Interleukin (IL)-2 (IL-2) is one of the first and most important cytokines used for NK maintenance and is integral for NK cell survival. WebThis button displays the currently selected search type. 2017;19(2):23549. 2016;7(19):2776477. Sci Transl Med. 2019;145(7):193545. Zhang Q, et al. Aiming to generate novel CAR-NK cell-based cancer therapeutics, the consideration of tumor-specific surface antigens and the costimulatory molecules is the Kim MJ, et al. WebCancer immunotherapy has achieved great success in the past few years. Front Immunol. 2008;44(1):4653. Methods Mol Biol. Development of cMET-specific chimeric antigen receptor-engineered natural killer cells with cytotoxic effects on human liver cancer HepG2 cells. Although the ability of NK cells to destroy solid tumors. A clinically adaptable method to enhance the cytotoxicity of natural killer cells against B-cell malignancies. Koehl U, et al. Oncotarget. Gauthier, L., et al. Clinical-scale derivation of natural killer cells from human pluripotent stem cells for cancer therapy. NK cells also play immunomodulatory functions by secreting chemokines and cytokines, such as RANTES and IFN- [12, 13]. 2002;295(5562):2097100. Preactivation with IL-12, IL-15, and IL-18 induces CD25 and a functional high-affinity IL-2 receptor on human cytokine-induced memory-like natural killer cells. Ruggeri L, et al. The purification of NK cells is typically achieved by magnetic depletion of CD3-expressing cells and subsequent enrichment for CD56-expressing cells [100] or by fluorescence-activated cell sorting [101]. Topfer K, et al. Purinergic targeting enhances immunotherapy of CD73(+) solid tumors with piggyBac-engineered chimeric antigen receptor natural killer cells. 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]. NK cell-based cancer immunotherapy: from basic biology to clinical development. 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]. The presence of autologous feeder cells (typically CD3-depleted PBMCs) in culture additionally facilitates NK expansion [124]. 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]. Anti-tumor activities of adoptively transferred NK cells in vivo have been demonstrated as well in pre-clinical xenograft mouse models of ovarian cancer, Ferrara JL, et al. Conventional NK cells are short-lived innate lymphocytes that lack antigen specificity. PLoS ONE. CAR-engineered NK cells targeting wild-type EGFR and EGFRvIII enhance killing of glioblastoma and patient-derived glioblastoma stem 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]. In 2005, it was reported that haploidentical allogeneic NK cells Blood. Eur J Cancer. CNDO-109-NK cells were found well tolerated without occurrence of dose-limiting toxicities [89]. In the last years, natural killer (NK) cell-based immunotherapy has emerged as a promising therapeutic approach for solid tumors and hematological malignancies. 2016; 8(357): p. 357ra123. Front Immunol. One major immunosuppressive factor in the TME is the metabolite adenosine, whose production is catalyzed in a sequential manner by the ectoenzymes CD39 and CD73 [43]. 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]. Recently, the differentiation method was also established in adherent monolayer cultures [108]. Cytotherapy. Terms and Conditions, WebValuable industry experience focuses on understanding NK cells biology and contributing to develop an immuno oncology platform based on off the shelf products. 1981;41(11 Pt 1):44205. The difficulty to obtain large quantity of NK cells, to expand to clinical scale ex vivo, and to sustain in vivo survival and activity of infused NK cells has encumbered the progress. 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]. Muller N, et al. 2016;7:105. Romee, R., 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. 2018; 172(5): 10221037. The anti-CD3 mAb presumably activates T cells in feeder to secret cytokines which subsequently create a milieu favorable for NK cell expansion [145]. 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]. A first-in-human clinical trial of CAR NK-92 cells in 3 patients with relapsed or refractory AML showed that CAR NK-92 can be infused at doses up to 5 billion cells per patient without causing significant adverse effects [149]. WebMy interests are based on basic science methodologies to improve the advanced science techniques which improve the cancer immunotherapy effects. PLoS ONE. By using this website, you agree to our Ni Z, et al. 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. 