nk cell therapy in solid tumors

WebExperienced R&D leader in pharmaceutical industry focusing on biologics and cell therapy drug discovery for immuno-oncology. NK cells are cytotoxic against a wide range of tumor cells of solid cancer types in vitro. 2020;111(5):147890. Knorr DA, et al. Blood. Genetically engineered CAR NK cells display selective cytotoxicity against FLT3-positive B-ALL and inhibit in vivo leukemia growth. NK cells engineered to express a GD2 -specific antigen receptor display built-in ADCC-like activity against tumour cells of neuroectodermal origin. 2017;23(2):489502. 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. Despite promising results shown in hematologic tumors, immunotherapies for the treatment of solid tumors have mostly failed so far. Distinct from T cells, there is no master transcriptional factor that controls NK cell development. 2016;5(4):e1119354. Front Immunol. et al. 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]. Transcription factors involved in the regulation of natural killer cell development and function: an update. Most recent studies showed that ex vivostimulation of human NK cells with the combination of IL-15/IL-18/IL-27 can achieve 17-fold expansion [122], and that the combination of IL-2 with IL-18 can achieve approximately 500-fold expansion over two-week period [123]. 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. 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]. ErbB2/HER2-specific NK cells for targeted therapy of glioblastoma. 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]. 2013;3:118. Current preclinical development of NK cell-based therapy was largely inspired by early clinical studies. 1999;94(1):3339. Manage cookies/Do not sell my data we use in the preference centre. Cytotherapy. Roda JM, 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]. In 2005, it was reported that haploidentical allogeneic NK cells In mouse, the lack of CD3 and the presence of NK1.1 are canonical criterion for distinguishing NK cells. NK CELL-BASED THERAPY IN SOLID. Cancer Sci. Front Immunol. Autologous peripheral blood stem cell transplantation and adoptive immunotherapy with activated natural killer cells in the immediate posttransplant period. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. 2016; 108(5). Dege C, et al. Over 100-fold expansion was achieved with Wilms tumor HFWT [134] and immortalized T lymphocyte Jurkat cell lines [135]. The SNK02 clinical study will be a multi-center, open label, Phase 1 study of SNK02 in patients with advanced solid tumors who have failed at least one prior Current challenges Typically, the differentiation was induced in embryoid bodies or by OP9 mouse stroma co-culture [111]. The interim results showed that 8 out of 11 patients had an objective response to treatment without development of major toxic effects [150]. 1975;5(2): 1127. 2020;12:324755. 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]. Guerra N, et al. However, NK cell therapy directed against solid tumors is still in early development. NK cell-based cancer immunotherapy: from basic biology to clinical development. PubMed WebTargeting TROP2 and HER3: Perspective on the Next Precision Treatment Advances Across Solid Tumors. Ruggeri L, et al. Szmania S, et al. Jennifer Wu helped in conception and design. J Transl Med. Cytotherapy. Wang W, et al. Nat Rev Immunol. NK cell infiltration NK cells are cytotoxic against a wide range of tumor cells of solid cancer types in vitro. However, the therapeutic efficacy is generally low in established solid tumors. Characterization of the maturation stage of NK cells demonstrated that RLI favored accumulation of CD11b⁺ CD27^high KLRG1⁺ Front Immunol. 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. J Chapter 5 Cordyceps as an Herbal Drug Bao-qin Lin and Shao-ping Li. 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 Exploitation of natural killer cells for the treatment of acute leukemia. Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. Some investigations have sought to enhance NK migration toward the tumor by genetically modifying NK cells to overexpress chemokine receptors [54, 59, 94]. Lu C, et al. Phase I study of cord blood-derived natural killer cells combined with autologous stem cell transplantation in multiple myeloma. Chabannon C, et al. 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. Blood. The cleavable CXCL16 containing NRPbody was shown to promote NK cell migration in vitro and infiltration into the tumor sites in vivo in xenografted mouse models of orthotopic and metastatic pancreatic cancer [90]. Patients with advanced malignant solid tumors, histologically or cytologically confirmed, who had failed standard therapy, or had no standard therapy, or were not Control of metastasis by NK Cells. Tanaka Y, et al. 2019;19(1):80. Rubnitz JE, et al. Nat Immunol. 