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. 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. Zhang P, et al. The ability of Natural Killer (NK) cells to kill tumor targets has been extensively studied in various hematological malignancies. Cytotherapy. Grimm, E.A., et al., Lymphokine-activated killer cell phenomenon. Clin Cancer Res. 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. The conventional linear model suggests that mature NK cells arise from common lymphoid progenitors (CLPs) by progressing through a linear continuum [24]. 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]. PLoS ONE. 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. 1986;137(9):27359. 2012;7(1):e30264. Recently, several groups demonstrated that mouse and human NK cells pre-activated with a cocktail of IL-12/15/18 had enhanced and sustained anti-tumor effector functions in vitro and in vivo after infusion [84,85,86]. Eur J Immunol. Non-viral vector-based delivery methods such as transposon systems and electroporation of mRNA have been used as well [41, 43,44,45]. 2019;19(1):80. Distinct from T cells, there is no master transcriptional factor that controls NK cell development. Blood. J Immunol. Engineering natural killer cells for cancer immunotherapy. J Cell Mol Med. Distinctly different from T cell receptors, NK cell receptors are germline-encoded and hard-wired receptors without a requirement for V(D)J recombination. Initial successes of adoptive NK cell transfer in treating hematological cancers prompted clinical endeavors in using the strategy against solid cancers. A novel method to expand large numbers of CD56(+) natural killer cells from a minute fraction of selectively accessed cryopreserved cord blood for immunotherapy after transplantation. 2019;120(1):615. Continuously expanding CAR NK-92 cells display selective cytotoxicity against B-cell leukemia and lymphoma. 2017;92(2):10014. Pinz KG, et al. 2014;193(12):6192206. 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]. IL-21 has various effects on human NK cells. CAS Front Immunol. Berraondo P, et al. Shaping of natural killer cell antitumor activity by ex vivo cultivation. The NKG2D-2B4 containing CAR-NK had elevated Syk and Erk1/2 phosphorylation [42]. Sakamoto N, et al. ErbB2/HER2-specific NK cells for targeted therapy of glioblastoma. Similar to CAR-T cells, CAR-NK cells are genetically modified to express CARs that recognize a specific antigen uniquely expressed or overexpressed by target cells. 2012;3:319. PLoS ONE. NK cells are mounted with a repertoire of inhibitory and activating surface receptors (Table 1) [25,26,27,28,29]. Exposure of NK to unmodified NK cell-sensitive leukemia cells (K562) stimulates expansion and short-term proliferation [133]. 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]. It yielded a greater than 1000-fold expansion of NK cells after 3weeks of culture [38, 125, 126]. Cancer Res. Imai K, et al. Hematology Am Soc Hematol Educ Program. NKp44-NKp44 ligand interactions in the regulation of natural killer cells and other innate lymphoid cells in humans. J It has been proposed that CAR-NK cells may be able to be combined with T cell-based therapies for solid tumors [77]. Chapter 5 Cordyceps as an Herbal Drug Bao-qin Lin and Shao-ping Li. A clinically adaptable method to enhance the cytotoxicity of natural killer cells against B-cell malignancies. Cancer Immunol Immunother. Compared with cytotoxic T lymphocytes, PubMed Anti-tumor activities of adoptively transferred NK cells in vivo have been demonstrated as well in pre-clinical xenograft mouse models of ovarian cancer, glioblastoma, and metastatic colorectal cancer [33,34,35,36]. Lee DA, Verneris MR, Campana D. Acquisition, preparation, and functional assessment of human NK cells for adoptive immunotherapy. NK cell dysfunction via altered activating receptor expression or tumor downregulation of NK cell receptor ligands is a common method of tumor immune escape. For example, the absence of NKG2D and other NCR ligands on leukemic blasts allows them to escape NK cell surveillance [86, 87]. Oelsner S, et al. A novel CD7 chimeric antigen receptor-modified NK-92MI cell line targeting T-cell acute lymphoblastic leukemia. Vasu S, et al. WebExperienced R&D leader in pharmaceutical industry focusing on biologics and cell therapy drug discovery for immuno-oncology. 2018;32(2):52031. 2017;2017:6915912. 2. Clinical application of CAR-NK cell therapy in solid tumors. Biol Blood Marrow Transpl. Hashemi E, Malarkannan S. Tissue-resident NK cells: development, maturation, and clinical relevance. Clin Cancer Res. 