et al. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Masuyama et al. NK cell-based cancer immunotherapy: from basic biology to clinical development. Immunobiology. PubMed Central 2009;69(9):40107. 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. Cytokine-free directed differentiation of human pluripotent stem cells efficiently produces hemogenic endothelium with lymphoid potential. 2013;4:101. 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. Stimulating antibodies is typically used along with irradiated allogeneic PBMC to further promote NK activation and expansion. Transcription factors involved in the regulation of natural killer cell development and function: an update. Cell Stem Cell. 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). Mol Ther Oncolytics. Eur J Immunol. Skeate R, et al. Ruggeri L, et al. It is widely used as an agent to combat solid tumors including lung, colorectal, gastric, gynecologic, and other types of cancer. Cerwenka A, Lanier LL. 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 2017;8:87. 2B4 costimulatory domain enhancing cytotoxic ability of anti-CD5 chimeric antigen receptor engineered natural killer cells against T cell malignancies. Currently, strategies vary depending on the clinical setting and source of cells. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. Liu E, et al. Bone marrow is considered to be the primary site of NK development. It has been proposed that CAR-NK cells may be able to be combined with T cell-based therapies for solid tumors [77]. Anticancer Res. Article 1985; 161(6): 146482. Lee J, et al. 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]. There has been an explosion of NK-based immunotherapies in pre-clinical development and clinical development. 2000;356(9244):17959. This approval was based on clinical study demonstrating that oNKord improves survival in year 1 of 80% vs. 35% in the control arm. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. 2015;194(7):320112. Blood Transfus. 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]. North J, et al. Chabannon C, et al. Cancer Res. WebThis button displays the currently selected search type. DNAM1 and 2B4 costimulatory domains enhance the cytotoxicity of anti-GPC3 chimeric antigen receptor-modified natural killer cells against hepatocellular cancer cells in vitro. J Immunol Res. 2015;17(11):158293. Targeting T-cell malignancies using anti-CD4 CAR NK-92 cells. Fehniger TA, et al. 2013;15(10):1297306. 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. In solid tumors, both autologous and allogeneic NK cells have demonstrated potential efficacy. Stem Cells Transl Med. T cells equipped with CARs have been shown to provide clinical benefit for patients with select liquid cancers. Choi YH, et al. Li Y, et al. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. 2002;100(4):126573. Using irradiated autologous PBMCs and anti-CD16 mAb, Lee et al. Many efforts are emerging for developing and engineering NK cell-based cancer immunotherapy. Recent evidence has challenged this model and suggests a possibility of more branched development in the form of both CLPs and common myeloid progenitors (CMPs) giving rise to NK cell progenitors. The mechanism of CTV-1-mediated NK priming is unclear. 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. 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]. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. 2012;7(1):e30264. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. Zhang P, et al. A simple method for in vitro preparation of natural killer cells from cord blood. 1975; 16(2): 21629. 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]. Huang Y, et al. Application of small molecule CHIR99021 leads to the loss of hemangioblast progenitor and increased hematopoiesis of human pluripotent stem cells. further pioneered the use of NK cells in non-transplant settings. J Immunother Cancer. 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]. In one study, Ng 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. PLoS ONE. Vasu S, et al. CAS WebPhysiological barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles to Chimeric antigen receptor T (CAR-T) cell therapy. 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. Typically, a dose of UCB or placenta donor can be expended to an amount sufficient for one adoptive transfer procedure. Transfusion. 2014;28(4):91727. Human NK cell development: one road or many? Front Immunol. Effective against blood cancers, natural killer cells also may be effective against solid tumors. Dhar P, Wu JD. They act as Mol Ther. Lee et al. NK cells in the tumor microenvironment Conventional roles of NK cells in immunity Detection of aberrant cells by NK cells is determined by the intergradation of Biol Blood Marrow Transpl. Liu B, 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). Childs RW, Berg M. Bringing natural killer cells to the clinic: ex vivo manipulation. Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic acid allogeneic tumors. 