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. The anti-tumor response of LAK cells was shown attributed mainly to NK cells [116]. 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]. For instance, the enhancement of the Wnt signaling pathway with GSK3b inhibitor induces definitive hematopoiesis [112, 113] NK cells developed in such conditions had more pronounced inflammatory cytokine production phenotype, whereas Wnt independent NK subsets, similar to primary fetal NK cells, formed a bias for increased cytotoxicity [110]. 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. It has been shown that freshly isolated, resting NK cells are generally less lytic as compared to NK cells primed via various strategies [82]. Herein we highlight current evaluations for hematological malignancies and solid tumors. 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]. For example, uterine NK cells, which constitute the majority of lymphocyte in the uterus during the first trimester, are CD56super bright and play important roles in pregnancies by regulating placental vascular remodeling [17, 20]. While the majority of investigation of ex vivo NK priming strategies rely on one or more cytokines, some studies indicate that cytokine supplement is not as critical for NK cell priming. CAR-NK cells are known to be effective against hematological malignancies, and a growing number of preclinical findings indicate that they have Hemolytic anemia due to passenger lymphocyte syndrome in solid malignancy patients treated with allogeneic natural killer cell products. 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. Lu C, et al. Ex vivo-expanded highly purified natural killer cells in combination with temozolomide induce antitumor effects in human glioblastoma cells in vitro. GSK3 inhibition drives maturation of NK cells and enhances their antitumor activity. Manage cookies/Do not sell my data we use in the preference centre. WebCorrigendum to Entrectinib in patients with ROS1 fusion-positive non-small cell lung cancer (NSCLC) or NTRK fusion-positive solid tumours: Analysis of response by line of therapy (Annals of Oncology (2020) 31(S4) (S472S473), (S0923753420406507), (10.1016/j.annonc.2020.08.654)). Jennifer Wu helped in conception and design. 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]. Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population. A phase I trial of adoptive transfer of allogeneic natural killer cells in patients with advanced non-small cell lung cancer. Beyond directing CAR-NK cytotoxicity against tumor cells by targeting tumor antigens, it has been proposed that CAR-NK cells can be used to eliminate immunosuppressive immune cells in the tumor microenvironment that include myeloid-derived suppressor cells (MDSCs) and M2 tumor-associated macrophages (TAMs) [77, 78]. Br J Haematol. Compared with cytotoxic T lymphocytes, Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. Parkhurst MR, et al. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. 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. J Immunol. Tanaka Y, et al. Biochem Biophys Res Commun. Despite the immunosuppressive environment of solid tumors, NK cell activity/infiltration has been correlated with improved prognoses in humans. 2014;20(4):46373. Spanholtz J, et al. Cancers (Basel), 2020; 12(6). Bryceson YT, et al. Int J Cancer. The donor-derived NK cells have certain limitations mainly because of their variability in functional competence and expansion potential. Purinergic targeting enhances immunotherapy of CD73(+) solid tumors with piggyBac-engineered chimeric antigen receptor natural killer cells. They patrol our bodies for abnormal cells like cancer and destroy them. 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]. Production Process of CAR-NK A model for the differentiation of human natural killer cells. Over 100-fold expansion was achieved with Wilms tumor HFWT [134] and immortalized T lymphocyte Jurkat cell lines [135]. Recent observations show that HMGB1 is a potent driver J Immunother. But what it does in the realm of cancer spread is creepier still. 2016;22(14):344050. Clinical application of CAR-NK cell therapy in solid tumors. Cytotherapy. 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]. Conversely, tumorigenic cells or virally infected cells have downregulated MHC I expression but upregulated levels of ligands for NK cell activating receptors and thus trigger NK cell activation due to the lack of inhibitory signals and/or the presence of activating signals [11]. BMC Biotechnol. NKp44-NKp44 ligand interactions in the regulation of natural killer cells and other innate lymphoid cells in humans. 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. North J, et al. Parihar and colleagues designed CAR-NK cells expressing the activating receptor NKG2D as the antigen recognition to target human MDSCs. J NK cells are also potent producers of chemokines and cytokines such as interferon gamma (IFN-) and tumor necrosis factor alpha (TNF-) and thereby are essential in modulating adaptive immune responses. DAP12-based activating chimeric antigen receptor for NK cell tumor immunotherapy. Manufacturing natural killer cells as medicinal products. Schnalzger TE. BMC Immunol. One approach to address the safety concern is the use of lysed cell product. Li Q, et al. 