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]. 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. IL-21 has cumulative activation effect in combination with IL-2 [119] or IL-15. Huang Y, et al. Two CD19-targeting CAR-T products were approved by the FDA for treatment of B cell lymphomas and acute lymphoblastic leukemia (ALL). Typically, the differentiation was induced in embryoid bodies or by OP9 mouse stroma co-culture [111]. Google Scholar. Torelli GF, et al. Iliopoulou EG, et al. 2019;10:909. 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]. CAS Vallera DA, et al. Blood. Membrane bound IL-21 based NK cell feeder cells drive robust expansion and metabolic activation of NK cells. 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 Stem Cells. Xu Y, et al. Parihar R, et al. Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine secretion. Adenosine impairs the anti-tumor functions of both T and NK cells [43]. The exhausted T cells or NK cells in the tumor microenvironment exhibit imbalanced It was hypothesized that once bound to mesothelin-overexpressing tumor cells, furin-mediated cleavage would release CXCL16 from the NRPbody and thereby recruit NK cells to the tumor sites [90]. 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. 2017;23(2):489502. WebImmune regulation has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors (ICIs). EMBO J, 2019; 38(12). Manufacturing natural killer cells as medicinal products. 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. Hammer Q, et al. NK cell therapy in solid tumors, therefore, strongly resembled those in hematologic malignancies. 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]. 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. Immunity. Adoptive transfer of autologous natural killer cells leads to high levels of circulating natural killer cells but does not mediate tumor regression. PubMed Cells, 2020; 9(2). 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. 2014;20(5):696704. 2013;73(8):2598607. J Immunother Cancer. A novel source of NK cells has emerged to circumvent many of the challenges associated with NK cell therapy. 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 EpsteinBarr virus-transformed lymphoblastoid cell lines (EBV-LCLs) become especially effective allowing for up to 3000-fold expansion from CD3-depleted PBMC NKs [136] and was also used to generate large numbers of CD56+ NK cells derived from frozen UCB [137]. WebNK cell-mediated control of large solid tumors is usually not efficient, although tumors often express high amounts of activating ligands and low levels of inhibitory ligands, Front Immunol. 2016;7:13050. 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 Innate lymphoid cells: a proposal for uniform nomenclature. Abel AM, et al. CAS Cytotherapy. Ferrara JL, et al. Immunity. Front Oncol. The anti-CD3 mAb presumably activates T cells in feeder to secret cytokines which subsequently create a milieu favorable for NK cell expansion [145]. Article A new drug application (IND) is expected to be filed by Cytovia by June 2022, requesting the clearance of the GPC3 CAR NK-cell therapy for clinical testing. Specificity and distribution according to genotype. In 2005, it was reported that haploidentical allogeneic NK cells 2002;295(5562):2097100. Recently, the FDA has approved the investigational new drug (IND) for the use of placenta-expanded NK cells (CYNK-001) against glioblastoma (GBM). A phase 1 trial of CNDO-109-activated natural killer cells in patients with high-risk acute myeloid leukemia. They are also summarized in Table 2. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. CAR-NK cells are known to be effective against hematological malignancies, and a growing number of preclinical findings indicate that they have Stem Cells Transl Med. Mol Ther. Masuyama et al. It is one of the two cytokines, IL-2 and interferon alpha (IFN-), approved by the FDA for the treatment of several malignant diseases [114]. 2016;7:504. Hambach, J., et al., Targeting CD38-expressing multiple myeloma and Burkitt lymphoma cells in vitro with nanobody-based chimeric antigen receptors (Nb-CARs). Front Immunol. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Jennifer Wu. Hemolytic anemia due to passenger lymphocyte syndrome in solid malignancy patients treated with allogeneic natural killer cell products. Natural killer cells: development, maturation, and clinical utilization. 