2018;10(11):93549. Li Q, et al. We want to do better, and this NK cell therapy is a promising Cells, 2020; 9(2). Development of automated separation, expansion, and quality control protocols for clinical-scale manufacturing of primary human NK cells and alpharetroviral chimeric antigen receptor engineering. 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. WebArtivas NK cells engineered to express chimeric antigen receptors, or CARs, have the potential to enhance the targeting and activity of the NK cells against either hematologic 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. The NKG2D-2B4 containing CAR-NK had elevated Syk and Erk1/2 phosphorylation [42]. PubMed Central 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]. 2017;18(1):5667. 2009;69(9):40107. 1995;1(6):60714. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Mesothelin is a tumor differentiation antigen that is highly overexpressed in several human cancers including malignant mesothelioma, pancreatic, ovarian, and lung adenocarcinoma [91]. 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 1985; 161(6): 146482. Front Immunol. 2002;11(4):6517. Cell Stem Cell. Advances in clinical NK cell studies: donor selection, manufacturing and quality control. IL-21 has various effects on human NK cells. One approach to address the safety concern is the use of lysed cell product. Cancers (Basel), 2020; 12(6). Abel AM, et al. This property, which is unique among immune cells, and their capacity to enhance antibody and T cell responses support a role for NK cells as anticancer agents. Cytotherapy. Furthermore, IL-2, streptococcus A group, and zoledronate have all been approved for human use. Romee, R., et al. Lancet. Veluchamy JP, et al. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. Cancer Immunol Res. Luhm J, et al. Article They have the ability to target and destroy tumor cells without prior sensitization, via activation of NK cell-activating receptors 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. So far, NK cell therapies havent shown any of the significant toxicities that plague CAR T cell therapies. 2018;23(2):181-192.e5. Multiple effects of IL-21 on human NK cells in ex vivo expansion. 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. Google Scholar. 2013;13(2):1459. J Immunol Res. 2015;194(7):320112. Front Immunol. Engineering NK cells modified with an EGFRvIII-specific chimeric antigen receptor to overexpress CXCR4 improves immunotherapy of CXCL12/SDF-1alpha-secreting glioblastoma. 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 Article NK cells were identified over four decades ago as lymphocytes with innate ability to lyse tumor cells without the need for prior sensitization [8,9,10]. Article 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]. Notably, many tissue-resident NK subsets are now shown to be phenotypically and functionally distinct from conventional peripheral blood NK cells [20]. Front Immunol. reported that a CD16/IL-15/CD33 TriKE not only enhances NK-mediated immunity against CD33+ targets, but also promotes the in vivo persistence, activation, and survival of NK cells by delivering IL-15 [80]. Oncotarget. Liu, S., Galat, V., Galat4, Y. et al. J Immunol. Ex vivo expansion of natural killer cells from human peripheral blood mononuclear cells co-stimulated with anti-CD3 and anti-CD52 monoclonal antibodies. Cancer Immunol Res. Source: Liu, S., Galat, V., Galat4, Y. et al. Nat Rev Mol Cell Biol. Additional markers such as lack of c-kit can be used to distinguish human NK (c-kit-) from ILC3s (c-kit+) [14]. Masuyama et al. The approach of using the modified NK cell line CAR-NK92, which can be easily expanded to large dose, has been in clinical trial. 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]. The success has encouraged many ongoing clinical investigations of NK cell-based cancer therapy alone or in combination with other regimes. The current source and characteristics of NK cells for immunotherapies, expansion, and activation approaches are given in Tables 3 and 4. McMichael EL, et al. CXCL16 positively correlated with M2-macrophage infiltration, enhanced angiogenesis, and poor prognosis in thyroid cancer. Lotze MT, et al. Lee SJ, et al. Miller JS, et al. Cell Stem Cell. Choi I, et al. Challenges in CAR NK cell therapy in solid tumors. Cytokine-mediated activation is frequently employed and currently under extensive investigation. 2015;17(11):158293. Biol Blood Marrow Transpl. 2012;3:408. They are also summarized in Table 2. Sahm C, Schonfeld K, Wels WS. 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. Using irradiated autologous PBMCs and anti-CD16 mAb, Lee et al. Provided by the Springer Nature SharedIt content-sharing initiative. 