2015;13:277. 2018;32(2):52031. Blood. Front Immunol. The conventional linear model suggests that mature NK cells arise from common lymphoid progenitors (CLPs) by progressing through a linear continuum [24]. Nat Commun. Hashemi E, Malarkannan S. Tissue-resident NK cells: development, maturation, and clinical relevance. Autologous natural killer cell therapy for human recurrent malignant glioma. WebBackground Acute ischemic stroke (AIS) due to large vessel occlusion (LVO) is a devastating cerebrovascular disorder, which could benefit from collateral circulation. Kim MJ, et al. 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]. 2014;20(4):46373. WebMy interests are based on basic science methodologies to improve the advanced science techniques which improve the cancer immunotherapy effects. WebChimeric antigen receptor T cells therapy (CAR-T therapy) is a class of ACT therapy. 2010;12(6):75063. 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]. Distinctly different from T cell receptors, NK cell receptors are germline-encoded and hard-wired receptors without a requirement for V(D)J recombination. Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. Clinical-scale derivation of natural killer cells from human pluripotent stem cells for cancer therapy. Characterization and ex vivo expansion of human placenta-derived natural killer cells for cancer immunotherapy. The current in-development BiKEs or TrikEs simultaneously engage with CD16 and tumor antigens, thereby inducing the formation of immune synapses and NK-mediated ADCC [79]. To date, more than 350 Cordyceps-related species have been found worldwide based on fungus and/or insect host. Article 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 2017;25(8):176981. Upon ligation, these receptors transmit either inhibitory or activating signals to control NK activation. CAS Mol Ther. Peptide-specific recognition of human cytomegalovirus strains controls adaptive natural killer cells. This work was supported by NIH/NCI grant 1R01CA208246, 1R01CA204021, 1R01CA212409, and DOD W81XWH-15-1-0406 (to J. D. Wu). et al. Innate lymphoid cells: a proposal for uniform nomenclature. Journal of Hematology & Oncology Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. Roda JM, et al. 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]. 2016;1441:34761. 2017;47(5):82033. Front Immunol. CAS 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]. BMC Biotechnol. Block copolymer-boron cluster conjugate for effective boron neutron capture therapy of solid tumors. Lee J, et al. Zhang P, et al. NK cells possess advantageous characteristics, including non-MHC-restricted recognition, ability to infiltrate Regulatory considerations for NK cells used in human immunotherapy applications. Cancer Immunol Immunother. Early clinical trials have demonstrated the overall safety of NK cell infusion, even in the allogeneic setting [4,5,6,7]. One study showed that overnight co-incubation with a leukemia cell line CTV-1 or its lysate without cytokines was sufficient to prime potent NK cells in vitro cytotoxicity against otherwise NK-insensitive tumor cells but not normal hemopoietic cells [88]. 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]. Challenges in CAR NK cell therapy in solid tumors. 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 NK cell-based cancer immunotherapy: from basic biology to clinical development. 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. Genssler S, et al. Google Scholar. Choi I, et al. 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. 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]. Jennifer Wu helped in conception and design. Liu E, et al. Smyth MJ, et al. NK cells originate from CD34+ hematopoietic stem cells. Liu B, et al. Upon activation, NK cells release cytotoxic granules containing perforin and granzymes to directly lyse tumor cells, in a similar fashion to activated cytotoxic T cells. Torelli GF, et al. Koehl U, et al. NK cell therapy in solid tumors, therefore, strongly resembled those in hematologic malignancies. Improved killing of ovarian cancer stem cells by combining a novel chimeric antigen receptor-based immunotherapy and chemotherapy. Chen X, et al. 2017;18(9):100415. CAR-NK cell therapy is a novel immunotherapy strategy by utilizing genetically-engineered NK cells to target specific cancer, which can be both liquid and Lancet. The anti-tumor response of LAK cells was shown attributed mainly to NK cells [116]. Jennifer Wu. In mouse, the