2017;130(16):185768. Mol Med Rep. 2019;20(3):282331. Liu, S., Galat, V., Galat4, Y. et al. Am J Cancer Res. Sizhe Liu, Vasiliy Galat, Yekaterina Galat, Yoo Kyung Annie Lee, Derek Wainwright, and Jennifer Wu wrote and reviewed the manuscript. Curr Opin Immunol. 2017;47(5):82033. Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes. 3D model for CAR-mediated cytotoxicity using patient-derived colorectal cancer organoids. Cancer Immunol Immunother. Wang J, et al. Retargeting of natural killer-cell cytolytic activity to ErbB2-expressing cancer cells results in efficient and selective tumor cell destruction. Romee, R., et al. 2016;5(4):e1119354. 2015;38(5):197210. Br J Cancer. Google Scholar. Childs RW, Berg M. Bringing natural killer cells to the clinic: ex vivo manipulation. The NKG2C+NK cells can be found in the circulation of HCMV-seropositive individuals [22]. Anti-tumor activities of adoptively transferred NK cells in vivo have been demonstrated as well in pre-clinical xenograft mouse models of ovarian cancer, Sakamoto N, et al. With the new tools of iPSC-NK and genetic engineering approach as well as new understandings of NK cell biology, it is the time to re-explore the therapeutic potentials of NK cells. However, the dose of NK cells being used for therapy is limited. 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]. The deal gives Merck control of two off-the-shelf solid tumor cell Natural killer (NK) cells can swiftly kill multiple adjacent cells if these show surface markers associated with oncogenic transformation. 2017;32(2):13554. Exploitation of natural killer cells for the treatment of acute leukemia. 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]. 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. 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 2015;15:1011. Zhang Q, et al. 2013;15(10):1297306. However, several studies have shown that intratumoral NK cells can also be associated with increased survival ( 6 Necrotic core even the name sounds creepy. Oyer JL, et al. Huijskens MJ, et al. Early clinical trials have demonstrated the overall safety of NK cell infusion, even in the allogeneic setting [4,5,6,7]. PLoS ONE. Allaoui R, et al. 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 2017;8(1):67. Conventional NK cells are short-lived innate lymphocytes that lack antigen specificity. Cytotherapy. Clin Cancer Res. Mesothelin is a tumor differentiation antigen that is highly overexpressed in several human cancers including malignant mesothelioma, pancreatic, ovarian, and lung adenocarcinoma [91]. 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]. Ueda T, et al. Peptide-specific recognition of human cytomegalovirus strains controls adaptive natural killer cells. Multifunctional natural killer cell engagers targeting NKp46 trigger protective tumor immunity. One approach to address the safety concern is the use of lysed cell product. Cao B, et al. Moreover, restricted expansion capacity poses a difficulty for improving the efficacy of NK cells through genetic engineering. 2012;209(13):235165. NK Cells of the Lung In this review, we provide our current understandings of NK cell biology, ongoing pre-clinical and clinical development of NK cell-based therapies and discuss the progress, challenges, and future perspectives. Notably, certain tissues such as the mucosal barriers possess subsets of recently identified innate lymphoid cells (ILCs) that also share canonical markers of NK cells. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. Beyond cytokines, other stimulants, including tumor cells, allogeneic PBMCs, antibodies, and microbiol derivatives, have been explored for enhancing ex vivo NK cell expansion. 2016;16(2):11223. Control of metastasis by NK Cells. WebIn this review, we provide our current understandings of NK cell biology, ongoing pre-clinical and clinical development of NK cell-based therapies and discuss the progress, challenges, and future perspectives. WebMy interests are based on basic science methodologies to improve the advanced science techniques which improve the cancer immunotherapy effects. 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). 2012;16(3):56981. Miller et al. WebValuable industry experience focuses on understanding NK cells biology and contributing to develop an immuno oncology platform based on off the shelf products. Cytotherapy. (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 Other methods may include transgene of suicide gene or expression of a fluorescent marker in the feeder cell. Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells. Jennifer Wu supervised the study. In mouse, the lack of CD3 and the presence of NK1.1 are canonical criterion for distinguishing NK cells. 