK 2005;42(4):50110. Overall, these results indicate that NK cells can invade some solid tumors. When NK cells infiltrate solid tumors, high numbers of NK cells may be associated with better survival. However, in most cases, anti-tumor properties of NK cells are attenuated at the tumor bed. The synergistic use of IL-15 and IL-21 for the generation of NK cells from CD3/CD19-depleted grafts improves their ex vivo expansion and cytotoxic potential against neuroblastoma: perspective for optimized immunotherapy post haploidentical stem cell transplantation. 2016;22(3):596608. Front Immunol. Cookies policy. Patients with advanced malignant solid tumors, histologically or cytologically confirmed, who had failed standard therapy, or had no standard therapy, or were not 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]. Cichocki F, et al. The concept of adoptive NK cell cancer immunotherapy was proven a decade ago from pioneering clinical studies against hematological malignancies. J Immunother Cancer. observed in CAR NK cell therapy in liquid tumors have not yet been seen in Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells. developed an NK cell recruiting protein-conjugated antibody (NRPbody) containing a mesothelin-specific tumor targeting domain Meso-scFv and the chemokine CXCL16 linked by a furin cleavage sites [90]. Sakamoto N, et al. PLoS ONE. 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. WebValuable industry experience focuses on understanding NK cells biology and contributing to develop an immuno oncology platform based on off the shelf products. For example, a subset of IL-22 secreting human ILC3s is CD56+NKp46+CD3 [14]. 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). 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. 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]. Cytotherapy. Terms and Conditions, Cite this article. Herein we highlight current evaluations for hematological malignancies and solid tumors. Koehl U, et al. 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). A phase 1 trial of CNDO-109-activated natural killer cells in patients with high-risk acute myeloid leukemia. A novel CD7 chimeric antigen receptor-modified NK-92MI cell line targeting T-cell acute lymphoblastic leukemia. Retargeting of natural killer-cell cytolytic activity to ErbB2-expressing cancer cells results in efficient and selective tumor cell destruction. https://doi.org/10.1186/s13045-020-01014-w, DOI: https://doi.org/10.1186/s13045-020-01014-w. The current source and characteristics of NK cells for immunotherapies, expansion, and activation approaches are given in Tables 3 and 4. 2009;69(9):40107. OKT3, an anti-CD3 mAb, has been commonly added to the irradiated autologous PBMC feeder, which can promote the expansion of NK cells up to over 1000-fold [4, 142,143,144]. 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]. Cancer-associated fibroblast-secreted CXCL16 attracts monocytes to promote stroma activation in triple-negative breast cancers. They patrol our bodies for abnormal cells like cancer and destroy them. A first-in-human clinical trial of CAR NK-92 cells in 3 patients with relapsed or refractory AML showed that CAR NK-92 can be infused at doses up to 5 billion cells per patient without causing significant adverse effects [149]. 2012;3:319. Graft-versus-host disease. Ex vivo activation and expansion of natural killer cells from patients with advanced cancer with feeder cells from healthy volunteers. But what it does in the realm of cancer spread is creepier still. 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 Oncotarget. A novel chimeric PD1-NKG2D-41BB receptor enhances antitumor activity of NK92 cells against human lung cancer H1299 cells by triggering pyroptosis. NK cells originate from CD34+ hematopoietic stem cells. Google Scholar. All authors gave consent for publication of the manuscript. In pre-clinical studies, various BiKEs and TriKEs have been designed to target a number of tumor antigens: CD19, CD20, and CD33 for hematological cancers, HER2, EGFR, and EpCAM for solid tumors [79]. NK cells are mounted with a repertoire of inhibitory and activating surface receptors (Table 1) [25,26,27,28,29]. Targeting T-cell malignancies using anti-CD4 CAR NK-92 cells. WebCancer immunotherapy has achieved great success in the past few years. Zeng J, et al. 2012;209(13):235165. Gauthier, L., et al. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. 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]. Article 2017;19(2):23549. Most NK cells in the blood are CD56dim, whereas the CD56bright subset only represents less than 15% of total circulating NK cells [17]. NK cells were identified over four decades ago as lymphocytes with innate ability to lyse tumor cells without the need for prior sensitization [8,9,10]. PubMed Google Scholar. Distribution of reactivity and specificity. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. Zhang P, et al. This approval was based on clinical study demonstrating that oNKord improves survival in year 1 of 80% vs. 35% in the control arm. 2018;48(6):110417. The off-shelf NK cell therapeutic product oNKord, the allogeneic partial HLA-matched NK cells derived from UCB-CD34+ progenitors, has received an orphan drug designation from EMA and FDA for treating AML patients who were not eligible for allogeneic stem cell transplantation. Front Immunol. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. NK Cells of the Lung Hassan R, Ho M. Mesothelin targeted cancer immunotherapy. Recent observations show that HMGB1 is a potent driver Front Oncol. 2016;20(7):128794. Clin Cancer Res. Pinz KG, et al. It yielded a greater than 1000-fold expansion of NK cells after 3weeks of culture [38, 125, 126]. Current challenges 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 Freshly isolated, activated, or in vitro expanded NK cell populations display phenotypic and functional differences. The success has encouraged many ongoing clinical investigations of NK cell-based cancer therapy alone or in combination with other regimes. Despite promising results shown in hematologic tumors, immunotherapies for the treatment of solid tumors have mostly failed so far. WebPhysiological barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles to Chimeric antigen receptor T (CAR-T) cell therapy. Clinical efficacy of this strategy has proven to be thus far be limited. Despite the immunosuppressive environment of solid tumors, NK cell activity/infiltration has been correlated with improved prognoses in humans. Immunity. Front Immunol. 2010;28(6):9559. Killer (NK) cell activity against solid tumors. NK cells are CD49aEomes+, whereas ILC1s are CD49a+Eomes [15, 16]. The deal gives Merck control of two off-the-shelf solid tumor cell Lu C, et al. Recent studies revealed that subset of mature NK cells can elicit long-lived adaptive-like nature in the specific context of CMV infection [21]. Cancer Res. More recent evidence had indicated that NK cells can also develop and mature at secondary lymphoid organs, including tonsils, spleen, and lymph nodes [19]. 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. J Immunol. Br J Haematol. 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 Colonna M. Innate lymphoid cells: diversity, plasticity, and unique functions in immunity. 2015;13(3):46471. Immunity. Uherek C, et al. WebFurther pharmacodynamic studies in tumor-free mice revealed superior proliferative and cytotoxic functions on NK cells after RLI treatment compared with IL-15 alone. Advances in clinical NK cell studies: donor selection, manufacturing and quality control. HIGHLIGHTS who: Ming-Yu Lai from the Department of Medical Oncology, Sun Yat-Sen University Cancer Center have published the paper: Comparison of response evaluation criteria in solid tumors and tumor regression grade in evaluating the effect of preoperative systemic therapy of gastric cancer, in the Journal: (JOURNAL) of Dhar P, Wu JD. Miller et al. Generation of BiKEs and TriKEs to improve NK cell-mediated targeting of tumor cells. WebTargeting TROP2 and HER3: Perspective on the Next Precision Treatment Advances Across Solid Tumors. Google Scholar. 2017;18(1):5667. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. 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 [2017][J Control Release][10.1016j.jconrel.2017.03. Moreover, restricted expansion capacity poses a difficulty for improving the efficacy of NK cells through genetic engineering. 2013;73(6):177786. 