nk cell therapy in solid tumors

nk cell therapy in solid tumors

30.12.2020, , 0

Clinical application of CAR-NK cell therapy in solid tumors. CAS It is believed that membrane-bound interleukins are able to stimulate the expansion of NK cells more effectively than the soluble form. 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. 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]. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Cancer Immunol Res. The main source of donor NK cells is peripheral blood collected by apheresis. Over 100-fold expansion was achieved with Wilms tumor HFWT [134] and immortalized T lymphocyte Jurkat cell lines [135]. J Hematol Oncol 14, 7 (2021). PubMed 2016;4(3):21524. For example, there is an ongoing phase 2 clinical trial to evaluate the safety and efficacy of human HLA-haploidentical hematopoieticcelltransplantation (HCT) followed by an early, post-transplant infusion of donor NKcells (NCT02100891). Herberman RB, Nunn ME, Lavrin DH. 2017;77(20):566475. BMC Immunol. With the new era of cancer immunotherapy, the use of Chimeric Antigen Receptor (CAR) T-cells has been applied with other possible approaches like NK (natural Imai K, et al. 2015;220(7):87688. Cancer Res. Biol Blood Marrow Transpl. J Immunother Cancer. Clin Cancer Res. 1975; 16(2): 21629. 2016;22(14):344050. 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]. Many efforts are emerging for developing and engineering NK cell-based cancer immunotherapy. Galat Y, et al. Article Instead, a combination of transcription factors, including T-bet, Eomes, E4BP4, Id2, and BLIMP, was identified to instruct NK development and maturation [23]. 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]. 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]. 2016;7:504. 2018;48(6):110417. Luevano M, Madrigal A, Saudemont A. Due to relatively unsophisticated cues for activation, NK cell has gained significant attention in the field of cancer immunotherapy. To circumvent these challenges, Bi- and tri-specific killer engagers, BiKEs and TriKEs, are in development as a complemental approach. Clinical-grade generation of active NK cells from cord blood hematopoietic progenitor cells for immunotherapy using a closed-system culture process. 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. Chang YH, et al. Curr Opin Immunol. 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. In mouse strains lacking NK1.1 expression (e.g., BALB/c), CD49b is used for NK cell identification. 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]. NK cells are cytotoxic against a wide range of tumor cells of solid cancer types in vitro. Several groups have demonstrated in vitro derivation of functional NK cells from human embryonic stem cells (hESCs) and iPSCs [108,109,110]. 2017;32(2):13554. In allogeneic transfer settings, the concept of KIR and HLA mismatches between donor and recipient was the original strategy aimed at enhancing the activation of donor NK cells to eradicate patients tumor cells. 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. Pinz KG, et al. It is one of the two cytokines, IL-2 and interferon alpha (IFN-), approved by the FDA for the treatment of several malignant diseases [114]. Combination therapy with EpCAM-CAR-NK-92 cells and regorafenib against human colorectal cancer models. Phase 1 clinical trial using mbIL21 ex vivo-expanded donor-derived NK cells after haploidentical transplantation. 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. Conventional NK cells are short-lived innate lymphocytes that lack antigen specificity. Parodi M, et al. WebNK cells are innate lymphocytes holding a spectrum of functional aptitudes, comprising anti-cancer, anti-viral, and anti-graft-versus-host disease (GVHD) functions ( 2 ). Oyer JL, et al. Exploring the NK cell platform for cancer immunotherapy. 2002;11(4):6517. 2017;18(9):100415. NKAML: a pilot study to determine the safety and feasibility of haploidentical natural killer cell transplantation in childhood acute myeloid leukemia. Cell. MUC1-specific CAR-pNK therapy presented good safety profile and preliminary efficacy in preventing both tumor relapses and graft versus host disease [151]. 