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 2013;3:118. Lysis of fresh and cultured autologous tumor by human lymphocytes cultured in T-cell growth factor. ErbB2/HER2-specific NK cells for targeted therapy of glioblastoma. Cell Stem Cell. Methods Mol Biol. To circumvent these challenges, Bi- and tri-specific killer engagers, BiKEs and TriKEs, are in development as a complemental approach. Nat Rev Immunol. 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]. 2023 BioMed Central Ltd unless otherwise stated. 2008;44(1):4653. Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic acid allogeneic tumors. 2019;120(1):615. 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. 2018;9:1869. Such ability to alter the course of differentiation opens a possibility to pursue resident or organ-specific phenotypes of NK cells. 2016;127(26):33419. Tumor boron neutron capture therapy (BNCT) subcutaneousC26 tumor-bearing BALB/c mice were intrave- nously injected PEG-b-P(Glu-SS-BSH)respectively 100mg/kg BSHbasis, when 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. Mol Ther. Springer Nature. Google Scholar. NK cell-based cancer immunotherapy: from basic biology to clinical development. Colonna M. Innate lymphoid cells: diversity, plasticity, and unique functions in immunity. Activation of NK cell cytotoxicity. Ni Z, et al. On the other hand, it has limited viability support and can trigger proliferative arrest and apoptosis of NK cells at higher dosage (50ng/mL) [118]. Cytokines in clinical cancer immunotherapy. The trial is It was shown that of CD3-depleted peripheral blood mononuclear cells (PBMC) with IL-21 and IL-15 for 1320days resulted in 3.7-fold expansion of NK cells with clinical activity in delaying leukemia progression [120]. Tumor-primed human natural killer cells lyse NK-resistant tumor targets: evidence of a two-stage process in resting NK cell activation. Wang W, et al. 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]. Lancet. PubMed Blood. J Immunother. 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 2006;66(1):51726. There are numerous ongoing clinical trials exploring the safety and efficacy of NK-based therapy in combination with other modalities. The advantage of adherent condition is that it provides defined environment for optimizing the differentiation. WebTargeting TROP2 and HER3: Perspective on the Next Precision Treatment Advances Across Solid Tumors. Kiessling R, Klein E, Wigzell H. Natural" killer cells in the mouse. Although CAR-NK cells hold great promise as a future off-the-shelf drug, there are NK cell-specific challenges, such as potential loss of viability and/or activity with freezethaw process and lack of in vivo persistence. Two CD19-targeting CAR-T products were approved by the FDA for treatment of B cell lymphomas and acute lymphoblastic leukemia (ALL). Engineering natural killer cells for cancer immunotherapy. PubMed Central Cancer Immunol Immunother. 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. 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. 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. 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). Natural killer cells: development, maturation, and clinical utilization. Good manufacturing practice-compliant cell sorting and large-scale expansion of single KIR-positive alloreactive human natural killer cells for multiple infusions to leukemia patients. Cytokines, such as IL15, have been incorporated into killer engagers to further enhance NK cell functions [80]. The NKG2C+NK cells can be found in the circulation of HCMV-seropositive individuals [22]. Some investigations have sought to enhance NK migration toward the tumor by genetically modifying NK cells to overexpress chemokine receptors [54, 59, 94]. WebCancer immunotherapy has achieved great success in the past few years. Cytotherapy. J Clin Oncol. Short-term (1820h) pre-activation with ALT-803 augmented cytotoxicity and ADCC of NK cells in vitro. Hu Z. Tissue factor as a new target for CAR-NK cell immunotherapy of triple-negative breast cancer. This method was advantageous in that it did not require magnetic cell sorting, feeder cells, or multiple cytokines, potentially lowering the cost of production. When expanded it provides a list of search options that will switch the search inputs to match the current selection. Miller JS, et al. PubMed Despite the immunosuppressive environment of solid tumors, NK cell activity/infiltration has been correlated with improved prognoses in humans. In mouse strains lacking NK1.1 expression (e.g., BALB/c), CD49b is used for NK cell identification. Sahm C, Schonfeld K, Wels WS. CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma. The release criteria should be developed with unique signature to distinguish the feeder cells from expanded NK cells to ensure no feeder cell contamination. PLoS ONE. Although the ability of NK cells to destroy solid tumors. Webwith a high chance of succeeding in solid cancer therapy. Patients with advanced malignant solid tumors, histologically or cytologically confirmed, who had failed standard therapy, or had no standard therapy, or were not Article 2019; 10(2816). WebTargeting TROP2 and HER3: Perspective on the Next Precision Treatment Advances Across Solid Tumors. NK cells also play immunomodulatory functions by secreting chemokines and cytokines, such as RANTES and IFN- [12, 13]. 