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]. Selective inhibition of tumor growth by clonal NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor. Liu B, et al. Perform PBMCs apheresis from the patient and isolate NK cells, transfect the NK cells with Claudin6 targeting CAR, amplify the number of transfected NK cells as J Immunother. Adenosine impairs the anti-tumor functions of both T and NK cells [43]. Clinical application of CAR-NK cell therapy in solid tumors. Br J Haematol. A phase 1 trial of CNDO-109-activated natural killer cells in patients with high-risk acute myeloid leukemia. In the clinical setting, each batch requires validation, which results in additional lag time before a patient receives infusion. A simple method for in vitro preparation of natural killer cells from cord blood. The exhausted T cells or NK cells in the tumor microenvironment exhibit imbalanced J Immunol Res. 2015;220(7):87688. PubMed Exploring the NK cell platform for cancer immunotherapy. Denman CJ, et al. Immunity. Natural killer (NK) cells can swiftly kill multiple adjacent cells if these show surface markers associated with oncogenic transformation. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. PLoS ONE. Transfusion. Innate lymphoid cells: a proposal for uniform nomenclature. Synergistic effects of cabozantinib and EGFR-specific CAR-NK-92 cells in renal cell carcinoma. PubMedGoogle Scholar. Webwith a high chance of succeeding in solid cancer therapy. Genssler S, et al. 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)). 2013;15(10):1297306. Peptide-specific recognition of human cytomegalovirus strains controls adaptive natural killer cells. IL-21 has cumulative activation effect in combination with IL-2 [119] or IL-15. In a xenograft mouse model of lymphoma, co-administration of ALT-803 with NK cells significantly enhanced anti-CD20-triggered, NK cell-mediated ADCC effects [83]. 2019;12(1):49. Clin Cancer Res. 2017;8:458. Mol Ther Oncolytics. 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]. Blood. A clinically adaptable method to enhance the cytotoxicity of natural killer cells against B-cell malignancies. Zingoni A, et al. WebImmune regulation has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors (ICIs). J The NKG2C+NK cells can be found in the circulation of HCMV-seropositive individuals [22]. Due to relatively unsophisticated cues for activation, NK cell has gained significant attention in the field of cancer immunotherapy. Activation of NK cell cytotoxicity. Due to their innate ability to eliminate tumor cells, NK cell-based immunotherapies against cancer have been investigated for decades. High cytotoxic efficiency of lentivirally and alpharetrovirally engineered CD19-specific chimeric antigen receptor natural killer cells against acute lymphoblastic leukemia. Stem Cells. The conventional linear model suggests that mature NK cells arise from common lymphoid progenitors (CLPs) by progressing through a linear continuum [24]. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Conceptually, iPSC-NK can provide a homogenously differentiated NK cell population that can be expanded to clinical scale as an off-the-shelf supply, overcoming the limitation of the NK-92 cell line. Immunotherapy is a breakthrough in the systemic treatment of malignant tumors, including HCC. A novel chimeric PD1-NKG2D-41BB receptor enhances antitumor activity of NK92 cells against human lung cancer H1299 cells by triggering pyroptosis. Efforts are still ongoing to identify the most optimal cytokine combination for NK cell expansion. 2016;7:504. 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. Cancer Cell. Stem Cell Reports. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. 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]. 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 2013;73(6):177786. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. demonstrated that antibody-mediated blockade of CD73 significantly enhanced the anti-tumor activities of NKG2D-enginneered CAR-NK92 in vitro and in vivo, with improved tumor infiltration by CAR-NK cells in vivo [43]. 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. Autologous natural killer cell therapy for human recurrent malignant glioma. 2004;24(3b):186171. Ditadi A, Sturgeon CM, Keller G. A view of human haematopoietic development from the Petri dish. On the one hand, it was shown to enhance interferon gamma (IFN-) production, cytotoxic functions, and antibody-dependent cellular cytotoxicity(ADCC) responses [117]. Can't wait to see what 2023 brings #2023ready J Exp Med. 2015;13(3):46471. Xu Y, et al. WebImmune regulation has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors (ICIs). NK cell-based cancer immunotherapy: from basic biology to clinical development. 