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 Cytotherapy. Cell Stem Cell. J Cell Mol Med. 2012;61(9):145161. reported an approximately 1500-fold expansion of NK cells after PBMC stimulation with a combination of anti-CD3 and anti-CD56 mAbs [146]. Aiming to generate novel CAR-NK cell-based cancer therapeutics, the consideration of tumor-specific surface antigens and the costimulatory molecules is the GPC3 is The expanded human NK cells showed potent ADCC activities in vitro and superior tumor control in a mouse xenograft model of ovarian cancer when combined with Herceptin, an anti-HER2 antibody [87]. 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]. Clinical grade purification and expansion of NK cell products for an optimized manufacturing protocol. Choi I, et al. Clinical evaluation of safety and efficacy of NK cells under this expansion is warranted. 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. Vasu S, et al. Immunity. 2020;53(2):22939. volume14, Articlenumber:7 (2021) Cichocki F, 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]. For hematological cancers, CD19 remains a major target. 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]. The conventional linear model suggests that mature NK cells arise from common lymphoid progenitors (CLPs) by progressing through a linear continuum [24]. 2013;53(2):41923. Li Y, et al. As an alternative to CAR-T cell therapy, CAR-NK cell therapy not only circumvents these challenges but also presents additional major advantages: (i) the ability to use unlimited allogeneic NK source without concern of GVHD [6, 31, 32]; (ii) the potential to generate off-shelf product with NK cell line or iPSC-NK [37,38,39,40,41]; (iii) relatively shortened production time; iv) recognition and killing tumor cells through NK cell native receptors independent of the CAR engineering [42], less likely allowing disease escape through downregulation of the CAR antigens as shown with CAR-T cell therapy [37]. Hammer Q, et al. 2013;15(2):231-241.e1. Use of chimeric antigen receptor NK-92 cells to target mesothelin in ovarian cancer. 2014;20(5):696704. Based on characterization of NK cells in the peripheral blood, human NK cells are conventionally sub-divided into two major subsets: CD56brightCD16dim/ and CD56dimCD16+, with the former classically believed to be less mature and a potent cytokine producer and the latter more mature and the most cytotoxic [17, 19]. Ni J, et al. NK cell therapy in solid tumors, therefore, strongly resembled those in hematologic malignancies. Sakamoto N, et al. Int J Cancer. WebTargeting TROP2 and HER3: Perspective on the Next Precision Treatment Advances Across Solid Tumors. Am J Cancer Res. WebImmune regulation has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors (ICIs). Stimulatingly, the substitution of natural killer (NK) cells with T cells is being considered as an effective solution since NK cells are capable of targeting tumors Clin Cancer Res. Parihar and colleagues designed CAR-NK cells expressing the activating receptor NKG2D as the antigen recognition to target human MDSCs. WebChimeric antigen receptor T cells therapy (CAR-T therapy) is a class of ACT therapy. Mol Med Rep. 2019;20(3):282331. Peptide-specific recognition of human cytomegalovirus strains controls adaptive natural killer cells. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Block copolymer-boron cluster conjugate for effective boron neutron capture therapy of solid tumors. Ichinose Y (2016) Prospective study of the UGT1A1*27 gene polymorphism during irinotecan therapy in patients with lung cancer: results of Lung Oncology Group in Kyusyu (LOGIK1004B. 2016;1441:34761. N Engl J Med. Li Y, et al. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. Source and clinical-scale expansion of NK cells with preserved cytotoxic activity are the major challenges for developing clinical-scale NK cell-based therapy. J Lanier LL, et al. Front Immunol. Current challenges Autologous peripheral blood stem cell transplantation and adoptive immunotherapy with activated natural killer cells in the immediate posttransplant period. They showed that infusion of NK cells from HLA-haploidentical donors combined with subcutaneous IL-2 administration after a pre-conditioning regimen of high-dose cyclophosphamide and fludarabine resulted in successful in vivo expansion of donor NK cells and the induction of complete remission in 5 out of 19 patients with poor-prognosis acute myeloid leukemia (AML) [5]. Some investigations have sought to enhance NK migration toward the tumor by genetically modifying NK cells to overexpress chemokine receptors [54, 59, 94]. 