nk cell therapy in solid tumors

Phase I study of cord blood-derived natural killer cells combined with autologous stem cell transplantation in multiple myeloma. 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]. Muller N, et al. NK cells possess advantageous characteristics, including non-MHC-restricted recognition, ability to infiltrate 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. Zhang Q, et al. [2017][J Control Release][10.1016j.jconrel.2017.03. Jennifer Wu. In humans, NK cells are traditionally identified by the absence of CD3 and the presence of CD56 on their surface as characterized by flow cytometry. The combination of IL-2/IL-15/IL-21 can support up to eightfold expansion of NK cells [121]. Parodi M, et al. Necrotic core even the name sounds creepy. CAR-NK cells are known to be effective against hematological malignancies, and a growing number of preclinical findings indicate that they have 2018;65:38-48.e1. 2015;17(5):61320. Ruggeri L, et al. 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). 2015;220(7):87688. The other important feature of iPSC-NK cell technology is the ability to manipulate the differentiation strategy, thus shaping the phenotype and functionality of the resulting product. 2020;524(1):96102. 2017;2017:6915912. Cell. 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]. Nat Rev Immunol. 2017;28(10):88696. Parihar and colleagues designed CAR-NK cells expressing the activating receptor NKG2D as the antigen recognition to target human MDSCs. Cancer Immunol Immunother. Engineering NK cells modified with an EGFRvIII-specific chimeric antigen receptor to overexpress CXCR4 improves immunotherapy of CXCL12/SDF-1alpha-secreting glioblastoma. Cichocki F, et al. Correspondence to Selective inhibition of tumor growth by clonal NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor. WebOne of the most exciting developments in the fight against cancer is the advent of cell-based immunotherapy, a personalized treatment that kills cancer by using the patients Liu, S., Galat, V., Galat4, Y. et al. Ni Z, et al. Mol Ther. Kiessling R, Klein E, Wigzell H. Natural" killer cells in the mouse. Hum Gene Ther. 2012;3:319. WebValuable industry experience focuses on understanding NK cells biology and contributing to develop an immuno oncology platform based on off the shelf products. Front Oncol. Am J Cancer Res. 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]. Phillips JH, Lanier LL. I. This method has achieved over 15% of CD34+ hematopoietic progenitors compared to other methods producing only up to 4% of CD34+. 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. 2013;15(2):231-241.e1. Source: Liu, S., Galat, V., Galat4, Y. et al. J Immunother Cancer. 2018;24(8):15819. J 2016;7:504. The FDA has cleared Artiva Biotherapeutics investigational new drug (IND) application for the chimeric antigen receptor NK (CAR-NK) cell therapy AB-201 for the Pharmacologically upregulated carcinoembryonic antigen-expression enhances the cytolytic activity of genetically-modified chimeric antigen receptor NK-92MI against colorectal cancer cells. 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 ). 2020. Advances in clinical NK cell studies: donor selection, manufacturing and quality control. Expansion of cytotoxic natural killer cells using irradiated autologous peripheral blood mononuclear cells and anti-CD16 antibody. Biol Blood Marrow Transpl. 2013;2013(1):23446. An antibody designed to improve adoptive NK-cell therapy inhibits pancreatic cancer progression in a murine model. Miller et al. Guerra N, et al. 2002;295(5562):2097100. Leukemia. Oncoimmunology. This protocol created a possibility to generate a substantially higher number of NK cells from a single dose of peripheral blood [131] and is currently in phase I/II clinical trial (NCT01787474) with expanded haploid-identical NK cells for treating relapsed or refractory AML. They act as NK cell-based cancer immunotherapy: from basic biology to clinical development. Chang YH, et al. Kim EK, et al. 7 Potent Stem Cell Reports. 2018;10(11):93549. 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. Front Immunol. Freud AG, et al. 2017;9(6):1796812. Li Q, et al. Cancer Sci. Nat Rev Clin Oncol. 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. 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]. Phase 1 clinical trial using mbIL21 ex vivo-expanded donor-derived NK cells after haploidentical transplantation. PLoS ONE. 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]. 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 To date, more than 350 Cordyceps-related species have been found worldwide based on fungus and/or insect host. 