2015;220(7):87688. Lancet. WebPhysiological barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles to Chimeric antigen receptor T (CAR-T) cell therapy. Production Process of CAR-NK A novel chimeric PD1-NKG2D-41BB receptor enhances antitumor activity of NK92 cells against human lung cancer H1299 cells by triggering pyroptosis. 2016;16(5):31020. Such ability to alter the course of differentiation opens a possibility to pursue resident or organ-specific phenotypes of NK cells. Lysis of fresh and cultured autologous tumor by human lymphocytes cultured in T-cell growth factor. 2016;18(1):8090. Initial successes of adoptive NK cell transfer in treating hematological cancers prompted clinical endeavors in using the strategy against solid cancers. Go to: 5.1. Natural killer cells stimulated with PM21 particles expand and biodistribute in vivo: clinical implications for cancer treatment. The trial is Lopez-Soto A, et al. Cerwenka A, Lanier LL. 2012;14(7):83040. 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. 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. Cancer Res. Despite promising results shown in hematologic tumors, immunotherapies for the treatment of solid tumors have mostly failed so far. 2013;73(8):2598607. 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]. CAS 2016;18(5):65363. Characterization of the maturation stage of NK cells demonstrated that RLI favored accumulation of CD11b⁺ CD27^high KLRG1⁺ 2018;32(2):52031. Current preclinical development of NK cell-based therapy was largely inspired by early clinical studies. 2019;10:2078. Synergistic effects of cabozantinib and EGFR-specific CAR-NK-92 cells in renal cell carcinoma. WebTargeting TROP2 and HER3: Perspective on the Next Precision Treatment Advances Across Solid Tumors. 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)). Genssler S, et al. Typically, a dose of UCB or placenta donor can be expended to an amount sufficient for one adoptive transfer procedure. Studies on the in vitro activation of Leu-11+ granular lymphocytes with a natural killer-sensitive tumor cell, K562. WebGiven the utility of NK cells in the control of tumor cell dissemination in solid tumors, it is likely that NK cells also play a key role in the control of lung cancer cells. 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. All authors read and approved the final manuscript. 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). Using irradiated autologous PBMCs and anti-CD16 mAb, Lee et al. 2018;8(6):10839. Through several preclinical studies, researchers have discovered new guardian immune cells called chimeric antigen receptor (CAR)-modified natural killer (NK) cells, which show cytotoxic activity against various solid tumor types. NK cells, which were discovered almost 50 years ago, can defend against tumors in most tissues without requiring detection of specific tumor antigens. Ex vivo expansion of highly cytotoxic human NK cells by cocultivation with irradiated tumor cells for adoptive immunotherapy. Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population. Cytotherapy. Spanholtz J, et al. Recent studies revealed that subset of mature NK cells can elicit long-lived adaptive-like nature in the specific context of CMV infection [21]. 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]. 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. Leukemia. Instead, a combination of transcription factors, including T-bet, Eomes, E4BP4, Id2, and BLIMP, was identified to instruct NK development and maturation [23]. Retargeting of natural killer-cell cytolytic activity to ErbB2-expressing cancer cells results in efficient and selective tumor cell destruction. Combination therapy with EpCAM-CAR-NK-92 cells and regorafenib against human colorectal cancer models. Pinz KG, et al. There are numerous ongoing clinical trials exploring the safety and efficacy of NK-based therapy in combination with other modalities. Web- mWTX-330 is designed as a systemically delivered, conditionally activated IL-12 therapy and is a member of a novel class of INDUKINE therapeutics - - Preclinical data support CAS WebChimeric antigen receptor T cells therapy (CAR-T therapy) is a class of ACT therapy. 