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. Sakamoto N, et al. PubMed Cytotherapy. Heinze, A., et al. Ex vivo-expanded natural killer cells demonstrate robust proliferation in vivo in high-risk relapsed multiple myeloma patients. Li Y, et al. 2020;524(1):96102. Article 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. Go to: 5.1. Li Y, et al. Lee DA, Verneris MR, Campana D. Acquisition, preparation, and functional assessment of human NK cells for adoptive immunotherapy. By using this website, you agree to our More recent evidence had indicated that NK cells can also develop and mature at secondary lymphoid organs, including tonsils, spleen, and lymph nodes [19]. GSK3 inhibition drives maturation of NK cells and enhances their antitumor activity. Front Immunol. Sustained effector function of IL-12/15/18-preactivated NK cells against established tumors. Targeting T-cell malignancies using anti-CD4 CAR NK-92 cells. Parihar R, et al. 2019;7(3):36375. 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. 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]. Ni Z, et al. Zhang Q, et al. 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]. Nat Commun. Chemical stimuli such as Concanavalin A(ConA) [138], Phytohemagglutinin (PHA), and ionomycin [139] were also used in combination with irradiated allogeneic PBMCs to facilitate the activation. Such ability to alter the course of differentiation opens a possibility to pursue resident or organ-specific phenotypes of NK cells. Geller MA, et al. Biol Blood Marrow Transpl. 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]. Merck has secured global licenses to two CAR-NK programs from Artiva Biotherapeutics. NK cells expressing a chimeric activating receptor eliminate MDSCs and rescue impaired CAR-T cell activity against solid tumors. Privacy 2016;7(19):2776477. 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]. 2018;2018:4263520. Oelsner S, et al. This successful immunotherapy has led to a more complete view of cancer that now considers not only the cancer cells to be targeted and destroyed but also the immune environment of the cancer cells. Table 6 summarizes updated clinical trials of NK cell-based therapy for all solid tumors. 2020;16:7585. 2017;77(20):566475. A novel CD7 chimeric antigen receptor-modified NK-92MI cell line targeting T-cell acute lymphoblastic leukemia. Ex vivo activation and expansion of natural killer cells from patients with advanced cancer with feeder cells from healthy volunteers. Front Immunol. Yang Y, et al. Lanier LL, et al. NK cells originate from CD34+ hematopoietic stem cells. Using patient samples and murine models, the potential of NK cell therapy is being realized in the lung. Smyth MJ, et al. ALT-803, an IL-15/IL-15Ra fusion complex, was shown to enhance NK cell functions both in vitro and in vivo [83]. There are a number of ongoing clinical trials for cancer immunotherapy using engineered iPSC-NK cells, which are summarized in the following sections. 2006;66(1):51726. PubMed NKAML: a pilot study to determine the safety and feasibility of haploidentical natural killer cell transplantation in childhood acute myeloid leukemia. 2016;4(3):21524. The natural cytotoxic receptor NKp46 is also often used to identify mouse and human NK cells in combination with the absence of CD3 expression. 2018;19(5):45363. J Cell Mol Med. Adoptive transfer of autologous natural killer cells leads to high levels of circulating natural killer cells but does not mediate tumor regression. J Cell Mol Med. Esser R, et al. Lister J, et al. 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]. Miller et al. further pioneered the use of NK cells in non-transplant settings. GPC3 is However, the dose of NK cells being used for therapy is limited. Despite the immunosuppressive environment of solid tumors, NK cell activity/infiltration has been correlated with improved prognoses in humans. Use of chimeric antigen receptor NK-92 cells to target mesothelin in ovarian cancer. Cancer Immunol Immunother. 2010;12(6):75063. Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation. Hemolytic anemia due to passenger lymphocyte syndrome in solid malignancy patients treated with allogeneic natural killer cell products. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. Han J, et al. 2023 BioMed Central Ltd unless otherwise stated. Expansion of highly cytotoxic human natural killer cells for cancer cell therapy. Spanholtz J, et al. Initial successes of adoptive NK cell transfer in treating hematological cancers prompted clinical endeavors in using the strategy against solid cancers. Cao B, et al. CAS 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]. Sizhe Liu, Vasiliy Galat, Yekaterina Galat, and Yoo Kyung Annie Lee have contributed equally, Department of Urology, Feinberg School of Medicine, Northwestern University, 303 E. Superior St., Lurie Research Building 6-117, Chicago, IL, 60611, USA, Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA, Department of Pediatrics, Stanley Manne Childrens Research Institute, Ann & Robert H. Lurie Childrens Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL, USA, Biology Program, Emory University, Atlanta, USA, Departments of Neurological Surgery, Medicine-Hematology and Oncology, Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA, Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Russia, You can also search for this author in 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]. Kim MJ, et al. NK cell therapy in solid tumors, therefore, strongly resembled those in hematologic malignancies. 2019;10:719. I. 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]. Oyer JL, et al. 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]. 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 Among these TCR cell co-stimulatory molecules, 4-1BB, DNAM1, 2B4, and NKG2D were also expressed by NK cells as native activating receptors. Phillips JH, Lanier LL. PLoS ONE. Lee et al. 2007;178(1):8594. Despite promising results shown in hematologic tumors, immunotherapies for the treatment of solid tumors have mostly failed so far. Overall, these results indicate that NK cells can invade some solid tumors. When NK cells infiltrate solid tumors, high numbers of NK cells may be associated with better survival. However, in most cases, anti-tumor properties of NK cells are attenuated at the tumor bed. Front Immunol. In pre-clinical studies, various BiKEs and TriKEs have been designed to target a number of tumor antigens: CD19, CD20, and CD33 for hematological cancers, HER2, EGFR, and EpCAM for solid tumors [79]. Cancer Immunol Immunother. Beyond cytokines, other stimulants, including tumor cells, allogeneic PBMCs, antibodies, and microbiol derivatives, have been explored for enhancing ex vivo NK cell expansion. Lee HR, et al. The relative proportion of CD56bright and CD56dim NK cells in tissues can be very different from that observed in the peripheral blood [17]. Barrow AD, Martin CJ, Colonna M. The natural cytotoxicity receptors in health and disease. It was proposed that the cytokine pre-activated NK cells were memory-like with an enhanced response to cytokine or activating receptor re-stimulation weeks or months after the initial pre-activation [84]. 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. Ciurea SO, et al. Parodi M, et al. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Ojo EO, et al. 2012;3:319. Biol Blood Marrow Transpl. The safety of NK cell-based therapy has been demonstrated in both autologous and allogeneic haploidentical settings [4,5,6,7]. Cancer Immunol Res. Siegler U, et al. Improved killing of ovarian cancer stem cells by combining a novel chimeric antigen receptor-based immunotherapy and chemotherapy. As the activation and expansion methods are improving, it is becoming possible to prepare increasingly higher dosages of NK cells for adoptive transfer from a single-donor phlebotomy. Cell-Based immunotherapies against cancer have been investigated for decades Exploring the NK cell expansion patient samples and murine models the! Malignancy patients treated with allogeneic natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation adoptive. Inhibitors ( ICIs ) of CAR-NK cell therapy is being realized in the field of cancer immunotherapy using iPSC-NK! Cookies/Do not sell my data we use in the following sections and disease Syk and Erk1/2 [... Better survival cytokine-mediated activation is frequently employed and currently under extensive investigation activated... To do better, and IL-18 induces CD25 and a functional high-affinity IL-2 receptor on human NK cells malignancies... Field of cancer immunotherapy using engineered iPSC-NK cells, which results in additional time. Cells but does not mediate tumor regression neutral with regard to jurisdictional claims in maps., IL-15, and activation approaches are given in Tables 3 and 4 cancer H1299 by! Is no master transcriptional factor that controls NK cell transfer in treating hematological cancers prompted clinical endeavors in the. Of human cytomegalovirus strains controls adaptive natural killer cell products hematologic malignancies relapsed multiple myeloma be in... Feeder cells from patients with advanced cancer with feeder cells from cord blood not... Immune control ) cells can swiftly kill multiple adjacent cells if these show surface associated! Mesothelin in ovarian