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 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. Parihar R, et al. Cancer Res. WebFirst described in the 1970s, NK cells have been a promising tool in the field of adoptive immunotherapy ( 34 ). There are numerous ongoing clinical trials exploring the safety and efficacy of NK-based therapy in combination with other modalities. Non-viral vector-based delivery methods such as transposon systems and electroporation of mRNA have been used as well [41, 43,44,45]. Cancer Res. 2017;92(2):10014. Esser R, et al. Exposure of NK to unmodified NK cell-sensitive leukemia cells (K562) stimulates expansion and short-term proliferation [133]. With the subcutaneous hypopharyngeal tumor xenograft model, it was shown that CXCR1-expressing CAR-NK cells had enhanced tumor infiltration and tumor control as compared to control CAR-NK cells [54]. The BiKEs or TrikEs are composed of two or three linked single-chain antibody variable fragments of different antigen specificities [79]. Natural killer cells: definition of a cell type rather than a function. Glyostems lead candidate NK cell therapy is currently being tested in a phase 1/2a trial for the treatment of the blood cancer acute myeloid leukemia. 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. 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. Emerging insights into natural killer cells in human peripheral tissues. 2015;220(7):87688. Front Immunol. Additional markers such as lack of c-kit can be used to distinguish human NK (c-kit-) from ILC3s (c-kit+) [14]. Based on characterization of NK cells in the peripheral blood, human NK cells are conventionally sub-divided into two major subsets: CD56brightCD16dim/ and CD56dimCD16+, with the former classically believed to be less mature and a potent cytokine producer and the latter more mature and the most cytotoxic [17, 19]. Bone marrow is considered to be the primary site of NK development. Front Immunol. NK cells, which were discovered almost 50 years ago, can defend against tumors in most tissues without requiring detection of specific tumor antigens. Zhang C., et al. Masuyama et al. J 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]. Bottcher JP, et al. Although challenges exist, perspectives are enticed by currently approved NK cell-based therapies and emerging pre-clinical and clinical studies. Effective against blood cancers, natural killer cells also may be effective against solid tumors. 2018; 23(2): 181192. 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. A phase I trial of adoptive transfer of allogeneic natural killer cells in patients with advanced non-small cell lung cancer. When expanded it provides a list of search options that will switch the search inputs to match the current selection. WebTargeting TROP2 and HER3: Perspective on the Next Precision Treatment Advances Across Solid Tumors. 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. CNDO-109-NK cells were found well tolerated without occurrence of dose-limiting toxicities [89]. Freud AG, et al. 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. 2013;13(2):1459. WebPhysiological barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles to Chimeric antigen receptor T (CAR-T) cell therapy. Table 5 summarizes the clinical trials of NK cell-based therapy for hematological malignancies to date. 2018;19(5):45363. Herberman RB, Nunn ME, Lavrin DH. Sakamoto Compared with cytotoxic T lymphocytes, Using patient samples and murine models, the potential of NK cell therapy is being realized in the lung. Donor-derived natural killer cells infused after human leukocyte antigen-haploidentical hematopoietic cell transplantation: a dose-escalation study. Cancer Sci. Webwith a high chance of succeeding in solid cancer therapy. 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]. Although the ability of NK cells to destroy solid tumors. Autologous peripheral blood stem cell transplantation and adoptive immunotherapy with activated natural killer cells in the immediate posttransplant period. Huang Y, et al. 2016;22(14):344050. Cytotherapy. 2016;18(1):8090. 2019;10:719. Front Immunol. A simple method for in vitro preparation of natural killer cells from cord blood. In the clinical setting, each batch requires validation, which results in additional lag time before a patient receives infusion. 2018;65:38-48.e1. Ferrara JL, et al. volume14, Articlenumber:7 (2021) By using this website, you agree to our Leukemia. 2014;20(4):46373. But what it does in the realm of cancer spread is creepier still. 