lack of CD3 and the presence of NK1.1 are canonical criterion for distinguishing NK cells. Natural killer (NK) cell is a specialized immune effector cell type that plays a critical role in immune activation against abnormal cells. The donor-derived NK cells have certain limitations mainly because of their variability in functional competence and expansion potential. They act as Nat Rev Immunol. Recent observations show that HMGB1 is a potent driver Topfer K, et al. Stem Cell Res Ther. The linear model proposes that CD56 marks a transition from immature into a more mature status and that immature CD56bright NK cells further differentiate into mature CD56dim populations in human [19, 24]. The current source and characteristics of NK cells for immunotherapies, expansion, and activation approaches are given in Tables 3 and 4. 2016;22(14):344050. 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 method was advantageous in that it did not require magnetic cell sorting, feeder cells, or multiple cytokines, potentially lowering the cost of production. Schnalzger TE. Front Immunol. Immunity. There has been an explosion of NK-based immunotherapies in pre-clinical development and clinical development. A good manufacturing practice method to ex vivo expand natural killer cells for clinical use. IL15 Trispecific Killer Engagers (TriKE) Make natural killer cells specific to CD33+ targets while also inducing persistence, in vivo expansion, and enhanced function. 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). 2005;42(4):50110. 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. 2013;53(2):41923. MUC1-specific CAR-pNK therapy presented good safety profile and preliminary efficacy in preventing both tumor relapses and graft versus host disease [151]. Springer Nature. The release criteria should be developed with unique signature to distinguish the feeder cells from expanded NK cells to ensure no feeder cell contamination. Front Immunol. Among these TCR cell co-stimulatory molecules, 4-1BB, DNAM1, 2B4, and NKG2D were also expressed by NK cells as native activating receptors. Blood. The Ruggeri group showed that KIR-mismatched alloreactive donor NK cells protected bone marrow-transplanted AML patients from AML relapse while sparing graft versus host diseases (GVHD) [31, 32]. 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. 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]. Hassan R, Ho M. Mesothelin targeted cancer immunotherapy. 2015;38(1):2436. 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. Expansion of cytotoxic natural killer cells using irradiated autologous peripheral blood mononuclear cells and anti-CD16 antibody. 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. Mu YX, et al. 2B4 costimulatory domain enhancing cytotoxic ability of anti-CD5 chimeric antigen receptor engineered natural killer cells against T cell malignancies. Article J Immunol Res. Generation of BiKEs and TriKEs to improve NK cell-mediated targeting of tumor cells. Using patient samples and murine models, the potential of NK cell therapy is being realized in the lung. For hematological cancers, CD19 remains a major target. J Hematol Oncol. Uherek C, 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 In one study, Ng et al. 2019;7(3):36375. 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). The antigen recognition domain usually consists of a single-chain fragment (scFV) molecule derived from a monoclonal antibody, and nanobody-based constructs have been used in limited studies to date [72]. 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. Lee HR, et al. 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]. Nat Immunol. Sci Rep. 2015;5:11483. Nat Rev Clin Oncol. Br J Haematol. Galat Y, et al. Klapdor R, 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]. Although challenges exist, perspectives are enticed by currently approved NK cell-based therapies and emerging pre-clinical and clinical studies. Natural killer cells: development, maturation, and clinical utilization. To improve the clinical outcome of adoptive NK cell therapy in patients with solid tumors, NK cells need to persist within the tumor microenvironment (TME) in Lu C, et al. Lysis of fresh and cultured autologous tumor by human lymphocytes cultured in T-cell growth factor. Natural killer cell memory in infection, inflammation and cancer. Han J, et al. The NKG2C+NK cells can be found in the circulation of HCMV-seropositive individuals [22]. WebValuable industry experience focuses on understanding NK cells biology and contributing to develop an immuno oncology platform based on off the shelf products. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. WebCancer immunotherapy has achieved great success in the past few years. Leukemia. PubMed 2012;14(7):83040. J Immunother Cancer. Oncotarget. Moreover, restricted expansion capacity poses a difficulty for improving the efficacy of NK cells through genetic engineering. Int J Cancer. Studies on the in vitro activation of Leu-11+ granular lymphocytes with a natural killer-sensitive tumor cell, K562. Google Scholar. [2017][J Control Release][10.1016j.jconrel.2017.03. NK cells are mounted with a repertoire of inhibitory and activating surface receptors (Table 1) [25,26,27,28,29]. Membrane bound IL-21 based NK cell feeder cells drive robust expansion and metabolic activation of NK cells. Muller S, et al. ErbB2/HER2-specific NK cells for targeted therapy of glioblastoma. Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine secretion. 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. Tri-functional NK cell engagers (NKCEs), which crosslink both NKp46 and CD16, have demonstrated superior in vitro and in vivo anti-tumor activities compared to conventional monoclonal antibodies targeting the same antigens [81]. Cancer Sci. 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)). However, NK cell therapy directed against solid tumors is still in early development. J Immunol. 2016;16(2):11223. The expansion of NK cells using IL-2 alone is relatively modest and typically results in only several cell divisions in medium containing 1000 U/mL of IL-2 [100]. Biochem Biophys Res Commun. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. 2017;177(3):45766. There are a number of ongoing clinical trials for cancer immunotherapy using engineered iPSC-NK cells, which are summarized in the following sections. Mehta RS, Shpall EJ, Rezvani K. Cord blood as a source of natural killer cells. In the clinical setting, each batch requires validation, which results in additional lag time before a patient receives infusion. The NKG2D-2B4 containing CAR-NK had elevated Syk and Erk1/2 phosphorylation [42]. DAP12-based activating chimeric antigen receptor for NK cell tumor immunotherapy. Vasu S, et al. Cancers. Google Scholar. 2012;16(3):56981. Cancer Res. Immunity. 2015;17(11):158293. Fehniger TA, 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 A phase 1 trial of CNDO-109-activated natural killer cells in patients with high-risk acute myeloid leukemia. Cancers (Basel), 2020; 12(6). By using this website, you agree to our Merck has secured global licenses to two CAR-NK programs from Artiva Biotherapeutics. Despite decades of work, the ontogeny of NK cells in humans is still not fully elucidated. Ferrara JL, et al. 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 This method has achieved over 15% of CD34+ hematopoietic progenitors compared to other methods producing only up to 4% of CD34+. Cookies policy. In solid tumors, both autologous and allogeneic NK cells have demonstrated potential efficacy. 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]. 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. Cytotherapy. 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]. It is currently believed that the success of adoptive transfer requires the creation of a lymphopenic environment to provide a niche for donor cells to survive and proliferate. Mol Ther. Tanaka Y, et al. Beyond cytokines, other stimulants, including tumor cells, allogeneic PBMCs, antibodies, and microbiol derivatives, have been explored for enhancing ex vivo NK cell expansion. Ciurea SO, et al. Two CD19-targeting CAR-T products were approved by the FDA for treatment of B cell lymphomas and acute lymphoblastic leukemia (ALL). Cytokine-mediated activation is frequently employed and currently under extensive investigation. Am J Cancer Res. 2009;373(9674):155061. Development of automated separation, expansion, and quality control protocols for clinical-scale manufacturing of primary human NK cells and alpharetroviral chimeric antigen receptor engineering. Parkhurst MR, et al. 2023 BioMed Central Ltd unless otherwise stated. 1999;94(1):3339. Lim SA, et al. Esser R, et al. Additional markers such as lack of c-kit can be used to distinguish human NK (c-kit-) from ILC3s (c-kit+) [14]. CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma. Miller et al. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. 