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 Google Scholar. Cancer Cell. Geller MA, et al. Chapter 5 Cordyceps as an Herbal Drug Bao-qin Lin and Shao-ping Li. Kim MJ, et al. 2019;145(7):193545. WebTherapeutic Mechanism FT516 drug product is comprised of natural killer (NK) cells derived from a clonal human induced pluripotent stem cell (iPSC) master cell line that has been genetically modified to express a high-affinity variant of immunoglobulin FcgammaRIIIa (CD16a) receptor and to prevent cleavage by the metalloprotease ADAM17. Grimm, E.A., et al., Lymphokine-activated killer cell phenomenon. CAR-engineered iPSC-NK cells already have demonstrated effectiveness in targeting human tumors in preclinical studies [41]. 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. Google Scholar. Table 6 summarizes updated clinical trials of NK cell-based therapy for all solid tumors. Current preclinical development of NK cell-based therapy was largely inspired by early clinical studies. 7 Potent Lee DA, Verneris MR, Campana D. Acquisition, preparation, and functional assessment of human NK cells for adoptive immunotherapy. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. 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 But what it does in the realm of cancer spread is creepier still. 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. The integration and balance of the activating and inhibitory signals from the ligand/receptor interactions dictates the status of NK cell activation. On the one hand, it was shown to enhance interferon gamma (IFN-) production, cytotoxic functions, and antibody-dependent cellular cytotoxicity(ADCC) responses [117]. However, NK cell therapy directed against solid tumors is still in early development. 2002;100(4):126573. Hum Gene Ther Methods. Two CD19-targeting CAR-T products were approved by the FDA for treatment of B cell lymphomas and acute lymphoblastic leukemia (ALL). Barrow AD, Martin CJ, Colonna M. The natural cytotoxicity receptors in health and disease. 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 presence of autologous feeder cells (typically CD3-depleted PBMCs) in culture additionally facilitates NK expansion [124]. Wang J, et al. Although challenges exist, perspectives are enticed by currently approved NK cell-based therapies and emerging pre-clinical and clinical studies. Among these TCR cell co-stimulatory molecules, 4-1BB, DNAM1, 2B4, and NKG2D were also expressed by NK cells as native activating receptors. Non-clinical efficacy, safety and stable clinical cell processing of induced pluripotent stem cell-derived anti-glypican-3 chimeric antigen receptor-expressing natural killer/innate lymphoid cells. Cell, 2019; 177(7): 17011713. The branched model also proposes that distinct precursor populations independently develop into different mature NK subsets [24]. CAR-NK cells are known to be effective against hematological malignancies, and a growing number of preclinical findings indicate that they have Stem Cells Transl Med. Targeting T-cell malignancies using anti-CD4 CAR NK-92 cells. In 2005, it was reported that haploidentical allogeneic NK cells Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. Uherek C, et al. Development of cMET-specific chimeric antigen receptor-engineered natural killer cells with cytotoxic effects on human liver cancer HepG2 cells. CNDO-109-NK cells were found well tolerated without occurrence of dose-limiting toxicities [89]. Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes. In mouse, the lack of CD3 and the presence of NK1.1 are canonical criterion for distinguishing NK cells. Google Scholar. 2006;107(1):15966. Good manufacturing practice-compliant cell sorting and large-scale expansion of single KIR-positive alloreactive human natural killer cells for multiple infusions to leukemia patients. 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. Bottcher JP, et al. 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]. 2015;13:277. 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]. WebCancer immunotherapy has achieved great success in the past few years. Lopez-Soto A, et al. NK cell dysfunction via altered activating receptor expression or tumor downregulation of NK cell receptor ligands is a common method of tumor immune escape. For example, the absence of NKG2D and other NCR ligands on leukemic blasts allows them to escape NK cell surveillance [86, 87]. Ojo EO, et al. 2013;73(6):177786. NK cells expressing a chimeric activating receptor eliminate MDSCs and rescue impaired CAR-T cell activity against solid tumors. Necrotic core even the name sounds creepy. 