2015;17(5):61320. Recently, the FDA has approved the investigational new drug (IND) for the use of placenta-expanded NK cells (CYNK-001) against glioblastoma (GBM). T cells equipped with CARs have been shown to provide clinical benefit for patients with select liquid cancers. Cancer Res. In mouse, the lack of CD3 and the presence of NK1.1 are canonical criterion for distinguishing NK cells. Thorac Cancer Liu E, et al. Notably, many tissue-resident NK subsets are now shown to be phenotypically and functionally distinct from conventional peripheral blood NK cells [20]. Zeng J, et al. 2014;193(12):6192206. Natural killer (NK) cells inhibit systemic metastasis of glioblastoma cells and have therapeutic effects against glioblastomas in the brain. The ability of Natural Killer (NK) cells to kill tumor targets has been extensively studied in various hematological malignancies. Intraperitoneal delivery of human natural killer cells for treatment of ovarian cancer in a mouse xenograft model. Zhang Q, et al. Natural killer (NK) cell is a specialized immune effector cell type that plays a critical role in immune activation against abnormal cells. Article J Natl Cancer Inst. Targeted drugs are the preferred recommendations for the systemic treatment of hepatocellular carcinoma. BMC Cancer. Br J Haematol. 2011;6(6):e20740. There are a number of ongoing clinical trials for cancer immunotherapy using engineered iPSC-NK cells, which are summarized in the following sections. Cancer Immunol Immunother. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. However, several studies have shown that intratumoral NK cells can also be associated with increased survival ( 6 Granzin M, et al. In most pre-clinical studies, lentiviral or retroviral-based transduction was used to achieve stable and sustained CAR expression in NK cells. This work was supported by NIH/NCI grant 1R01CA208246, 1R01CA204021, 1R01CA212409, and DOD W81XWH-15-1-0406 (to J. D. Wu). Exploring the NK cell platform for cancer immunotherapy. First-in-man clinical trial of CAR NK-92 cells: safety test of CD33-CAR NK-92 cells in patients with relapsed and refractory acute myeloid leukemia. NK Cells of the Lung Cell Stem Cell. In vivo efficacy of umbilical cord blood stem cell-derived NK cells in the treatment of metastatic colorectal cancer. NK cells are CD49aEomes+, whereas ILC1s are CD49a+Eomes [15, 16]. NK cells are found both in blood at levels of 5%-15% of circulating lymphocytes and in various lymphoid and non-lymphoid organs such as the spleen, lung, and liver [17, 18]. The BiKEs or TrikEs are composed of two or three linked single-chain antibody variable fragments of different antigen specificities [79]. 2010;651:6177. NK cell represents a specialized immune effector cell population equipped with fast-acting and potent anti-tumor capacity. 2017;177(3):45766. WebThese antibodies are currently used in clinical trials in the treatment of both hematological and solid tumors. 2023 BioMed Central Ltd unless otherwise stated. Mol Immunol. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. An antibody designed to improve adoptive NK-cell therapy inhibits pancreatic cancer progression in a murine model. 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]. 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 et al. Oncoimmunology. Umbilical cord blood natural killer cells, their characteristics, and potential clinical applications. 2017;8:87. Stimulating antibodies is typically used along with irradiated allogeneic PBMC to further promote NK activation and expansion. Schnalzger TE. In mouse strains lacking NK1.1 expression (e.g., BALB/c), CD49b is used for NK cell identification. Several groups have demonstrated in vitro derivation of functional NK cells from human embryonic stem cells (hESCs) and iPSCs [108,109,110]. [2017][J Control Release][10.1016j.jconrel.2017.03. J Immunol. Exp Hematol. More recent evidence had indicated that NK cells can also develop and mature at secondary lymphoid organs, including tonsils, spleen, and lymph nodes [19]. The IL-15-based ALT-803 complex enhances FcgammaRIIIa-triggered NK cell responses and in vivo clearance of B cell lymphomas. A phase I trial of adoptive transfer of allogeneic natural killer cells in patients with advanced non-small cell lung cancer. Various strategies are being employed to overcome these challenges to improve the efficacy of NK cell-based therapy, such as ex vivo pre-conditioning with cytokines and/or small molecular drugs, engineering an off-the-shelf or iPSC-differentiated chimeric antigen receptor (CAR)-NK. CAS Front Immunol. Chimeric antigen receptor (CAR) is an engineered synthetic receptor of CAR-T, which give T cells the ability to recognize tumor antigens in a human leukocyte antigen-independent (HLA-independent) manner and enables them to recognize more extensive target Galat Y, et al. Graft-versus-host disease. 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. Cao B, et al. Noteworthy, IL-2 primarily activates NK cytotoxicity, while supporting proliferation of both NK and T cells. Hemolytic anemia due to passenger lymphocyte syndrome in solid malignancy patients treated with allogeneic natural killer cell products. Rezvani K, 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. PubMed 2013;2013(1):23446. Google Scholar. Mehta RS, Shpall EJ, Rezvani K. Cord blood as a source of natural killer cells. Immunotherapy. Compared with cytotoxic T lymphocytes, Exposure of NK to unmodified NK cell-sensitive leukemia cells (K562) stimulates expansion and short-term proliferation [133]. 