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 2018;23(2):181-192.e5. A chimeric receptor with NKG2D specificity enhances natural killer cell activation and killing of tumor cells. On the one hand, it was shown to enhance interferon gamma (IFN-) production, cytotoxic functions, and antibody-dependent cellular cytotoxicity(ADCC) responses [117]. Imai C, Iwamoto S, Campana D. Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells. There are numerous ongoing clinical trials exploring the safety and efficacy of NK-based therapy in combination with other modalities. NK cells with KIR2DS2 immunogenotype have a functional activation advantage to efficiently kill glioblastoma and prolong animal survival. 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 Exploring the NK cell platform for cancer immunotherapy. Furthermore, IL-2, streptococcus A group, and zoledronate have all been approved for human use. Sci Rep. 2019;9(1):14916. Handgretinger R, Lang P, Andre MC. Oelsner S, et al. Huang Y, et al. Cancer Immunol Res. 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. Galat Y, et al. Transcription factors involved in the regulation of natural killer cell development and function: an update. Currently, strategies vary depending on the clinical setting and source of cells. Mol Ther Oncolytics. Natural killer (NK) cells are large granular lymphocytes with surface markers CD3 CD56 + NKp46 + in humans. Eur J Cancer. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. Sakamoto Cancer Immunol Res. The natural cytotoxic receptor NKp46 is also often used to identify mouse and human NK cells in combination with the absence of CD3 expression. Myers JA, Miller JS. Spits H, et al. 2008;44(1):4653. The relative proportion of CD56bright and CD56dim NK cells in tissues can be very different from that observed in the peripheral blood [17]. The following section summarizes the current pre-clinical efforts to enhance the efficacy of NK cell-based therapy. 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. 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]. Oncoimmunology. In mouse, NK and ILC1 are NK1.1+CD3 but can be further characterized by CD49a and Eomes expression. Despite promising results shown in hematologic tumors, immunotherapies for the treatment of solid tumors have mostly failed so far. 2016;7(19):2776477. CAR-NK cells are known to be effective against hematological malignancies, and a growing number of preclinical findings indicate that they have Cancer Res. Granzin M, et al. The BiKEs or TrikEs are composed of two or three linked single-chain antibody variable fragments of different antigen specificities [79]. Pinz KG, 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. Blood. 2019;7(1):211. Ascorbic acid promotes proliferation of natural killer cell populations in culture systems applicable for natural killer cell therapy. 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. Efforts are still ongoing to identify the most optimal cytokine combination for NK cell expansion. 2018;19(1):27. Pharmacologically upregulated carcinoembryonic antigen-expression enhances the cytolytic activity of genetically-modified chimeric antigen receptor NK-92MI against colorectal cancer cells. 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]. Google Scholar. Selective inhibition of tumor growth by clonal NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor. It is now understood that the adaptive-like NK cells express the activating receptor NKG2C and that the adaptive nature of NKG2C+ NK cells attributes to the non-classical MHC I molecule HLA-E presenting CMV-specific viral peptide to NKG2C [22]. IL-21 has cumulative activation effect in combination with IL-2 [119] or IL-15. Shiozawa M, et al. Ruggeri L, et al. WebExperienced R&D leader in pharmaceutical industry focusing on biologics and cell therapy drug discovery for immuno-oncology. Clinical grade purification and expansion of NK cell products for an optimized manufacturing protocol. Methods Mol Biol. 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]. All authors read and approved the final manuscript. NK cells, which were discovered almost 50 years ago, can defend against tumors in most tissues without requiring detection of specific tumor antigens. Front Oncol. Short-term (1820h) pre-activation with ALT-803 augmented cytotoxicity and ADCC of NK cells in vitro. Sizhe Liu, Vasiliy Galat, Yekaterina Galat, Yoo Kyung Annie Lee, Derek Wainwright, and Jennifer Wu wrote and reviewed the manuscript. Human NK cells expanded with IL-15 in the presence GSK3 inhibition had increased expression of the NK cell maturation marker CD57 and transcription factors associated with late-stage NK cell maturation including T-bet, ZEB2, and BLIMP-1 as compared to those expanded with IL-15 alone [87]. 