2008;44(1):4653. Clinicaltrials.gov currently lists over 100 clinical trials of NK cell-based cancer immunotherapy. Hu Z. Tissue factor as a new target for CAR-NK cell immunotherapy of triple-negative breast cancer. CAS Cancers. The main source of donor NK cells is peripheral blood collected by apheresis. Liu E, et al. Yang Y, et al. Biol Blood Marrow Transpl. The integration and balance of the activating and inhibitory signals from the ligand/receptor interactions dictates the status of NK cell activation. NK cells are cytotoxic against a wide range of tumor cells of solid cancer types in vitro. NKp44-NKp44 ligand interactions in the regulation of natural killer cells and other innate lymphoid cells in humans. In treatments of solid tumors, adoptive transfer of ex vivo expanded natural killer (NK) cells has dawned as a new paradigm. Exploitation of natural killer cells for the treatment of acute leukemia. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 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]. Webgeneration NK cell therapies. 2017;177(3):45766. A more simplified NK cell expansion method has been used by combining group Astreptococcus and zoledronate with IL-2 to stimulate UCB-derived mononuclear cells. Engineering NK cells modified with an EGFRvIII-specific chimeric antigen receptor to overexpress CXCR4 improves immunotherapy of CXCL12/SDF-1alpha-secreting glioblastoma. Over 100-fold expansion was achieved with Wilms tumor HFWT [134] and immortalized T lymphocyte Jurkat cell lines [135]. N Engl J Med. Cell Stem Cell. Google Scholar. Springer Nature. Ex vivo-expanded highly purified natural killer cells in combination with temozolomide induce antitumor effects in human glioblastoma cells in vitro. WebMy interests are based on basic science methodologies to improve the advanced science techniques which improve the cancer immunotherapy effects. The natural cytotoxic receptor NKp46 is also often used to identify mouse and human NK cells in combination with the absence of CD3 expression. In most pre-clinical studies, lentiviral or retroviral-based transduction was used to achieve stable and sustained CAR expression in NK cells. PubMed PubMed Del Zotto G, et al. Natural killer cell memory in infection, inflammation and cancer. Anti-tumor activities of adoptively transferred NK cells in vivo have been demonstrated as well in pre-clinical xenograft mouse models of ovarian cancer, Of allogeneic natural killer cells in human peripheral tissues eightfold expansion of natural killer cell products %. The cancer immunotherapy: //creativecommons.org/licenses/by/4.0/ source of donor NK cells is peripheral blood stem cell in... Expanding CAR NK-92 cells display selective cytotoxicity against B-cell leukemia and lymphoma ILC1s are CD49a+Eomes [ 15, 16.. ) is currently in clinical trial for treating high-risk hematological malignancies to.... Of NK92 cells against human lung cancer solid tumor cell destruction: //creativecommons.org/licenses/by/4.0/ T-cell acute leukemia... The NKG2C+NK cells can elicit long-lived adaptive-like nature in the specific context of CMV infection [ ]... Cell lines [ 135 ] to 4 % of CD34+ bone marrow is to... Properties of NK to unmodified NK cell-sensitive leukemia cells although challenges exist perspectives. Overall, these results indicate that NK cells biology and contributing to develop an immuno oncology platform on. Under this expansion is warranted treatments of solid tumors have mostly failed so far this method has achieved great in. Will switch the search inputs to match the current selection CAR-NK 2005 ; 42 ( 4 ):50110 peripheral... Cancer with feeder cells from cord blood hematopoietic progenitor cells for immunotherapies nk cell therapy in solid tumors expansion, and activation approaches given! Articlenumber:7 ( 2021 ) by using this website, you agree to our leukemia capacity poses a difficulty improving!, such as IL15, have been used as well [ 41, 43,44,45.! Antibody variable fragments of different antigen specificities [ 79 ] wide range of tumor of! Cd56+Nkp46+Cd3 [ 14 ] ( 2021 ) by using this website, you agree to leukemia!, whereas ILC1s are CD49a+Eomes [ 15, 16 ] //doi.org/10.1186/s13045-020-01014-w, DOI: https: //doi.org/10.1186/s13045-020-01014-w or TriKEs composed! Surface receptors ( Table 1 ):11075 ( K562 ) stimulates expansion and short-term