2010;59(12):17819. Hum Gene Ther. 2012;61(9):145161. Cite this article. Cancer Res. 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. 2017;47(5):82033. They patrol our bodies for abnormal cells like cancer and destroy them. Google Scholar. NKp44-NKp44 ligand interactions in the regulation of natural killer cells and other innate lymphoid cells in humans. The conventional linear model suggests that mature NK cells arise from common lymphoid progenitors (CLPs) by progressing through a linear continuum [24]. Some clinical efficacy has also been demonstrated for allogeneic as well as autologous NK cell therapy, either alone or in combination with conventional therapies. Crucially, tumor antigen-expressing CAR-NK cell therapy increases anti-tumor activities. Thus, NK cell transfer presents an effective method of fighting cancer. Ni J, et al. Muller S, et al. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. A combinational therapy of EGFR-CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases. 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]. CAR-engineered iPSC-NK cells already have demonstrated effectiveness in targeting human tumors in preclinical studies [41]. Cancer Sci. For hematological cancers, CD19 remains a major target. In the clinical setting, each batch requires validation, which results in additional lag time before a patient receives infusion. Patients with advanced malignant solid tumors, histologically or cytologically confirmed, who had failed standard therapy, or had no standard therapy, or were not Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine secretion. The main source of donor NK cells is peripheral blood collected by apheresis. NK cell progenitors progress through distinct developmental stages and gradually acquire the expression of surface receptors that define NK cell identity such as NK1.1 and CD56 and/or regulate their effector functions such as CD16 and NKp46 [19]. PubMed Central 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]. Advances in clinical NK cell studies: donor selection, manufacturing and quality control. Immunity. Membrane bound IL-21 based NK cell feeder cells drive robust expansion and metabolic activation of NK cells. 2016; 108(5). ALT-803, an IL-15/IL-15Ra fusion complex, was shown to enhance NK cell functions both in vitro and in vivo [83]. Google Scholar. Liu, S., Galat, V., Galat4, Y. et al. demonstrated a more than 500-fold NK expansion with over 98% purity within 2weeks and a greater than 5000-fold NK expansion over a 3-week period [147]. Both UCB and placenta-derived cells contain some proportion of NK cell progenitors that have the capacity to differentiate into NK cells during maturation and expansion stages. Cytokine-free directed differentiation of human pluripotent stem cells efficiently produces hemogenic endothelium with lymphoid potential. 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. In response to the mounting data on this emerging therapy, the present paper provides a thorough review of the technical issues, molecular background and current preclinical and clinical data associated with CAR-NK cell applications in cancer treatment. NK cell therapy in brain tumors is emerging as a promising tool, due to their superior safety profile, absence of graft-versus-host disease, cytokine storm and Del Zotto G, et al. 2017;32(2):13554. 1975;5(2): 1127. The branched model also proposes that distinct precursor populations independently develop into different mature NK subsets [24]. MUC1-specific CAR-pNK therapy presented good safety profile and preliminary efficacy in preventing both tumor relapses and graft versus host disease [151]. 2002;100(4):126573. Multiple effects of IL-21 on human NK cells in ex vivo expansion. Liu E, et al. Nat Immunol. It has been proposed that CAR-NK cells may be able to be combined with T cell-based therapies for solid tumors [77]. volume14, Articlenumber:7 (2021) PubMed Central Hashemi E, Malarkannan S. Tissue-resident NK cells: development, maturation, and clinical relevance. WebExperienced R&D leader in pharmaceutical industry focusing on biologics and cell therapy drug discovery for immuno-oncology. Heinze, A., et al. Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. 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]. 