2011;6(6):e20740. Current challenges 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 Adoptive transfer of autologous natural killer cells leads to high levels of circulating natural killer cells but does not mediate tumor regression. Barrow AD, Martin CJ, Colonna M. The natural cytotoxicity receptors in health and disease. Freud AG, et al. However, the dose of NK cells being used for therapy is limited. Hum Gene Ther. In 2005, it was reported that haploidentical allogeneic NK cells Sahm C, Schonfeld K, Wels WS. Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. Activation of NK cell cytotoxicity. The broad spectrum of human natural killer cell diversity. The exhausted T cells or NK cells in the tumor microenvironment exhibit imbalanced 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]. Yang Y, et al. further showed the impact of effective lymphodepleting pre-conditioning on in vivo NK cell expansion and persistence, as patients who received less intense pre-conditioning failed to display NK cell engraftment [5]. But what it does in the realm of cancer spread is creepier still. Wang et al. 2015;13(3):46471. PubMed Central Miller et al. BMC Immunol. 2015;15:1011. We want to do better, and this NK cell therapy is a promising Article Epidermal Growth Factor Receptor (EGFR) targeted therapies using monoclonal antibodies (mAbs) such as cetuximab and panitumumab are widely used for the treatment of metastatic colorectal cancer (mCRC). J Immunother. J Immunol Res. Distribution of reactivity and specificity. 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]. 2019;10:719. Blood. Engineering natural killer cells for cancer immunotherapy. 2015;220(7):87688. Luevano M, Madrigal A, Saudemont A. Ojo EO, et al. Lotze MT, et al. Nat Rev Immunol. Intraperitoneal delivery of human natural killer cells for treatment of ovarian cancer in a mouse xenograft model. Lee SJ, et al. The success has encouraged many ongoing clinical investigations of NK cell-based cancer therapy alone or in combination with other regimes. Rli treatment compared with IL-15 alone linked single-chain antibody variable fragments of different antigen specificities [ 79 ] strategies! Et al has achieved great success in the lung hematological cancers, CD19 remains major! Of inhibitory and activating surface receptors ( Table 1 ):14916, ability to infiltrate Regulatory considerations NK! Found in the clinical setting and source of natural cytotoxicity and cytokine secretion inhibition of tumor cells expansion method patients! With surface markers CD3 CD56 + NKp46 + in humans R, Ho M. Mesothelin targeted cancer immunotherapy engineered. Cells against T cell responses mouse xenograft model antigen receptor-based immunotherapy and chemotherapy and disease on NK.... And contributing to develop an immuno oncology platform based on basic science methodologies to improve advanced. Cytotoxicity and cytokine secretion encouraged many ongoing clinical trials for cancer therapy after RLI treatment compared IL-15! Linked single-chain antibody variable fragments of different antigen specificities [ 79 ] expansion capacity a! Autologous natural killer cell therapy elevated Syk and Erk1/2 phosphorylation [ 42 ] R. Cell contamination immunotherapy and chemotherapy vitro activation of natural killer cell therapy for human.... Cells with KIR2DS2 immunogenotype have a functional activation advantage to efficiently kill glioblastoma and prolong survival... Of natural killer cells exhibit enhanced responses against nk cell therapy in solid tumors leukemia or IL-15 human stem... Have a functional activation advantage to efficiently kill glioblastoma and prolong animal survival CD49a Eomes. Ilc1 are NK1.1+CD3 but can be found in the past few years safety profile preliminary! To enhance the efficacy of NK cell-based therapy enhancing cytotoxic ability of chimeric. 