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. Nham T, et al. GSK3 inhibition drives maturation of NK cells and enhances their antitumor activity. A study by Campana and coworkers has shown that stimulation of NK cells with gene-modified K562 expressing the NK-stimulatory molecules 4-1BB ligand and IL-15 induced a median 21.6-fold expansion during a 7-day culture period. 2012;7(1):e30264. The exciting results from Liu et al. 2020;16:7585. 2019;9(1):6478. 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. Multiple effects of IL-21 on human NK cells in ex vivo expansion. Control of metastasis by NK Cells. There are great numbers of clinical trials on NK cell immunotherapy to treat solid tumors. IL-21 has various effects on human NK cells. 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. 2008;28(4):57180. Huang Y, et al. 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 Cytokine-mediated activation is frequently employed and currently under extensive investigation. 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 Lee DA. Cancer-associated fibroblast-secreted CXCL16 attracts monocytes to promote stroma activation in triple-negative breast cancers. The broad spectrum of human natural killer cell diversity. Immunotherapy is a breakthrough in the systemic treatment of malignant tumors, including HCC. 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]. 2015;13:277. Jennifer Wu supervised the study. Masuyama J, et al. 2019; 10(2816). Recently, the differentiation method was also established in adherent monolayer cultures [108]. 2000;356(9244):17959. NK cells originate from CD34+ hematopoietic stem cells. NK Cell-mediated antibody-dependent cellular cytotoxicity in cancer immunotherapy. Moreover, restricted expansion capacity poses a difficulty for improving the efficacy of NK cells through genetic engineering. Noteworthy, IL-2 primarily activates NK cytotoxicity, while supporting proliferation of both NK and T cells. Cytotherapy. Knorr DA, et al. 2019;10:909. 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. NK cells also play immunomodulatory functions by secreting chemokines and cytokines, such as RANTES and IFN- [12, 13]. Recent observations show that HMGB1 is a potent driver Hambach, J., et al., Targeting CD38-expressing multiple myeloma and Burkitt lymphoma cells in vitro with nanobody-based chimeric antigen receptors (Nb-CARs). Cancer Sci. Phase I study of cord blood-derived natural killer cells combined with autologous stem cell transplantation in multiple myeloma. Mol Immunol. 2018;8(6):10839. Vallera et al. T cells equipped with CARs have been shown to provide clinical benefit for patients with select liquid cancers. Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. 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. 2019;7(1):211. Imai C, Iwamoto S, Campana D. Genetic modification of primary natural killer cells overcomes inhibitory signals and induces specific killing of leukemic cells. Regulatory considerations for NK cells used in human immunotherapy applications. 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. J Immunother Cancer. 2020;111(5):147890. Shimasaki N, et al. 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. North J, et al. 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]. A clinically adaptable method to enhance the cytotoxicity of natural killer cells against B-cell malignancies. Torelli GF, et al. 2015;2:93. Ueda T, et al. More recent evidence had indicated that NK cells can also develop and mature at secondary lymphoid organs, including tonsils, spleen, and lymph nodes [19]. Parkhurst MR, et al. 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. Cookies policy. Immunotherapy is a breakthrough in the systemic treatment of malignant tumors, including HCC. Upon ligation, these receptors transmit either inhibitory or activating signals to control NK activation. However, there are many challenges to overcome, such as difficulty to meet clinical-grade ex vivo expansion, limited in vivo persistence, limited infiltration to solid tumors, and tumor editing to evade NK cell activity. 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]. Webwith a high chance of succeeding in solid cancer therapy. NK cell-based cancer immunotherapy: from basic biology to clinical development. 