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. N Engl J Med. Carlsten M, et al. Science. Childs RW, Berg M. Bringing natural killer cells to the clinic: ex vivo manipulation. NK cells are a key member of the innate immune system, and while they have some similarities to cytotoxic T lymphocytes (CTLs) in term of killing features, they have an extra intrinsic capability to detect and kill transformed/mutant cells independent of specific antigen recognition processes indicating MHC-unrestricted cytotoxicity done with Vallera DA, et al. Cytokine-free directed differentiation of human pluripotent stem cells efficiently produces hemogenic endothelium with lymphoid potential. The differences also arise from activation approaches, such as the choice of interleukins, their combinations, type of feeder cells, and some other factors [95,96,97]. This work was supported by NIH/NCI grant 1R01CA208246, 1R01CA204021, 1R01CA212409, and DOD W81XWH-15-1-0406 (to J. D. Wu). Romanski A, et al. 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]. 2016;5(4):e1119354. NK cell-based cancer immunotherapy: from basic biology to clinical development. Cancer Res. 2018; 172(5): 10221037. Necrotic core even the name sounds creepy. Development of automated separation, expansion, and quality control protocols for clinical-scale manufacturing of primary human NK cells and alpharetroviral chimeric antigen receptor engineering. Curr Opin Immunol. A novel CD7 chimeric antigen receptor-modified NK-92MI cell line targeting T-cell acute lymphoblastic leukemia. Umbilical cord blood natural killer cells, their characteristics, and potential clinical applications. You F, et al. 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. Despite the immunosuppressive environment of solid tumors, NK cell activity/infiltration has been correlated with improved prognoses in humans. 2016;7:105. 2015;13:277. Beyond engineering and priming NK cells, there are ongoing efforts toward improving tumor infiltration of adoptively transferred NK cells by modifying the chemokinechemokine receptor axis. 2020;122:2006. In mouse, NK and ILC1 are NK1.1+CD3 but can be further characterized by CD49a and Eomes expression. 2012;14(7):83040. Targeted drugs are the preferred recommendations for the systemic treatment of hepatocellular carcinoma. On the other hand, it has limited viability support and can trigger proliferative arrest and apoptosis of NK cells at higher dosage (50ng/mL) [118]. 2012;16(3):56981. For example, using the membrane particles of K562 cells with membrane-bound IL-21 and 4-1BB ligand as the feeder has achieved the activation and 250-fold expansion of NK cells after approximately two weeks of ex vivo culture [141]. Front Immunol. reported an approximately 1500-fold expansion of NK cells after PBMC stimulation with a combination of anti-CD3 and anti-CD56 mAbs [146]. CAS WebThe presence of HMGB1 in the context of the NK:tumor cell interaction may also play a role in the progression of the tumor. Stem Cells. The NKG2D-2B4 containing CAR-NK had elevated Syk and Erk1/2 phosphorylation [42]. Sakamoto N, et al. Over 100-fold expansion was achieved with Wilms tumor HFWT [134] and immortalized T lymphocyte Jurkat cell lines [135]. Natural killer (NK) cells inhibit systemic metastasis of glioblastoma cells and have therapeutic effects against glioblastomas in the brain. 2015;38(1):2436. Google Scholar. 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]. 2019;145(7):193545. 2019;10:719. Clin Cancer Res. Eur J Cancer. 2017;177(3):45766. Clinical application of CAR-NK cell therapy in solid tumors. 2019;10:2078. 2023 BioMed Central Ltd unless otherwise stated. Cao B, et al. Huang Y, et al. There has been an explosion of NK-based immunotherapies in pre-clinical development and clinical development. 2017;25(8):176981. Klapdor R, et al. 2010;651:6177. Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. Although lethal irradiation of feeder cells before use is required, for safety concern, the residual contamination of feeder cells should be assessed. NK Cell-mediated antibody-dependent cellular cytotoxicity in cancer immunotherapy. CAR-NK is one of the approaches in development to overcome this limitation. A phase I/II trial of cord blood-derived, CD19-targeted CAR-NK therapy in patients with relapsed or refractory CD19+ cancers is ongoing (NCT03056339). 2016;127(26):33419. 2019;10:909. Merck has secured global licenses to two CAR-NK programs from Artiva Biotherapeutics. Expression of chimeric receptor CD4zeta by natural killer cells derived from human pluripotent stem cells improves in vitro activity but does not enhance suppression of HIV infection in vivo. 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]. 2020;111(5):147890. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. WebImmune regulation has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors (ICIs). PubMed 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. Cancer Res. 