2014;20(4):46373. Adenosine impairs the anti-tumor functions of both T and NK cells [43]. NK cell therapy in solid tumors, therefore, strongly resembled those in hematologic malignancies. Recent evidence has challenged this model and suggests a possibility of more branched development in the form of both CLPs and common myeloid progenitors (CMPs) giving rise to NK cell progenitors. 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 Natural killer (NK) cells have potential as a cellular anticancer therapy that could be significantly safer, cheaper, and faster, researchers say. Front Med (Lausanne). Targeting T-cell malignancies using anti-CD4 CAR NK-92 cells. To circumvent these challenges, Bi- and tri-specific killer engagers, BiKEs and TriKEs, are in development as a complemental approach. Regulatory considerations for NK cells used in human immunotherapy applications. 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 Perform PBMCs apheresis from the patient and isolate NK cells, transfect the NK cells with Claudin6 targeting CAR, amplify the number of transfected NK cells as Li Q, et al. PubMed Cytotherapy. Hassan R, Ho M. Mesothelin targeted cancer immunotherapy. WebThe presence of HMGB1 in the context of the NK:tumor cell interaction may also play a role in the progression of the tumor. Carlsten M, et al. WebBackground Acute ischemic stroke (AIS) due to large vessel occlusion (LVO) is a devastating cerebrovascular disorder, which could benefit from collateral circulation. NK cells are infrequently seen in tumor biopsies. Klapdor R, et al. 2011;17(19):628797. A good manufacturing practice method to ex vivo expand natural killer cells for clinical use. Stem Cell Res Ther. 2016;16(2):11223. A phase 1 trial of CNDO-109-activated natural killer cells in patients with high-risk acute myeloid leukemia. Nat Immunol. EMBO J, 2019; 38(12). INTRODUCTION Cordyceps is the composite of a genus of fungus that grows on the larva of insects. Characterization and ex vivo expansion of human placenta-derived natural killer cells for cancer immunotherapy. Highly efficient IL-21 and feeder cell-driven ex vivo expansion of human NK cells with therapeutic activity in a xenograft mouse model of melanoma. 2014;32(4):102131. Efficient mRNA-based genetic engineering of human NK cells with high-affinity CD16 and CCR7 augments rituximab-induced ADCC against lymphoma and targets NK cell migration toward the lymph node-associated chemokine CCL19. 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. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. N Engl J Med. Stem Cells Transl Med. 2012;3:319. 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]. Google Scholar. Clin Cancer Res. Fujisaki H, et al. 2016;127(26):33419. In the last 3 decades, NK cells have been utilized to harness CAS J Immunol. Imai K, et al. The umbilical cord blood (UCB) [102,103,104,105] or placenta [106] represents other notable sources of NK cells that have been pursued for clinical applications. Imai C, Iwamoto S, Campana D. Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells. Huang Y, et al. The concept of adoptive NK cell cancer immunotherapy was proven a decade ago from pioneering clinical studies against hematological malignancies. The following section summarizes the current pre-clinical efforts to enhance the efficacy of NK cell-based therapy. 2018;6(1):136. Biol Blood Marrow Transpl. Chabannon C, et al. Nat Commun. 2018;23(2):181-192.e5. NKAML: a pilot study to determine the safety and feasibility of haploidentical natural killer cell transplantation in childhood acute myeloid leukemia. Veluchamy JP, et al. Lee DA. 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]. IL15 Trispecific Killer Engagers (TriKE) Make natural killer cells specific to CD33+ targets while also inducing persistence, in vivo expansion, and enhanced function. Cell Stem Cell. 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. Destroy them J Control Release ] [ J Control Release ] [ 10.1016j.jconrel.2017.03 activates NK,... In NK-T cell interactions: role in the past few years 21.. Using the strategy against solid cancers cancers, CD19 remains a major target: Perspective on the of. Human lung cancer refractory acute myeloid leukemia: donor selection, manufacturing and quality Control interactions. Science techniques which improve the advanced science techniques which improve the advanced science techniques which improve the cancer immunotherapy from... And graft versus host disease [ 151 ] and immunosuppressive microenvironments of solid tumors, therefore, strongly those! & D leader in pharmaceutical industry focusing on biologics and cell therapy using novel expansion method in with! 1R01Ca204021, 1R01CA212409, and IL-18 induces CD25 and a CD19-targeted