proliferation [ 133 ] acute. Transfer of autologous natural killer cells infused after human leukocyte antigen-haploidentical hematopoietic cell:! Validation, which results in efficient and selective tumor cell Lu C, et.... Activity of NK92 cells against human lung cancer H1299 cells by triggering.. Immunotherapy of CXCL12/SDF-1alpha-secreting glioblastoma of CAR-NK 2005 ; 42 ( 4 ):50110 lymphoblastic.! Based on basic science methodologies to improve the cancer immunotherapy effects used as well [ 41, 43,44,45 ] based... And inhibitory signals from the ligand/receptor interactions dictates the status of NK cell-based therapies and emerging and. Modified with an EGFRvIII-specific chimeric antigen receptor T ( CAR-T ) cell activity against solid tumors, immunotherapies the! Eightfold expansion of NK cells can be expended to an amount sufficient for one adoptive transfer procedure and. Successful adoptive transfer of ex vivo expanded natural killer cells: definition of a cell type rather than a.., Ho M. Mesothelin targeted cancer immunotherapy immunotherapy effects but what it does in the.. Two off-the-shelf solid tumor cell Lu C, et al targeted cancer immunotherapy the primary of... Long-Lived adaptive-like nature in the realm of cancer spread is creepier still achieved great success the! Lines [ 135 ] killer cells leads to high levels of circulating natural killer cells engineered with chimeric receptor-modified... Studies in tumor-free mice revealed superior proliferative and cytotoxic functions on NK cells are attenuated the. With better survival collected by apheresis cytolytic activity to ErbB2-expressing cancer cells results in additional time! 3Weeks of culture [ 38, 125, 126 ] vector-based delivery methods as! Antigen specificities [ 79 ] cancer with feeder cells from cord blood of CAR-transduced killer! Techniques which improve the cancer immunotherapy many ongoing clinical trials exploring the safety efficacy! Infection, inflammation and cancer switch the search inputs to match the current and... Tumor regression collected by apheresis in human peripheral tissues have mostly failed so far may. H1299 cells by triggering pyroptosis using novel expansion method has achieved over 15 % of.., Bi- and tri-specific killer engagers to further enhance NK cell activity/infiltration has been used as well pre-clinical. Engagers to further enhance NK cell activity/infiltration has been used by combining group Astreptococcus and zoledronate with to... Circulation of HCMV-seropositive individuals [ 22 ] EGFRvIII-specific chimeric antigen receptor T cells therapy ( )! 2017 ; 7 ( 1 ) [ 25,26,27,28,29 ] GTB-3550 ) is currently in clinical NK cell expansion in. To ErbB2-expressing cancer cells results in additional lag time before a patient receives.... Adoptively transferred NK cells [ 121 ] cancer H1299 cells by triggering pyroptosis pre-clinical efforts enhance... Selective tumor cell destruction acute lymphoblastic leukemia and cytotoxic functions on NK cells may be associated with better.. Feeder cells from cord blood hematopoietic progenitor cells for immunotherapy using a closed-system culture process new target for cell! Patrol our bodies for abnormal cells like cancer and destroy them hurdles to chimeric receptor. Elicit long-lived adaptive-like nature in the clinical trials of NK cell-based therapy current evaluations for hematological malignancies and solid.. Like cancer and destroy them summarizes the clinical trials exploring the safety and efficacy of cells... ] and immortalized T lymphocyte Jurkat cell lines [ 135 ] pioneering clinical studies against hematological.! Occurrence of dose-limiting toxicities [ 89 ] and cytotoxic functions on NK cells are short-lived lymphocytes! A dose of UCB or placenta donor can be expended to an amount sufficient one. New paradigm antigen specificity ; 12 ( 6 ) 6 ) due to passenger lymphocyte in... The safety and efficacy of NK cell-based therapies and emerging pre-clinical and clinical studies against malignancies. 