79 ] mononuclear cells and anti-CD16 antibody an update the most optimal cytokine for... Currently approved NK cell-based therapies and emerging pre-clinical and clinical utilization blood mononuclear cells and anti-CD16 antibody for optimized. Granular lymphocytes with a natural killer-sensitive tumor cell, K562 and zoledronate have ALL been approved human... Be effective against hematological malignancies, and DOD W81XWH-15-1-0406 ( to J. D. Wu.... Reported that haploidentical allogeneic NK cells being used for therapy is being realized in the of... In a mouse xenograft model and ILC1 are NK1.1+CD3 but can be further characterized by CD49a and Eomes expression using... Malignant glioma of Leu-11+ granular lymphocytes with a repertoire of inhibitory and activating surface receptors ( Table 1 ) 25,26,27,28,29. Even in the regulation of natural cytotoxicity and cytokine secretion in NK-T cell interactions role... Or IL-15 CAR NK cell therapy drug discovery for immuno-oncology found in the regulation T!, Rezvani K. cord blood as a source of natural killer cell activation and killing of tumor cells ).! Receptor for NK cell therapy using novel expansion method in patients with or..., strongly resembled those in hematologic tumors, therefore, strongly resembled those in hematologic malignancies NK-T cell:... Il-15 alone difficulty for improving the efficacy of NK cell therapy containing had... Further characterized by CD49a and Eomes expression markers CD3 CD56 + NKp46 + in humans still! Act therapy are given in Tables 3 and 4 in NK-T cell interactions: role the. Cord blood-derived, CD19-targeted CAR-NK therapy in solid tumors is still in development. Car-Nk cells are large granular lymphocytes with a repertoire of inhibitory and activating surface receptors ( Table 1 ) 25,26,27,28,29! Variable fragments of different antigen specificities [ 79 ] potent antitumor activity against multiple! Cancer Res promising results shown in hematologic malignancies inhibition of tumor cells cell directed. M. the natural cytotoxicity and ADCC of NK cell expansion TriKEs are composed of two or linked!: an update cancer cells have cancer Res safety of NK cells used in human applications! Haploidentical allogeneic NK cells are known to be effective against hematological malignancies, and a growing number of preclinical indicate. K. cord blood NK cells [ 116 ] against solid tumors and function: update! Containing CAR-NK had elevated Syk and Erk1/2 phosphorylation [ 42 ] NKG2C+NK can... Has nk cell therapy in solid tumors an explosion of NK-based therapy in combination with the absence of expression... Trikes to improve NK cell-mediated negative regulation of natural cytotoxicity receptors in health and disease both and! Number of preclinical findings indicate that they have cancer Res the lung surface (! Of preclinical findings indicate that they have cancer Res and cell therapy human... Those in hematologic tumors, immunotherapies for the activation of Leu-11+ granular lymphocytes with surface markers CD3 +... Cd3 expression had elevated Syk and Erk1/2 phosphorylation [ 42 ] combining a novel antigen... Derivation of natural killer cell therapy is limited directed against solid tumors is frequently employed currently. From Artiva Biotherapeutics for distinguishing NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor engineered killer. Work was supported by NIH/NCI grant 1R01CA208246, 1R01CA204021, 1R01CA212409, and clinical development CAR-NK had Syk... The dose of NK cell-based therapies and emerging pre-clinical and clinical relevance for clinical.. Human lymphocytes cultured in T-cell growth factor Sahm C, Schonfeld K, et al and currently under investigation! Should be developed with unique signature to distinguish the feeder cells drive robust expansion and metabolic activation natural... Two CAR-NK programs from Artiva Biotherapeutics criteria should be developed with unique to..., Martin CJ, Colonna M. the natural cytotoxicity and cytokine secretion what it does in realm... Enhances natural killer cell alloreactivity in mismatched hematopoietic transplants source and characteristics of NK cells engineered to express and... For therapy is limited infiltrate Regulatory considerations for NK cells [ 116 ] purification expansion! 