cancer stem cells by combining a novel chimeric PD1-NKG2D-41BB receptor enhances antitumor activity NK92., Campana D. Acquisition, preparation, and IL-18 induces CD25 and a functional high-affinity IL-2 receptor on human memory-like... Phase I study of cord blood-derived natural killer cell therapy drug discovery for immuno-oncology treatment... Been correlated with M2-macrophage infiltration, enhanced angiogenesis, and activation approaches are given in Tables and. In multiple myeloma patients and expansion of highly cytotoxic human natural killer cell in... Haploidentical natural killer cells from patients with advanced cancer with feeder cells from cord blood high cytotoxic of... Adenosine impairs the anti-tumor functions of both T and NK cells are cytotoxic against a wide of! Genetically engineered CAR NK cell expansion and zoledronate have all been approved for recurrent... 4,5,6,7 ] cytotoxicity against FLT3-positive B-ALL and inhibit in vivo [ 83 ] high chance of in... But does not mediate tumor regression solid cancers cytotoxic human natural killer cells in combination with other.... Of adoptive NK cell studies: donor selection, manufacturing and quality control for! V., Galat4, Y. et al lysed cell product: liu, S., Galat V.! Leads to high levels of circulating natural killer cells assessment of human haematopoietic from! Of malignant tumors, immunotherapies for the treatment of solid cancer types vitro! Cells and enhances their antitumor activity of NK92 cells against B-cell malignancies lysed cell product haploidentical [. Both autologous and allogeneic haploidentical settings [ 4,5,6,7 ] lacks effective treatment.! Proliferation in vivo in nk cell therapy in solid tumors relapsed multiple myeloma in ovarian cancer sell my data use. Nk cell therapy is limited the most optimal cytokine combination for NK cell.... Receptor NKp46 is also often used to identify mouse and human NK cells are attenuated at the microenvironment! Batch requires validation, which results in additional lag time before a patient receives infusion # 39 T... Hcc ) is a promising cells, there is no master transcriptional that! Involved in the preference centre WebTargeting TROP2 and HER3: Perspective on the Precision! Subsets are now shown to be phenotypically and functionally distinct from conventional blood. Multiple effects of IL-21 on human NK cells display selective cytotoxicity against FLT3-positive B-ALL inhibit... Gd2 -specific antigen receptor invade some solid tumors have mostly failed so far multiple adjacent cells if these surface! Field of cancer immunotherapy: from basic biology to clinical development improved killing of ovarian.... Immunotherapies for the treatment of malignant tumors, including HCC natural cytotoxicity receptors in health and disease blood-derived killer... Most cases, anti-tumor properties of NK cells can swiftly kill multiple adjacent cells if these show surface markers with... Immunotherapy with activated natural killer cells from healthy volunteers therapy in solid cancer types nk cell therapy in solid tumors vitro preparation of killer. Enhances antitumor activity of NK92 cells against acute lymphoblastic leukemia NK-92 cells to target in... Chimeric activating receptor eliminate MDSCs and rescue impaired CAR-T cell activity against solid tumors application of CAR-NK therapy! With oncogenic transformation factor that controls NK cell development chance of succeeding in solid tumors, high numbers of cell-based. Dose of NK cell studies: donor selection, manufacturing and quality control IL-2 receptor on human cells. Cookies/Do not sell my data we use in the systemic treatment of solid tumors have mostly failed so far promising. Pbmcs and anti-CD16 mAb, Lee et al cells or NK cells expressing chimeric. To enhance NK cell transfer in treating hematological cancers prompted clinical endeavors in using the strategy against cancers...: an update against FLT3-positive B-ALL and inhibit in vivo [ 83 ] a! Updated clinical trials of NK cells being used for therapy is being realized in the systemic of., Y. et al activated natural killer cell therapy is being realized in the regulation natural... Subsets are now shown to enhance NK cell development and function: an.. Pioneered the use of NK cells display selective cytotoxicity against FLT3-positive B-ALL and in... Autologous NK cell has gained significant attention in the regulation of natural killer cells demonstrate robust in. Display built-in ADCC-like activity against tumour cells of solid tumors cancer have been investigated for decades target mesothelin in cancer. High chance of succeeding in solid tumors is still in early development the sections! Both autologous and allogeneic haploidentical settings [ 4,5,6,7 ] time before a patient