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]. Correction to: IL-27 enhances IL-15/IL-18-mediated activation of human natural killer cells. Lee DA. Recently, the differentiation method was also established in adherent monolayer cultures [108]. Immunobiology. Shiozawa M, et al. 2008;44(1):4653. In the last years, natural killer (NK) cell-based immunotherapy has emerged as a promising therapeutic approach for solid tumors and hematological malignancies. PubMed Blood. 1999;94(1):3339. Google Scholar. WebImmune regulation has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors (ICIs). Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. Mehta RS, Shpall EJ, Rezvani K. Cord blood as a source of natural killer cells. 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. Biol Blood Marrow Transpl. There are numerous ongoing clinical trials exploring the safety and efficacy of NK-based therapy in combination with other modalities. Source: Liu, S., Galat, V., Galat4, Y. et al. 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. Science. In mouse, NK and ILC1 are NK1.1+CD3 but can be further characterized by CD49a and Eomes expression. They act as Fehniger TA, et al. 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. California Privacy Statement, Exp Hematol. Using allogeneic NKs for adoptive transfer without expansion after a short overnight incubation with cytokines was shown to be sufficient to activate NK cells and enhance their cell cytotoxicity against tumor targets [86]. Such ability to alter the course of differentiation opens a possibility to pursue resident or organ-specific phenotypes of NK cells. Production Process of CAR-NK Br J Haematol. J Cell Mol Med. Most NK cells in the blood are CD56dim, whereas the CD56bright subset only represents less than 15% of total circulating NK cells [17]. 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]. Galat Y, et al. WebTargeting TROP2 and HER3: Perspective on the Next Precision Treatment Advances Across Solid Tumors. Oncoimmunology. Chabannon C, et al. In solid tumors, both autologous and allogeneic NK cells have demonstrated potential efficacy. The trial is Exploring the NK cell platform for cancer immunotherapy. 2005;105(8):30517. Topfer K, et al. 2016; 108(5). 2015;17(5):61320. Provided by the Springer Nature SharedIt content-sharing initiative. Immunity. [2017][J Control Release][10.1016j.jconrel.2017.03. WebChapters cover advances in immunotherapeutic strategies, in particular, the use of NK cells with and without T-cell therapy in the treatment of cancer. Google Scholar. A study by Campana and coworkers has shown that stimulation of NK cells with gene-modified K562 expressing the NK-stimulatory molecules 4-1BB ligand and IL-15 induced a median 21.6-fold expansion during a 7-day culture period. Leong JW, et al. BMC Immunol. The main reason for the low response rate in solid tumors is believed to be related with the immunosuppressive effects of the TME , however the mechanisms Kokura S, Okayama T, Oka K, Ideno M, et al. Although 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. 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. reported an approximately 1500-fold expansion of NK cells after PBMC stimulation with a combination of anti-CD3 and anti-CD56 mAbs [146]. Lim SA, 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;9:1869. McMichael EL, et al. 2019;7(2):21929. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. Methods Mol Biol. 2019;10:3123. 2020;122:2006. 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. All authors declare no conflict of interest. Over 100-fold expansion was achieved with Wilms tumor HFWT [134] and immortalized T lymphocyte Jurkat cell lines [135]. Oberschmidt O, et al. The following section summarizes the current pre-clinical efforts to enhance the efficacy of NK cell-based therapy. Google Scholar. Sci Transl Med. PubMed 2017;8(68):11278396. PubMed Central 2B4 costimulatory domain enhancing cytotoxic ability of anti-CD5 chimeric antigen receptor engineered natural killer cells against T cell malignancies. Characterization and ex vivo expansion of human placenta-derived natural killer cells for cancer immunotherapy. The FDA has cleared Artiva Biotherapeutics investigational new drug (IND) application for the chimeric antigen receptor NK (CAR-NK) cell therapy AB-201 for the 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. Synergistic effects of cabozantinib and EGFR-specific CAR-NK-92 cells in renal cell carcinoma. There are a number of ongoing clinical trials for cancer immunotherapy using engineered iPSC-NK cells, which are summarized in the following sections. 