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]. WebChapters cover advances in immunotherapeutic strategies, in particular, the use of NK cells with and without T-cell therapy in the treatment of cancer. Lopez-Soto A, et al. Activation of NK cell cytotoxicity. 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. PubMed NK cells, which were discovered almost 50 years ago, can defend against tumors in most tissues without requiring detection of specific tumor antigens. Carlsten M, et al. MUC1-specific CAR-pNK therapy presented good safety profile and preliminary efficacy in preventing both tumor relapses and graft versus host disease [151]. Chang YH, et al. Zhang C., et al. 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. Siegler U, et al. Specificity and distribution according to genotype. Cytokines in clinical cancer immunotherapy. Despite promising results shown in hematologic tumors, immunotherapies for the treatment of solid tumors have mostly failed so far. We want to do better, and this NK cell therapy is a promising Most NK cells in the blood are CD56dim, whereas the CD56bright subset only represents less than 15% of total circulating NK cells [17]. Stem Cells. 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. Lee HR, et al. The ability of Natural Killer (NK) cells to kill tumor targets has been extensively studied in various hematological malignancies. 1981;41(11 Pt 1):44205. Am J Cancer Res. Sci Rep. 2015;5:11483. Nat Rev Immunol. Efforts are still ongoing to identify the most optimal cytokine combination for NK cell expansion. Lotze MT, et al. PubMed The conventional linear model suggests that mature NK cells arise from common lymphoid progenitors (CLPs) by progressing through a linear continuum [24]. The NKG2D-2B4 containing CAR-NK had elevated Syk and Erk1/2 phosphorylation [42]. 2019;7(3):36375. They are also summarized in Table 2. 2017;77(20):566475. 2015;13:277. J Immunol. Mol Med Rep. 2019;20(3):282331. Granzin M, et al. Fujisaki H, et al. Br J Haematol. Targeting immunosuppressive components in the TME to re-invigorate NK functions is also under investigation. Efficient mRNA-based genetic engineering of human NK cells with high-affinity CD16 and CCR7 augments rituximab-induced ADCC against lymphoma and targets NK cell migration toward the lymph node-associated chemokine CCL19. Oyer JL, et al. Short-term (1820h) pre-activation with ALT-803 augmented cytotoxicity and ADCC of NK cells in vitro. Ueda T, et al. Source: Liu, S., Galat, V., Galat4, Y. et al. 2015;38(1):2436. Eur J Cancer. 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. Imai K, et al. WebHappy New Year to you! 2020;111(5):147890. The natural cytotoxic receptor NKp46 is also often used to identify mouse and human NK cells in combination with the absence of CD3 expression. Google Scholar. NKp44-NKp44 ligand interactions in the regulation of natural killer cells and other innate lymphoid cells in humans. 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. Natural killer cells: development, maturation, and clinical utilization. WebValuable industry experience focuses on understanding NK cells biology and contributing to develop an immuno oncology platform based on off the shelf products. Nat Rev Immunol. Lanier LL, et al. Stem Cell Reports. 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. 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]. J Immunol. Cichocki F, Grzywacz B, Miller JS. Heinze, A., et al. California Privacy Statement, 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]. 1986;137(9):27359. Ex vivo activation and expansion of natural killer cells from patients with advanced cancer with feeder cells from healthy volunteers. PubMed Central Clinical evaluation of safety and efficacy of NK cells under this expansion is warranted. Natural killer (NK) cells inhibit systemic metastasis of glioblastoma cells and have therapeutic effects against glioblastomas in the brain. Handgretinger R, Lang P, Andre MC. 2016;5(9):e1219007. Article Methods Mol Biol. NK cells engineered to express a GD2 -specific antigen receptor display built-in ADCC-like activity against tumour cells of neuroectodermal origin. 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 Front Immunol. Curr Opin Immunol. Koehl U, et al. Patients with advanced malignant solid tumors, histologically or cytologically confirmed, who had failed standard therapy, or had no standard therapy, or were not Correction to: IL-27 enhances IL-15/IL-18-mediated activation of human natural killer cells. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. 2014;32(4):102131. Early clinical trials have demonstrated the overall safety of NK cell infusion, even in the allogeneic setting [4,5,6,7]. Membrane bound IL-21 based NK cell feeder cells drive robust expansion and metabolic activation of NK cells. Colonna M. Innate lymphoid cells: diversity, plasticity, and unique functions in immunity. 2019;145(7):193545. 2017;19(2):23549. Mehta RS, Shpall EJ, Rezvani K. Cord blood as a source of natural killer cells. Gras Navarro A, et al. Ditadi A, Sturgeon CM, Keller G. A view of human haematopoietic development from the Petri dish. 2017;8:458. 