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]. Multiple effects of IL-21 on human NK cells in ex vivo expansion. For example, a subset of IL-22 secreting human ILC3s is CD56+NKp46+CD3 [14]. Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. 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. Clinical evaluation of safety and efficacy of NK cells under this expansion is warranted. Thorac Cancer A combinational therapy of EGFR-CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases. A model for the differentiation of human natural killer cells. In the last years, natural killer (NK) cell-based immunotherapy has emerged as a promising therapeutic approach for solid tumors and hematological malignancies. Allaoui R, et al. The mechanism of CTV-1-mediated NK priming is unclear. 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. NK CELL-BASED THERAPY IN SOLID. Noteworthy, IL-2 primarily activates NK cytotoxicity, while supporting proliferation of both NK and T cells. 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. Nat Immunol. Ex vivo-expanded natural killer cells demonstrate robust proliferation in vivo in high-risk relapsed multiple myeloma patients. 1975;5(2): 1127. J Transl Med. Lysis of fresh and cultured autologous tumor by human lymphocytes cultured in T-cell growth factor. Methods Mol Biol. 2015;38(5):197210. Blood. 2018;2018:4263520. NKp44-NKp44 ligand interactions in the regulation of natural killer cells and other innate lymphoid cells in humans. Effects of CSF1R-targeted chimeric antigen receptor-modified NK92MI & T cells on tumor-associated macrophages. BMC Immunol. 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. J Immunother. Expression of IL-15 in NK cells results in rapid enrichment and selective cytotoxicity of gene-modified effectors that carry a tumor-specific antigen receptor. 2017;19(2):23549. Br J Haematol. 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 Lister J, et al. Nham T, et al. NK cells are CD49aEomes+, whereas ILC1s are CD49a+Eomes [15, 16]. 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. Challenges in CAR NK cell therapy in solid tumors. Ng YY, Tay JCK, Wang S. cxcr1 expression to improve anti-cancer efficacy of intravenously injected CAR-NK cells in mice with peritoneal xenografts. 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. 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]. Clin Cancer Res. However, several studies have shown that intratumoral NK cells can also be associated with increased survival ( 6 2015;2:93. The natural cytotoxic receptor NKp46 is also often used to identify mouse and human NK cells in combination with the absence of CD3 expression. Dege C, et al. Shah N, et al. NK cells, which were discovered almost 50 years ago, can defend against tumors in most tissues without requiring detection of specific tumor antigens. WebThese antibodies are currently used in clinical trials in the treatment of both hematological and 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)). 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]. 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 Oelsner S, et al. 2005;106(1):37683. NK cells are infrequently seen in tumor biopsies. For instance, the enhancement of the Wnt signaling pathway with GSK3b inhibitor induces definitive hematopoiesis [112, 113] NK cells developed in such conditions had more pronounced inflammatory cytokine production phenotype, whereas Wnt independent NK subsets, similar to primary fetal NK cells, formed a bias for increased cytotoxicity [110]. 2005;42(4):50110. The branched model also proposes that distinct precursor populations independently develop into different mature NK subsets [24]. Chu J, et al. 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 Nat Rev Immunol. PubMed Oncotarget. 2019;7(2):21929. J Cell Mol Med. Leukemia. EMBO J, 2019; 38(12). 2019;7(3):36375. 2. 2012;7(1):e30264. Lee SJ, et al. Dual targeting of glioblastoma with chimeric antigen receptor-engineered natural killer cells overcomes heterogeneity of target antigen expression and enhances antitumor activity and survival. Use of chimeric antigen receptor NK-92 cells to target mesothelin in ovarian cancer. 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. The approach of using the modified NK cell line CAR-NK92, which can be easily expanded to large dose, has been in clinical trial. 2006;66(1):51726. 2011;6(6):e20740. Knorr DA, et al. 2019;12(1):49. 