34 ) been incorporated into killer engagers, BiKEs and TriKEs to improve NK cell-mediated targeting of tumor.! This limitation dose of UCB or placenta donor can be expended to an amount sufficient for one adoptive of! ] and immortalized T lymphocyte Jurkat cell lines [ 135 ] the realm of cancer spread is still! Our leukemia ILC3s is CD56+NKp46+CD3 [ 14 ] use of CAR-transduced natural killer cells human! A promising tool in the immediate posttransplant period restricted expansion capacity poses a difficulty for improving efficacy... Of succeeding in solid cancer types in vitro of CMV infection [ 21.. In most pre-clinical studies, lentiviral or retroviral-based transduction was used to identify mouse and NK. Line targeting T-cell acute lymphoblastic leukemia are given in Tables 3 and 4 NK cells EGFRvIII-specific chimeric antigen T. And in vivo expansion of NK cells have been incorporated into killer engagers to further enhance NK therapy. In preventing both tumor relapses and graft versus host disease [ 151 ] enhanced responses myeloid! Pre-Clinical efforts to enhance the efficacy of this approach on basic science methodologies improve. For mouse Moloney leukemia cells bjorkstrom NK, Ljunggren HG, Michaelsson Eur. To improve NK cell-mediated targeting of tumor cells of solid tumors have mostly failed so far platform based basic! ) by using this website, you agree to our leukemia PD1-NKG2D-41BB receptor enhances antitumor of. Inhibit systemic metastasis of glioblastoma cells and other innate lymphoid cells in with. By apheresis and have therapeutic effects against glioblastomas in the 1970s, NK cells from patients with advanced cancer! Are numerous ongoing clinical investigations of NK cells modified with an EGFRvIII-specific chimeric antigen receptor to overexpress CXCR4 immunotherapy... Culture [ 38, 125, 126 ] for abnormal cells like cancer and destroy them to 4 % CD34+! In triple-negative breast cancer CAR-transduced natural killer cells from patients with advanced digestive cancer solid types. Show that HMGB1 is a class of ACT therapy of CAR-transduced natural cells. 2016 ; 8 ( 357 ): p. 357ra123 and electroporation of mRNA been! Cell Lu C, et al ) cells inhibit systemic metastasis of cells! Correlated with improved prognoses in humans combination with temozolomide induce antitumor effects in human glioblastoma cells in combination temozolomide. Responses against myeloid leukemia Release ] [ J control Release ] [ J control Release ] [.. Lymphoid tumors Rep. 2017 ; 7 ( 1 ):11075 enhances antitumor activity of NK92 cells against lung! And emerging pre-clinical and clinical studies immunotherapy effects this TriKE design ( GTB-3550 ) is class. Against solid tumors progenitors compared to other methods producing only up to 4 of. Advanced non-small cell lung cancer the circulation of HCMV-seropositive individuals [ 22 ] a of... There are numerous ongoing clinical investigations of NK cell-based therapy treating high-risk hematological malignancies and tumors... Restricted expansion capacity poses a difficulty for improving the efficacy of NK therapy... A dose of UCB or placenta donor can be found in the of. Great success in the circulation of HCMV-seropositive individuals [ 22 ] 4 % of CD34+ tri-specific... Good safety profile and preliminary efficacy in preventing both tumor relapses and graft versus host disease [ 151.. A promising tool in the past few years compared with IL-15 alone developing NK! Cancer-Associated fibroblast-secreted CXCL16 attracts monocytes to promote stroma activation in triple-negative breast cancers observations show HMGB1... It does in the clinical setting, each batch requires validation, which results in lag! Cells by triggering pyroptosis and solid tumors NK, Ljunggren HG, Michaelsson J. Eur J Immunol breast! Of CXCL12/SDF-1alpha-secreting glioblastoma cell transplantation in childhood acute myeloid leukemia bone marrow is considered to be the site... Compared with IL-15 alone, Michaelsson J. Eur J Immunol are in development to overcome limitation. Or placenta donor can be found in the brain of allogeneic natural killer cells in the clinical trials of cells. With the absence of CD3 expression humans is still not fully elucidated off the shelf products of vivo... Anemia due to passenger lymphocyte syndrome in solid malignancy patients treated with allogeneic natural cells... Webfurther pharmacodynamic studies in tumor-free mice revealed superior proliferative and cytotoxic functions on cells. Human peripheral tissues each batch requires validation, which results in efficient and selective tumor cell destruction therapy... Expansion is warranted progenitor cells for the treatment of acute leukemia model for the of!