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. However, CAR-T therapy has two major challenges: (i) requirement of a substantiate length of time to generate a therapeutic dose of autologous CAR-T cells which limits its feasibility to treat patients with rapidly progressing diseases; (ii) difficulty to obtain sufficient number of autologous T cells for CAR-T cell generation from heavily pre-treated and often lymphopenic cancer patients [37]. Clinicaltrials.gov currently lists over 100 clinical trials of NK cell-based cancer immunotherapy. This method was advantageous in that it did not require magnetic cell sorting, feeder cells, or multiple cytokines, potentially lowering the cost of production. PubMed The concept of adoptive NK cell cancer immunotherapy was proven a decade ago from pioneering clinical studies against hematological malignancies. Parkhurst MR, et al. CAS Parihar and colleagues designed CAR-NK cells expressing the activating receptor NKG2D as the antigen recognition to target human MDSCs. Potently cytotoxic natural killer cells initially emerge from erythro-myeloid progenitors during mammalian development. Using patient samples and murine models, the potential of NK cell therapy is being realized in the lung. Hematology Am Soc Hematol Educ Program. It yielded a greater than 1000-fold expansion of NK cells after 3weeks of culture [38, 125, 126]. Ojo EO, et al. 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. 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]. J Immunother Cancer. Retargeting of natural killer-cell cytolytic activity to ErbB2-expressing cancer cells results in efficient and selective tumor cell destruction. Jennifer Wu. 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]. CAR-NK cells are known to be effective against hematological malignancies, and a growing number of preclinical findings indicate that they have By using this website, you agree to our Part of Moreover, highly cytotoxic NK cells derived using such method are capable of producing endogenous cytokines that improve their survival, proliferation, and function [132]. Uherek C, 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 Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. 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. This method resulted in a 1,560-fold expansion of NK cells with a purity of 92.37% after 21days of ex vivo culture[107]. Geller MA, et al. This TriKE design (GTB-3550) is currently in clinical trial for treating high-risk hematological malignancies (NCT03214666). Distinctly different from T cell receptors, NK cell receptors are germline-encoded and hard-wired receptors without a requirement for V(D)J recombination. Sakamoto In a xenograft mouse model of lymphoma, co-administration of ALT-803 with NK cells significantly enhanced anti-CD20-triggered, NK cell-mediated ADCC effects [83]. Rezvani K, et al. Cancer Immunol Immunother. The broad spectrum of human natural killer cell diversity. The safety of NK cell-based therapy has been demonstrated in both autologous and allogeneic haploidentical settings [4,5,6,7]. Cytotherapy. Thus, feeder-free approaches are an alternative or a more desirable method to avoid safety concerns associated with the clinical application of cancer cell-derived feeder cells. Studies on the in vitro activation of Leu-11+ granular lymphocytes with a natural killer-sensitive tumor cell, K562. 2009;373(9674):155061. 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]. The IL-15-based ALT-803 complex enhances FcgammaRIIIa-triggered NK cell responses and in vivo clearance of B cell lymphomas. 3D model for CAR-mediated cytotoxicity using patient-derived colorectal cancer organoids. In summary, NK cells are functional in tumor surveillance and can be manipulated by artificial activation techniques to present a highly effective anticancer tool against hematopoietic malignancies and, dependent on successful further rearming and mobilization, against solid tumors in the future. The feasibility of utilizing allogeneic NK cells, the established safety profiles, and the fast-acting nature of NK cells largely have led to the emerging effort to develop off-the-shelf NK cell-based cancer immunotherapy. Kang L, et al. Cancer Immunol Res. 2013;73(6):177786. Adoptive transfer of autologous natural killer cells leads to high levels of circulating natural killer cells but does not mediate tumor regression. It is iPSC-differentiated NK cells (iPSC-NK). However, a more complex scenario has recently emerged. However, several studies have shown that intratumoral NK cells can also be associated with increased survival ( 6 Hum Gene Ther. WebChimeric antigen receptor T cells therapy (CAR-T therapy) is a class of ACT therapy. Hassan R, Ho M. Mesothelin targeted cancer immunotherapy. 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. 1999;94(1):3339. Block copolymer-boron cluster conjugate for effective boron neutron capture therapy of solid tumors. CAR-engineered NK cells targeting wild-type EGFR and EGFRvIII enhance killing of glioblastoma and patient-derived glioblastoma stem cells. This method has achieved over 15% of CD34+ hematopoietic progenitors compared to other methods producing only up to 4% of CD34+. Sci Rep. 2020;10(1):2815. PubMed Front Immunol. J Transl Med. Methods Mol Biol. PubMedGoogle Scholar. Am J Cancer Res. Esser R, et al. Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. 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]. Production Process of CAR-NK J Exp Med. Continuously expanding CAR NK-92 cells display selective cytotoxicity against B-cell leukemia and lymphoma. The integration and balance of the activating and inhibitory signals from the ligand/receptor interactions dictates the status of NK cell activation. 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]. 2018;23(2):181-192.e5. However, NK cell therapy 2015;6:368. 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). Oncoimmunology. Genetically engineered CAR NK cells display selective cytotoxicity against FLT3-positive B-ALL and inhibit in vivo leukemia growth. 2005;42(4):50110. Sizhe Liu, Vasiliy Galat, Yekaterina Galat, Yoo Kyung Annie Lee, Derek Wainwright, and Jennifer Wu wrote and reviewed the manuscript. Beyond engineering and priming NK cells, there are ongoing efforts toward improving tumor infiltration of adoptively transferred NK cells by modifying the chemokinechemokine receptor axis. Nat Commun. 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. 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 NK cells possess advantageous characteristics, including non-MHC-restricted recognition, ability to infiltrate There are numerous ongoing clinical trials exploring the safety and efficacy of NK-based therapy in combination with other modalities. Kim EK, et al. Cancer Cell. Nat Rev Immunol. 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]. Highly efficient IL-21 and feeder cell-driven ex vivo expansion of human NK cells with therapeutic activity in a xenograft mouse model of melanoma. Expression of IL-15 in NK cells results in rapid enrichment and selective cytotoxicity of gene-modified effectors that carry a tumor-specific antigen receptor. Such ability to alter the course of differentiation opens a possibility to pursue resident or organ-specific phenotypes of NK cells. The release criteria should be developed with unique signature to distinguish the feeder cells from expanded NK cells to ensure no feeder cell contamination. Han J, et al. WebFirst described in the 1970s, NK cells have been a promising tool in the field of adoptive immunotherapy ( 34 ). NK Cells of the Lung Provided by the Springer Nature SharedIt content-sharing initiative. Front Immunol. WebTargeting TROP2 and HER3: Perspective on the Next Precision Treatment Advances Across Solid Tumors. Li Y, et al. PubMed Article 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. Purinergic targeting enhances immunotherapy of CD73(+) solid tumors with piggyBac-engineered chimeric antigen receptor natural killer cells. Cytokine-mediated activation is frequently employed and currently under extensive investigation. J Immunother. WebCancer immunotherapy has achieved great success in the past few years. In 2005, it was reported that haploidentical allogeneic NK cells 2011;6(6):e20740. Exposure of NK to unmodified NK cell-sensitive leukemia cells (K562) stimulates expansion and short-term proliferation [133]. Challenges in CAR NK cell therapy in solid tumors. 2004;24(3b):186171. NK cells are a key member of the innate immune system, and while they have some similarities to cytotoxic T lymphocytes (CTLs) in term of killing features, they have an extra intrinsic capability to detect and kill transformed/mutant cells independent of specific antigen recognition processes indicating MHC-unrestricted cytotoxicity done with EMBO J, 2019; 38(12). 2017;8(68):11278396. 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]. Oelsner S, et al. Advances in clinical NK cell studies: donor selection, manufacturing and quality control. NK CELL-BASED THERAPY IN SOLID. 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. Google Scholar. Leukemia. Chen X, et al. PubMed Muller S, et al. 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]. Tang X, et al. An antibody designed to improve adoptive NK-cell therapy inhibits pancreatic cancer progression in a murine model. BMC Cancer. demonstrated that antibody-mediated blockade of CD73 significantly enhanced the anti-tumor activities of NKG2D-enginneered CAR-NK92 in vitro and in vivo, with improved tumor infiltration by CAR-NK cells in vivo [43]. In vivo efficacy of umbilical cord blood stem cell-derived NK cells in the treatment of metastatic colorectal cancer. Felices M, et al. It was shown that the hMesothelin-CAR-NK cells containing the shared native NK cell signaling molecule, such as NKG2D-2B4, exhibited superior in vitro and in vivo anti-tumor activities in comparison with which contains CD28-CD137 [42]. Webfirst described in the regulation of natural killer cells and source of cells simple method for in vitro of! On NK cells with therapeutic activity in a murine model and contributing to an!, Lee et al glioblastomas in the field of adoptive immunotherapy ( 34 ) donor can expended... 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