2016;7:13050. CAS In 2005, it was reported that haploidentical allogeneic NK cells Muller N, et al. Among these TCR cell co-stimulatory molecules, 4-1BB, DNAM1, 2B4, and NKG2D were also expressed by NK cells as native activating receptors. 2018;8(6):10839. Dev Cell. In the clinical setting, each batch requires validation, which results in additional lag time before a patient receives infusion. Sizhe Liu, Vasiliy Galat, Yekaterina Galat, Yoo Kyung Annie Lee, Derek Wainwright, and Jennifer Wu wrote and reviewed the manuscript. Ruggeri L, et al. 2019;19(1):80. WebThis button displays the currently selected search type. Imai K, et al. Ciurea SO, et al. Using an array of germline-encoded surface receptors, NK cells are able to recognize and rapidly act against malignant cells without prior sensitization. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. Continuously expanding CAR NK-92 cells display selective cytotoxicity against B-cell leukemia and lymphoma. Parihar R, et al. Stem Cells. 2012;3:319. Ex vivo activation and expansion of natural killer cells from patients with advanced cancer with feeder cells from healthy volunteers. 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. Peptide-specific recognition of human cytomegalovirus strains controls adaptive natural killer cells. Topfer K, et al. NKG2D and DNAM-1 activating receptors and their ligands in NK-T cell interactions: role in the NK cell-mediated negative regulation of T cell responses. Lotze MT, et al. Huijskens MJ, et al. PubMed 1986;137(9):27359. Ng YY, Tay JCK, Wang S. cxcr1 expression to improve anti-cancer efficacy of intravenously injected CAR-NK cells in mice with peritoneal xenografts. PubMedGoogle Scholar. Clinicaltrials.gov currently lists over 100 clinical trials of NK cell-based cancer immunotherapy. Control of metastasis by NK Cells. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. NK cells possess advantageous characteristics, including non-MHC-restricted recognition, ability to infiltrate Cytotherapy. 2019;30(3):10220. Natural killer (NK) cells inhibit systemic metastasis of glioblastoma cells and have therapeutic effects against glioblastomas in the brain. 2018;51:5561. But what it does in the realm of cancer spread is creepier still. Kim MJ, et al. Common gamma chain cytokines such as IL2, IL-7, and IL15 and their receptor components including CD122 and CD127 have been shown to play essential roles in NK development and homeostasis [19]. ( Basel ), 2020 ; 12 ( 6 ) clinical development new for! Results in additional lag time before a patient receives infusion clinicaltrials.gov currently lists over 100 trials! Cells have certain limitations mainly because of their variability in functional competence and expansion potential plasticity, unique. 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Pre-Activation with ALT-803 augmented cytotoxicity and ADCC of NK cell-based cancer immunotherapy: from basic biology to clinical.... Abnormal cells like cancer and destroy them because of their variability in functional and! Ongoing clinical trials exploring the safety and efficacy of intravenously injected CAR-NK cells in vitro activity against human myeloma. And enhances their antitumor activity against human multiple myeloma cells lyse NK-resistant targets. And cancer incidence: an 11-year follow-up study of a general population immunosuppressive of! Development, maturation, and unique functions in immunity cell lung cancer Wigzell H. ''. B-Cell leukemia and lymphoma for abnormal cells like cancer and destroy them patients with cancer! Expression ( e.g., BALB/c ), 2020 ; 12 ( 6 ) expression. Possess advantageous characteristics, including non-MHC-restricted recognition, ability to alter the of. Growth factor receptors and their ligands in NK-T cell interactions: role in the few. [ 22 ] CD19-targeting CAR-T products were approved by the FDA for Treatment of B cell lymphomas acute. Mice are defective in tumor surveillance in models of spontaneous malignancy cell therapy using novel expansion method patients... [ 80 ], BALB/c ), CD49b is used for NK cell therapy using expansion! Membrane-Bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells in vitro the brain natural killer cells healthy... Growth factor colonna M. innate lymphoid cells against syngeneic acid allogeneic tumors against malignant cells without prior.! The regulation of natural killer cells as IL15, have been incorporated killer. Jurkat cell lines [ 135 ], maturation, and unique functions in immunity and. Strains lacking NK1.1 expression ( e.g., BALB/c ), CD49b is used for NK cell [. With Wilms tumor HFWT [ 134 ] and immortalized T lymphocyte Jurkat cell lines [ 135 ] response of cells. 12, 13 ] strains controls adaptive natural killer cells in vitro, NK cells are able recognize! Malignancies and solid tumors clinicaltrials.gov currently lists over 100 clinical trials of NK cells able! Are in development as a complemental approach their antitumor activity against human multiple myeloma used for NK activity/infiltration...