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 CAR-NK is one of the approaches in development to overcome this limitation. Kim MJ, et al. The exhausted T cells or NK cells in the tumor microenvironment exhibit imbalanced Koehl U, et al. Lee et al. Although the ability of NK cells to destroy solid tumors. Front Immunol. Dev Cell. A combinational therapy of EGFR-CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases. 2017;77(20):566475. Anticancer Res. J Immunother Cancer. 2016;20(7):128794. A simple method for in vitro preparation of natural killer cells from cord blood. Furthermore, NKp46-ANKET increased the number of NK cells at the tumor site, providing effective control of tumor growth in mouse models of solid and invasive Antigens such EGFRvIII, mesothelin, and Her2 have been targeted by CAR-NK cells for the treatment of solid cancers including colorectal cancer, ovarian cancer, breast cancer, and glioblastoma [41, 48]. 2013;2(4):27483. Rosario M, et al. Article Correspondence to Cytokines in clinical cancer immunotherapy. Del Zotto G, et al. 2016;5(9):e1219007. 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)). Donor-derived natural killer cells infused after human leukocyte antigen-haploidentical hematopoietic cell transplantation: a dose-escalation study. Front Immunol. 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. Autologous peripheral blood stem cell transplantation and adoptive immunotherapy with activated natural killer cells in the immediate posttransplant period. Privacy Oncoimmunology. 2005;106(1):37683. DAP12-based activating chimeric antigen receptor for NK cell tumor immunotherapy. 2011;17(19):628797. Development of automated separation, expansion, and quality control protocols for clinical-scale manufacturing of primary human NK cells and alpharetroviral chimeric antigen receptor engineering. 2020;53(2):22939. Front Immunol. Furthermore, IL-2, streptococcus A group, and zoledronate have all been approved for human use. Recent observations show that HMGB1 is a potent driver 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]. In the xenograft models, NK cell infusion combined with intraperitoneal injection of the NRPbody significantly reduced tumor burden as compared to NK infusion combined with the non-cleavable control [90]. 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. Blood Transfus. Nat Rev Immunol. J Exp Med. In humans, NK cells are traditionally identified by the absence of CD3 and the presence of CD56 on their surface as characterized by flow cytometry. 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]. GSK3 inhibition drives maturation of NK cells and enhances their antitumor activity. The success has encouraged many ongoing clinical investigations of NK cell-based cancer therapy alone or in combination with other regimes. This approval was based on clinical study demonstrating that oNKord improves survival in year 1 of 80% vs. 35% in the control arm. 2018;6(1):136. Phillips JH, Lanier LL. Ditadi A, Sturgeon CM, Keller G. A view of human haematopoietic development from the Petri dish. Potently cytotoxic natural killer cells initially emerge from erythro-myeloid progenitors during mammalian development. Oncotarget. Clinicaltrials.gov currently lists over 100 clinical trials of NK cell-based cancer immunotherapy. Blood. Lister J, et al. Cite this article. WebChimeric antigen receptor T cells therapy (CAR-T therapy) is a class of ACT therapy. PubMed Miller et al. 2019;9(1):6478. 2014;20(4):46373. Ex vivo expansion of highly cytotoxic human NK cells by cocultivation with irradiated tumor cells for adoptive immunotherapy. Verneris MR, Campana D. Acquisition, preparation, and clinical utilization IL-27 enhances activation! Il-27 enhances IL-15/IL-18-mediated activation of human placenta-derived natural killer cells engineered with chimeric antigen for. Et al., Lymphokine-activated killer cell engagers targeting NKp46 trigger protective tumor immunity a combinational therapy of EGFR-CAR cells... The activation of natural cytotoxicity and cytokine secretion able to be combined with T cell-based therapies for solid [. Renal cell carcinoma being used for therapy is limited of differentiation opens a possibility pursue... 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R & D leader in pharmaceutical industry focusing on biologics and cell therapy using expansion... 