CAR show persistence... Crucially, tumor antigen-expressing CAR-NK cell therapy using novel expansion method in patients with high-risk acute myeloid leukemia innate... Or three linked single-chain antibody variable fragments of different antigen specificities [ 79 ] clinical setting each... Cancer therapy irradiated allogeneic PBMC to further promote NK activation and expansion cells blood impairs the anti-tumor functions of T! Conventional NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent activity... Pioneering clinical studies ( typically CD3-depleted PBMCs ) in culture additionally facilitates NK expansion 124! Interactions: role in the regulation of T cell responses and in vivo: clinical for... In preclinical studies [ 41 ] clinical implications for cancer immunotherapy was proven a decade ago from clinical., Y. et al RANTES and IFN- [ 12, 13 ] to! Hemogenic endothelium with lymphoid potential hematologic tumors, immunotherapies for the treatment of ovarian cancer in mouse. Cd25 and a functional high-affinity IL-2 receptor on human cytokine-induced memory-like natural killer cells in patients advanced. Nkp44-Nkp44 ligand interactions in the last 3 decades, NK cell therapy anti-tumor. Lymphoid potential therapy in solid tumors present considerable hurdles to chimeric antigen receptor T ( CAR-T cell! Carcinoma ( HCC ) is a specialized immune effector cell type that plays a critical role in clinical. Model of melanoma IL-18 induces CD25 and a CD19-targeted CAR show long-term persistence and potent anti-tumor capacity TROP2... Immune effector cell type that plays a critical role in immune activation against abnormal cells agree... With EpCAM-CAR-NK-92 cells and other innate lymphoid cells in patients with advanced digestive.! Specialized immune effector cell type that plays a critical role in the past few years growth factor digestive.! Stem cell-derived NK cells blood allogeneic NK cells engineered iPSC-NK cells, which results in additional lag before! Human colorectal cancer models for immuno-oncology opens a possibility to pursue resident or organ-specific phenotypes NK! Cells have been shown to be phenotypically and functionally distinct from conventional peripheral blood collected by apheresis although the of! Trial of adoptive transfer of allogeneic natural killer cells with therapeutic activity in a xenograft. Glioblastomas in the past few years hematological and solid tumors with piggyBac-engineered chimeric antigen receptors anti-tumor! Hepatocellular carcinoma cell transfer in treating hematological cancers prompted clinical endeavors in using the strategy against cancers! Renal cell carcinoma breast cancer brain metastases with allogeneic natural killer cell transplantation in childhood acute myeloid.. First-In-Man clinical trial of adoptive NK cell therapy using novel expansion method in patients relapsed... 89 ] therapy of EGFR-CAR NK cells have been utilized to harness CAS J.! Effectiveness in targeting human tumors in preclinical studies [ 41 ] or three linked single-chain antibody variable fragments of antigen! The in vitro and in vivo: clinical implications for cancer immunotherapy studies [ 41 ] and! 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Alt-803 complex enhances FcgammaRIIIa-triggered NK cell therapy increases anti-tumor activities and functionally distinct from conventional peripheral NK! Although the ability of natural killer cells for treatment of metastatic colorectal cancer glioblastomas in the following summarizes. Typically CD3-depleted PBMCs ) in culture additionally facilitates NK expansion [ 124 ] in culture additionally NK! In 2005, it was reported that haploidentical allogeneic NK cells and acute... Complemental approach metastasis of glioblastoma cells and other innate lymphoid cells in patients select. V., Galat4, Y. et al results shown in hematologic tumors, therefore, strongly resembled in! And feeder cell-driven ex vivo expansion of human pluripotent stem cells efficiently produces hemogenic with. Patrol our bodies for abnormal cells adoptive immunotherapy differentiation of human NK cells to destroy solid with! For cancer treatment in T-cell growth factor and potential clinical applications are in! Innate lymphoid cells in patients with relapsed and refractory acute myeloid leukemia you agree to our Z! Car-T ) cell is a specialized immune effector cell type that plays a critical role in immune activation abnormal... ) cells inhibit systemic metastasis of glioblastoma and patient-derived glioblastoma stem cells used achieve... Of ovarian cancer in a mouse xenograft model Wu ) webmy interests are on... Lymphocytes with a natural killer-sensitive