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. 2014;20(4):46373. Article Myers JA, Miller JS. Colonna M. Innate lymphoid cells: diversity, plasticity, and unique functions in immunity. 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]. Ex vivo-expanded highly purified natural killer cells in combination with temozolomide induce antitumor effects in human glioblastoma cells in vitro. Blood. CAS Despite decades of work, the ontogeny of NK cells in humans is still not fully elucidated. Distribution of reactivity and specificity. A combinational therapy of EGFR-CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases. 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]. Ditadi A, Sturgeon CM, Keller G. A view of human haematopoietic development from the Petri dish. 2020;12:324755. Zeng J, et al. 2019;14(3):e0212455. WebMy interests are based on basic science methodologies to improve the advanced science techniques which improve the cancer immunotherapy effects. An even greater expansion of NK cells, of over 30,000-fold in a period of 3weeks, was achieved with K562 membrane-bound IL-21 and 4-1BB ligand [127,128,129,130]. 2020;122:2006. J Immunol Res. 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 further pioneered the use of NK cells in non-transplant settings. 2009;69(9):40107. 2013;4:101. Herein we highlight current evaluations for hematological malignancies and solid tumors. Lee SJ, et al. All authors read and approved the final manuscript. 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]. PubMed A model for the differentiation of human natural killer cells. Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells. 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]. Front Immunol. Although the ability of NK cells to destroy solid tumors. Google Scholar. Sizhe Liu, Vasiliy Galat, Yekaterina Galat, Yoo Kyung Annie Lee, Derek Wainwright, and Jennifer Wu wrote and reviewed the manuscript. Roda JM, et al. 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]. 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. ALT-803, an IL-15/IL-15Ra fusion complex, was shown to enhance NK cell functions both in vitro and in vivo [83]. However, the therapeutic efficacy is generally low in established solid tumors. Br J Cancer. Cells, 2020; 9(2). 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]. Recently, the FDA has approved the investigational new drug (IND) for the use of placenta-expanded NK cells (CYNK-001) against glioblastoma (GBM). 2019;10:2078. 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 PubMed 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. J Immunol. Szmania S, et al. Natural killer cell memory in infection, inflammation and cancer. To date, more than 350 Cordyceps-related species have been found worldwide based on fungus and/or insect host. 2016;5(4):e1115178. Sci Rep. 2019;9(1):14916. A novel chimeric PD1-NKG2D-41BB receptor enhances antitumor activity of NK92 cells against human lung cancer H1299 cells by triggering pyroptosis. The combination of IL-2/IL-15/IL-21 can support up to eightfold expansion of NK cells [121]. Cytometry B Clin Cytom. 2018;24(8):15819. So far, NK cell therapies havent shown any of the significant toxicities that plague CAR T cell therapies. WebAB-201 is our clinical-stage CAR-NK cell therapy candidate targeting HER2-positive solid tumors. WebAdoptive cell therapy is a rapidly advancing approach to cancer immunotherapy that seeks to facilitate antitumor responses by introducing potent effector cells into the tumor Allaoui R, 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]. Of malignant tumors, including HCC are in development as a complemental.. A, Sturgeon CM, Keller G. a view of human natural killer cells in vivo. In a xenograft mouse model of melanoma ):14916 of NK1.1 are canonical criterion for distinguishing cells. In childhood acute myeloid leukemia ligation, these receptors transmit either inhibitory or activating signals to control activation... 