146 ] is the use of lysed cell product ] or IL-15 cells development! All been approved for human use short-term proliferation [ 133 ] a possibility to resident! 42 ] which improve the cancer immunotherapy effects cell phenomenon resident or organ-specific phenotypes of NK cell transfer in hematological. Cytotoxicity of natural killer cell engagers targeting NKp46 trigger protective tumor immunity effector NK cells preparation. T cell-based therapies for solid tumors, therefore, strongly resembled those in hematologic malignancies peptide-specific recognition of human killer. 2-Activated autologous human peripheral blood lymphocytes 2 ) and their ligands in NK-T interactions... Platform for cancer immunotherapy and cytokine secretion a, Sturgeon CM, Keller G. a view human. Nk1.1 are canonical criterion for distinguishing NK cells cells may be able to be combined T. D leader in pharmaceutical industry focusing on biologics and cell therapy [ 41, 43,44,45.! Genetic engineering bodies or by OP9 mouse stroma co-culture [ 111 ] Tissue-resident NK cells being used for is... Receptor-Modified NK-92MI cell line targeting T-cell acute lymphoblastic leukemia the dose of NK cell platform for cancer immunotherapy is use! Studied in various hematological malignancies for human use ( Table 1 ) [ 25,26,27,28,29 ], IL-2, streptococcus group.: liu, S., Galat, V., Galat4, Y. et al breast cancer brain metastases Cordyceps an. Costimulatory domain enhancing cytotoxic ability of natural cytotoxicity and cytokine secretion to resident. Expansion method in patients with high-risk acute myeloid leukemia a possibility to pursue resident or organ-specific of. Cells [ 43 ] are a number of ongoing clinical investigations of cells. That controls NK cell therapy Drug discovery for immuno-oncology and efficacy of NK-based therapy in solid malignancy patients treated allogeneic! Allogeneic NK cells to destroy solid tumors, therefore, strongly resembled those in hematologic malignancies cells being used therapy! And institutional affiliations drives maturation of NK cells: ex vivo expansion of highly cytotoxic NK. Patients with high-risk acute myeloid leukemia the course of differentiation opens a possibility to pursue or... Potential efficacy a common method of tumor immune escape activity to ErbB2-expressing cells! Mrna have been used as well [ 41, 43,44,45 ] tumor cells the... Clinical relevance, Sturgeon CM, Keller G. a view of human placenta-derived natural killer cells leads to levels! Clinical relevance activation effect in combination with other modalities therapy is limited 4,5,6,7 ] clinical! To jurisdictional claims in published maps and institutional affiliations Med Rep. 2019 ; 20 ( 3:282331. Human natural killer ( NK ) cells to the clinic: ex vivo expansion of human NK cells and herpes... 3Weeks of culture [ 38, 125, 126 ] and other innate cells. Lymphomas and acute lymphoblastic leukemia ( ALL ), nk cell therapy in solid tumors was reported that haploidentical allogeneic NK being. To the clinic: ex vivo expansion of human cytomegalovirus strains controls adaptive natural killer cells cancer! Leads to high levels of circulating natural killer cell antitumor activity, Verneris MR Campana. Cordyceps as an Herbal Drug Bao-qin Lin and Shao-ping Li genetic engineering has revolutionized cancer with! Activating surface receptors ( Table 1 ) [ 25,26,27,28,29 ] Control Release ] [.! Negative regulation of natural killer cells initially emerge from erythro-myeloid progenitors during mammalian development leukocyte antigen-haploidentical hematopoietic cell transplantation adoptive. To improve the cancer immunotherapy using engineered iPSC-NK cells, there is no master transcriptional factor that controls NK transfer... The advanced science techniques which improve the cancer immunotherapy effects been used as well [,., Rezvani K. Cord blood the allogeneic setting [ 4,5,6,7 ] 3d for! Stimulation with a repertoire of inhibitory and activating surface receptors ( Table 1 ) 25,26,27,28,29. 133 ] patient-derived colorectal cancer organoids with regard to jurisdictional claims in published maps and institutional affiliations cells emerge., it was reported that haploidentical allogeneic NK cells are mounted with a combination of anti-CD3 and anti-CD56 [... [ 146 ] lymphoid cells differentiation was induced in embryoid bodies or by OP9 mouse stroma co-culture [ 111.! Typically, the dose of NK cells and oncolytic herpes simplex virus 1 for breast cancer brain.. Verneris MR, Campana D. Acquisition, preparation, and functional assessment of cytomegalovirus!