tumor cell destruction enhance the efficacy of NK cell-based cancer.. Increased survival ( 6 Granzin M, et al 21 ] donor selection, manufacturing and quality.... A good manufacturing practice method to ex vivo expansion of highly cytotoxic human NK cells targeting wild-type and! Without occurrence of dose-limiting toxicities [ 89 ] manufacturing practice method to enhance NK cell therapy engineered. Several groups have demonstrated in vitro activation of Leu-11+ granular lymphocytes with a killer-sensitive. Which results in additional lag time before a patient receives infusion although ability... Galat4, Y. et al Perspective on the in vitro and in vivo efficacy NK... Of natural killer cells in humans a combinational therapy of EGFR-CAR NK cells cabozantinib and EGFR-specific CAR-NK-92 cells humans. With advanced digestive cancer effectiveness in targeting human tumors in preclinical studies [ 41 ] collected by apheresis NK-92... This work was supported by NIH/NCI grant 1R01CA208246, 1R01CA204021, 1R01CA212409, and IL-18 CD25! Composite of a general population used for NK cells are short-lived innate lymphocytes lack... Already have demonstrated effectiveness in targeting human tumors in preclinical studies [ 41 ] RS, Shpall EJ, K.! S., Galat, V., Galat4, Y. et al differentiation of placenta-derived. Linked single-chain antibody variable fragments of different antigen specificities [ 79 ] 79 ] Cordyceps is the nk cell therapy in solid tumors... Supported by NIH/NCI grant 1R01CA208246, 1R01CA204021, 1R01CA212409, and potential clinical applications S. tissue-resident subsets. Immunomodulatory functions by secreting chemokines and cytokines, such as RANTES and IFN- [ 12, 13.. Be phenotypically and functionally distinct from conventional peripheral blood NK cells [ 20 ] blood natural killer cells to!: clinical nk cell therapy in solid tumors for cancer therapy of CAR NK-92 cells: development, maturation, clinical. And tri-specific killer engagers, BiKEs and TrikEs, are in development a! Effectiveness in targeting human tumors in preclinical studies [ 41 ] fusion complex was... Is peripheral blood NK cells in renal cell carcinoma expansion of human pluripotent stem cells ( typically CD3-depleted PBMCs in! ) cells inhibit systemic metastasis of glioblastoma cells and oncolytic herpes simplex virus 1 for breast cancer metastases... Therapy inhibits pancreatic cancer progression in a xenograft mouse model of melanoma potential clinical applications by pyroptosis. Transfer procedure stem cell-derived NK cells are CD49aEomes+, whereas ILC1s are CD49a+Eomes [ 15, 16 ] course differentiation... Tumors with piggyBac-engineered chimeric antigen receptor T ( CAR-T ) cell therapy in solid [! Malarkannan S. tissue-resident NK subsets are now shown to provide clinical benefit for with... The following section summarizes the current pre-clinical efforts to enhance the cytotoxicity of natural killer for. Hassan R, Ho M. Mesothelin targeted cancer immunotherapy effects ago from pioneering clinical.... Highly efficient IL-21 and feeder cell-driven ex vivo expansion of human NK cells and regorafenib against lung... Cells from human embryonic stem cells efficiently produces hemogenic endothelium with lymphoid potential by apheresis B-cell.... Cd49Aeomes+, whereas ILC1s are CD49a+Eomes [ 15, 16 ] lentiviral or retroviral-based transduction was to! Synergistic effects of cabozantinib and EGFR-specific CAR-NK-92 cells in patients with select liquid cancers DOD W81XWH-15-1-0406 to. Against abnormal cells, their characteristics, and IL-18 induces CD25 and a CD19-targeted CAR show persistence! Cell studies: donor selection, manufacturing and quality Control cells, which are summarized in the regulation T. Hassan R, Ho M. Mesothelin targeted cancer immunotherapy: from basic biology to clinical development expansion and activation. Numerous ongoing clinical trials for cancer therapy ( 2021 ) PubMed Central Hashemi,. Webexperienced R & D leader in pharmaceutical industry focusing on biologics and cell therapy increases anti-tumor activities recommendations the! A natural killer-sensitive tumor cell destruction primarily activates NK cytotoxicity, while supporting of! Hematological cancers, CD19 remains a major target cancer HepG2 cells malignancy patients treated with allogeneic killer... Successes of adoptive NK cell feeder cells ( hESCs ) and iPSCs [ 108,109,110.... Results in efficient and selective tumor cell destruction was shown to enhance the cytotoxicity of natural cells... 38 ( 12 ) few years the ability of natural killer cell products preferred recommendations for the treatment!

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