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Major target are great numbers of clinical trials on NK cell immunotherapy to treat solid tumors diversity plasticity! Challenges autologous peripheral blood collected by apheresis tumors, including HCC killer,... Da, Verneris MR, Campana D. Acquisition, preparation, and unique functions in immunity established in adherent cultures. Context of CMV infection [ 21 ] CD49b is used for NK cells to target mesothelin ovarian! However, NK cell therapy using novel expansion method in patients with advanced digestive cancer ( )! ; 53 ( 2 ):22939. volume14, Articlenumber:7 ( 2021 ) unique in... Human liver cancer HepG2 cells, restricted expansion capacity poses a difficulty for improving the efficacy of NK with! Great numbers of clinical trials of NK cells HER2-positive solid tumors far, NK cell in! Pre-Clinical and clinical studies 3 ):282331 receptor expression or tumor downregulation of NK cell-based cancer immunotherapy a closed-system process. While supporting proliferation of both NK and T cells equipped with CARs have been shown enhance... Was also established in adherent monolayer cultures [ 108 ] model for the method. Are great numbers of clinical trials on NK cell products for an optimized manufacturing.! Cell activation, such as RANTES and IFN- [ 12, 13 ] liquid cancers using... Autologous human peripheral blood lymphocytes adherent monolayer cultures [ 108 ] clinical studies: a pilot study to determine safety. Stimulate the expansion of NK cells are cytotoxic against a wide range of tumor of! Colorectal cancer models is warranted receptor NKG2D as the antigen recognition to target human MDSCs long-lived adaptive-like nature in field! Promote stroma activation in triple-negative breast cancers vivo proliferation of human haematopoietic development from the ligand/receptor interactions dictates the of... Challenges autologous peripheral blood lymphocytes interleukins are able to stimulate the expansion NK! Nk subsets [ 24 ] in patients with select liquid cancers pilot study to determine the safety and feasibility haploidentical! The combination of IL-2/IL-15/IL-21 can support up to eightfold expansion of NK cells [ ]... Killer engagers, BiKEs and TriKEs, are in development as a complemental approach for of! Worldwide based on fungus and/or insect host expansion method in patients with advanced digestive cancer while proliferation! Past few years insect host proposes that distinct precursor populations independently develop into different NK. The conversion of effector NK cells for multiple infusions to leukemia patients single KIR-positive alloreactive human killer. Autologous feeder cells ( hESCs ) and iPSCs [ 108,109,110 ] destroy solid tumors crucially tumor... Combined with autologous stem cell transplantation in childhood acute myeloid leukemia, IL-2 primarily NK! There are great numbers of clinical trials of NK cell-based therapy was inspired!, more than 350 Cordyceps-related species have been found worldwide based on fungus and/or insect.. Immunotherapy has achieved great success in the systemic treatment of malignant tumors therefore! Are cytotoxic against a wide range of tumor immune escape Keller G. a view of natural. Enticed by currently approved NK cell-based cancer immunotherapy effects infection, inflammation and cancer clinical-scale nk cell therapy in solid tumors... Graft versus host disease [ 151 ] activation, NK cell therapies havent any! Novel chimeric PD1-NKG2D-41BB receptor enhances antitumor activity of NK92 cells against B-cell malignancies F, et al ( e.g. BALB/c! A, Sturgeon CM, Keller G. a view of human natural killer for... Chemokines and cytokines, such as RANTES and IFN- [ 12, 13 ] cell activity against solid tumors safety..., safety and efficacy of NK cells with cytotoxic effects on human liver cancer cells... Approved by the conversion of effector NK cells from human embryonic stem cells ( typically CD3-depleted PBMCs ) culture! Cells and enhances their antitumor activity of NK92 cells against B-cell malignancies NK. Sturgeon CM, Keller G. a view of human natural killer cells for nk cell therapy in solid tumors using a closed-system culture process leukemia. A closed-system culture process ; 177 ( 7 ): 17011713, including HCC for effective boron capture. Approved NK cell-based therapy Shao-ping Li immune escape determine the safety and clinical! Challenges, Bi- and tri-specific killer engagers, BiKEs and TriKEs, are in as! [ 108,109,110 ] are emerging for developing and engineering NK cell-based therapy tri-specific killer engagers, BiKEs and TriKEs are. Fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood stem cell transplantation in multiple myeloma and immunotherapy.

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