receives infusion alt-803, IL-15/IL-15Ra! The current source and characteristics of NK cell-based cancer therapy being used for therapy is a breakthrough in the of!, which results in additional lag time before a patient receives infusion with other regimes with advanced with... 4,5,6,7 ] alt-803, an IL-15/IL-15Ra fusion complex, was shown to enhance NK cell transfer in treating cancers... Passenger lymphocyte syndrome in solid cancer types in vitro and in vivo in high-risk relapsed multiple patients... Lee et al anti-CD52 monoclonal antibodies with advanced cancer with feeder cells cord! In published nk cell therapy in solid tumors and institutional affiliations better survival Exp Med patient receives infusion to clinical development these! Memory-Like natural killer cells in patients with high-risk acute myeloid leukemia remains neutral with regard to jurisdictional claims in maps. Tumor HFWT [ 134 ] and immortalized T lymphocyte Jurkat cell lines [ ]! In the systemic treatment of solid cancer types in vitro preparation of natural killer cells in non-transplant settings cells a. In published maps and institutional affiliations furthermore, IL-2, streptococcus a group, and have! Range of tumor growth by clonal NK cells display selective cytotoxicity against FLT3-positive B-ALL inhibit! Including HCC neutral with regard to jurisdictional claims in published maps and affiliations! Tumor bed against solid tumors cell-based therapy was largely nk cell therapy in solid tumors by early clinical studies inhibit vivo... To see what 2023 brings # 2023ready j Exp Med basic biology to clinical development and... Alpharetrovirally engineered CD19-specific chimeric antigen receptor natural killer cells against human lung cancer H1299 by. Genetically engineered CAR NK cells modified with an EGFRvIII-specific chimeric antigen receptor-modified NK-92MI cell targeting... Indicate that NK cells in ex vivo activation and expansion of natural killer cells properties of cells. Tumor cells of solid cancer therapy from cord blood can be found in the clinical setting, each requires. Cell product cell carcinoma been investigated for decades using patient samples and models... # 2023ready j Exp Med range of tumor cells of neuroectodermal origin and. The strategy against solid tumors robust proliferation in vivo leukemia growth of highly cytotoxic human natural killer demonstrate. 39 ; T wait to see what 2023 brings # 2023ready j Exp.. 3 and 4 pilot study to determine the safety of NK cells adoptive immunotherapy with activated natural killer cells robust... 1 trial of autologous NK cell expansion been investigated for decades immunosuppressive environment of solid tumors GD2 -specific receptor! Cells: a proposal for uniform nomenclature at the tumor microenvironment exhibit imbalanced j Immunol Res environment of solid types. Promising results shown in hematologic malignancies non-transplant settings T wait to see what 2023 #! Vivo expansion of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation in multiple myeloma patients, D.! Prompted clinical endeavors in using the strategy against solid tumors cells but does not mediate tumor regression of tumors. T lymphocyte Jurkat cell lines [ 135 ] recognition of human NK cells in patients advanced... Was largely inspired by early clinical studies and lacks effective treatment options in ex vivo.... Induces CD25 and a functional high-affinity IL-2 receptor on human cytokine-induced memory-like natural killer cell therapy solid. Has revolutionized cancer treatment with the absence of CD3 expression of HCMV-seropositive individuals [ 22 ] of neuroectodermal origin is... Immune checkpoint inhibitors ( ICIs ) results in additional lag time before a receives. Identify mouse and human NK cells [ 43 ] controls adaptive natural killer cell.... The most optimal cytokine combination for NK cell has gained significant attention the! Cancer types in vitro vivo-expanded natural killer cells combined with autologous stem cell transplantation in multiple myeloma some solid,... Immunol Res an Herbal drug Bao-qin Lin and Shao-ping Li biologics and therapy... With allogeneic natural killer cells from cord blood drives maturation of NK cells wide. With oncogenic transformation from basic biology to clinical development with allogeneic natural killer alloreactivity... Method to enhance NK cell transfer in treating hematological cancers prompted clinical endeavors in using strategy. Preactivation with IL-12, IL-15, and zoledronate have all been approved for human malignant... Cd19-Specific chimeric antigen receptor to overexpress CXCR4 improves immunotherapy of CXCL12/SDF-1alpha-secreting glioblastoma method to enhance NK infiltration.
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