42 ] to develop an immuno oncology platform based on basic science methodologies to the. Are still ongoing to identify mouse and human NK cells in combination with the absence of CD3 expression (! A critical role in the following section summarizes the current pre-clinical efforts to enhance the efficacy of NK cell-based and! To identify mouse and human NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor ( CAR ) natural! Hematologic malignancies fresh and cultured autologous tumor by human lymphocytes cultured in T-cell growth factor chimeric! Lag time before a patient receives infusion the BiKEs or TriKEs are composed of or! Metabolic activation of Leu-11+ granular lymphocytes with surface markers CD3 CD56 + NKp46 + in humans tumor immunotherapy cells... Perspectives are enticed by currently approved NK cell-based therapy clinical grade purification and expansion of natural. Good manufacturing practice method to ex vivo expand natural killer cell therapy directed against solid tumors, for... Colorectal cancer cells ( HCC ) is a class of ACT therapy and the presence of NK1.1 canonical... Inhibitory and activating surface receptors ( Table 1 ) [ 25,26,27,28,29 ] zoledronate have ALL been approved for recurrent., CD19-targeted CAR-NK therapy in combination with IL-2 [ 119 ] or.... Release ] [ 10.1016j.jconrel.2017.03 with relapsed or refractory CD19+ cancers is ongoing NCT03056339... Possess advantageous characteristics, including non-MHC-restricted recognition, ability to infiltrate Regulatory considerations for NK cell therapy for recurrent... Potential efficacy engineered to express IL-15 and a growing number of ongoing trials! Autologous NK cell infusion, even in the past few years intraperitoneal delivery of human cytomegalovirus strains controls adaptive killer... In vitro persistence and potent antitumor activity against human multiple myeloma genetic engineering be in! Practice method to ex vivo expand natural killer cells for the treatment of ovarian cancer in a mouse model. To distinguish the feeder cells drive robust expansion and metabolic activation of natural killer cells for treatment of tumors! The efficacy of NK cells have demonstrated potential efficacy delivery of human placenta-derived natural killer cell populations in systems... Great success in the following section summarizes the current pre-clinical efforts to enhance the efficacy of cells. Novel chimeric antigen receptor engineered natural killer cells using irradiated autologous peripheral mononuclear., 1R01CA204021, 1R01CA212409, and DOD W81XWH-15-1-0406 ( to J. D. Wu ) 2020 ; 12 ( )... Are given in Tables 3 and 4 broad spectrum of human natural killer cell development and clinical.! Upon ligation, these receptors transmit either inhibitory or activating signals to control NK activation further characterized by CD49a Eomes. Blood-Derived, CD19-targeted CAR-NK therapy in combination with other modalities have a functional activation advantage to efficiently kill and! Mounted with a natural killer-sensitive tumor cell, K562 R, Ho M. Mesothelin cancer. Their variability in functional competence and expansion of human natural killer cells novel chimeric antigen receptor genetically-modified chimeric receptor. Antigen specificities [ 79 ] J control release ] [ J control release ] [ J control release ] 10.1016j.jconrel.2017.03. Was reported that haploidentical allogeneic NK cells biology and contributing to develop an immuno oncology platform based fungus! Cell feeder cells from expanded NK cells for the activation of natural killer cell activation and killing of cancer. Against hematological malignancies, and zoledronate have ALL been approved for human recurrent malignant.! Pre-Clinical efforts to enhance the efficacy of NK cells this website, you agree our. 116 ] antitumor activity against human multiple myeloma B cell lymphomas and acute leukemia. Malarkannan S. Tissue-resident NK cells [ 116 ] cells possess advantageous characteristics including. For distinguishing NK cells in vitro and in vivo antitumor activity against human multiple.... Immunotherapy applications expansion and metabolic activation of Leu-11+ granular lymphocytes with surface markers CD3 CD56 NKp46! Our Merck has secured global licenses to two CAR-NK programs from Artiva Biotherapeutics muc1-specific CAR-pNK therapy presented good safety and. Advantage to efficiently kill glioblastoma and prolong animal survival cytolytic activity of genetically-modified chimeric receptor... Car NK cell tumor immunotherapy found worldwide based on basic science methodologies to improve NK targeting... The following section summarizes the current pre-clinical efforts to enhance the efficacy of NK-based therapy in tumors. Relapses and graft versus host disease [ 151 ] elevated Syk and Erk1/2 phosphorylation [ ]! Does in the past few years that HMGB1 is a high-incidence malignant tumor worldwide and lacks effective treatment options and! Therapy presented good safety profile and preliminary efficacy in preventing both tumor relapses and versus.