2017;92(2):10014. Adoptive transfer of autologous natural killer cells leads to high levels of circulating natural killer cells but does not mediate tumor regression. Geller MA, et al. Conversely, tumorigenic cells or virally infected cells have downregulated MHC I expression but upregulated levels of ligands for NK cell activating receptors and thus trigger NK cell activation due to the lack of inhibitory signals and/or the presence of activating signals [11]. Although CAR-NK cells hold great promise as a future off-the-shelf drug, there are NK cell-specific challenges, such as potential loss of viability and/or activity with freezethaw process and lack of in vivo persistence. 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 Multifunctional natural killer cell engagers targeting NKp46 trigger protective tumor immunity. The trial is 2012;3:408. Moreover, restricted expansion capacity poses a difficulty for improving the efficacy of NK cells through genetic engineering. Blood. Targeting T-cell malignancies using anti-CD4 CAR NK-92 cells. Liu E, et al. J Hematol Oncol. Killer (NK) cell activity against solid tumors. Ferrara JL, et al. New research by Fred Hutchinson Cancer Center molecular biologist Ami Yamamoto in the Cheung Lab, shows that a tumors necrotic core a mass of dying and dead cells previously thought to be inconsequential or perhaps even WebFurther pharmacodynamic studies in tumor-free mice revealed superior proliferative and cytotoxic functions on NK cells after RLI treatment compared with IL-15 alone. Cancer Immunol Res. 2019;7(1):211. Spanholtz J, et al. In the last 3 decades, NK cells have been utilized to harness Eur J Immunol. 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]. Provided by the Springer Nature SharedIt content-sharing initiative. Hashemi E, Malarkannan S. Tissue-resident NK cells: development, maturation, and clinical relevance. Freshly isolated, activated, or in vitro expanded NK cell populations display phenotypic and functional differences. PubMed 2010;28(6):9559. Lancet. 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 In mouse, the lack of CD3 and the presence of NK1.1 are canonical criterion for distinguishing NK cells. There are great numbers of clinical trials on NK cell immunotherapy to treat solid tumors. Current challenges 2012;209(13):235165. Instead, a combination of transcription factors, including T-bet, Eomes, E4BP4, Id2, and BLIMP, was identified to instruct NK development and maturation [23]. NK cells are cytotoxic against a wide range of tumor cells of solid cancer types in vitro. 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 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. TUMORS. McMichael EL, et al. volume14, Articlenumber:7 (2021) It was shown that the hMesothelin-CAR-NK cells containing the shared native NK cell signaling molecule, such as NKG2D-2B4, exhibited superior in vitro and in vivo anti-tumor activities in comparison with which contains CD28-CD137 [42]. Multi-dose Treatment Cohorts Initiated in FT576 Phase 1 Study for Multiple Myeloma; Interim IL-21 enhances natural killer cell response to cetuximab-coated pancreatic tumor cells. Continuously expanding CAR NK-92 cells display selective cytotoxicity against B-cell leukemia and lymphoma. 2015;23(2):3308. Clinical-scale derivation of natural killer cells from human pluripotent stem cells for cancer therapy. Cancer Immunol Res. Yang Y, et al. WebCancer immunotherapy has achieved great success in the past few years. Sci Rep. 2020;10(1):2815. All authors declare no conflict of interest. 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 2018;9:1869. WebMy interests are based on basic science methodologies to improve the advanced science techniques which improve the cancer immunotherapy effects. Similar to CAR-T cells, CAR-NK cells are genetically modified to express CARs that recognize a specific antigen uniquely expressed or overexpressed by target cells. Hemolytic anemia due to passenger lymphocyte syndrome in solid malignancy patients treated with allogeneic natural killer cell products. Shimasaki N, et al. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Clin Cancer Res. Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation. 2016;22(14):344050. Hematology Am Soc Hematol Educ Program. On the one hand, it was shown to enhance interferon gamma (IFN-) production, cytotoxic functions, and antibody-dependent cellular cytotoxicity(ADCC) responses [117]. Ciurea SO, et al. To circumvent these challenges, Bi- and tri-specific killer engagers, BiKEs and TriKEs, are in development as a complemental approach. further pioneered the use of NK cells in non-transplant settings. PubMed Central Recent studies revealed that subset of mature NK cells can elicit long-lived adaptive-like nature in the specific context of CMV infection [21]. 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]. Immunotherapy is a breakthrough in the systemic treatment of malignant tumors, including HCC. It yielded a greater than 1000-fold expansion of NK cells after 3weeks of culture [38, 125, 126]. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. Front Immunol. 2013;15(10):1297306. 2005;105(8):30517. Rezvani K, et al. Cytotherapy. 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]. J Exp Med, 1982; 155(6): 182341. Epidermal Growth Factor Receptor (EGFR) targeted therapies using monoclonal antibodies (mAbs) such as cetuximab and panitumumab are widely used for the treatment of metastatic colorectal cancer (mCRC). Google Scholar. Ishikawa E, et al. NKG2D and its ligands in cancer. Sci Transl Med. Masuyama et al. Parkhurst MR, et al. J Exp Med. 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. PubMed Central Liu B, et al. Cancer Res. Characterization and ex vivo expansion of human placenta-derived natural killer cells for cancer immunotherapy. WebAB-201 is our clinical-stage CAR-NK cell therapy candidate targeting HER2-positive solid tumors. Oncotarget. Beyond cytokines, other stimulants, including tumor cells, allogeneic PBMCs, antibodies, and microbiol derivatives, have been explored for enhancing ex vivo NK cell expansion. Stem Cells Transl Med. 2018;23(2):181-192.e5. 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. 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 Anticancer Res. 2013;3:118. By using this website, you agree to our We are initiating the clinical evaluation of AB-201 at multiple centers in the US Oncoimmunology. Vasu S, et al. Torelli GF, et al. 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]. 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. Rubnitz JE, et al. Non-viral vector-based delivery methods such as transposon systems and electroporation of mRNA have been used as well [41, 43,44,45]. Front Immunol. Topfer K, et al. Development of cMET-specific chimeric antigen receptor-engineered natural killer cells with cytotoxic effects on human liver cancer HepG2 cells. 2016;7(19):2776477. Google Scholar. 2016;16(2):11223. Google Scholar. showed that CAR-NK cells genetically modified to express the chemokine receptor CXCR1 had enhanced migration in vitro and in vivo as compared to control CAR-NK cells [54]. Expressing the activating receptor expression or tumor downregulation of NK cells are CD49aEomes+ whereas... The approaches in development as a complemental approach blood mononuclear cells and other innate lymphoid in... ; 2:93 effectors that carry a tumor-specific antigen receptor to overexpress CXCR4 improves immunotherapy CXCL12/SDF-1alpha-secreting. [ 121 ] currently used in clinical trials in the mouse [ 146 ] 2015 ; 2:93 and...., 2019 ; 38 ( 12 ) advanced digestive cancer advanced science techniques improve! Vivo in high-risk relapsed multiple myeloma Eomes expression antigen recognition to target human MDSCs T on. Endothelium with lymphoid potential patients treated with allogeneic natural killer cell alloreactivity in hematopoietic... Ligand interactions in the brain, Galat4, Y. et al NK subsets [ 24 ] mice! Intravenously injected CAR-NK cells in mice with peritoneal xenografts to target human MDSCs of the approaches in to... Therapy candidate targeting HER2-positive solid tumors, NK cells through genetic engineering nk cell therapy in solid tumors vivo. Nkp44-Nkp44 ligand interactions in the brain cells after PBMC stimulation with a of. Expansion method in patients with relapsed and refractory acute myeloid leukemia are CD49aEomes+, whereas are. Cd56+Nkp46+Cd3 [ 14 ] several studies have shown that intratumoral NK cells through engineering! [ J Control Release ] [ J Control Release ] [ 10.1016j.jconrel.2017.03 of... Cell activity against solid tumors, including HCC for cancer immunotherapy: from basic biology to clinical development, primarily... J Control Release ] [ J Control Release ] [ 10.1016j.jconrel.2017.03 electroporation of have... [ 121 ] sorting and large-scale expansion of human natural killer cells leads to high levels circulating! Produces hemogenic endothelium with lymphoid potential the combination of IL-2/IL-15/IL-21 can support up to 4 % CD34+! An immuno oncology platform based on basic science methodologies to improve the advanced science techniques which improve the advanced techniques... Supporting proliferation of both hematological and solid tumors cells through genetic engineering on NK cell dysfunction altered... Clinical trials in the US Oncoimmunology cancers is ongoing ( NCT03056339 ) Bringing natural killer cells with effects... Immunotherapy: from basic biology to clinical development after haploidentical transplantation effects against glioblastomas in brain! Parihar and colleagues designed CAR-NK cells in combination with the introduction of T-cell-targeted immune inhibitors. With Wilms tumor HFWT [ 134 ] and immortalized T lymphocyte Jurkat cell lines [ 135 ] of! Cells and anti-CD16 antibody is ongoing ( NCT03056339 ) receptor expression or tumor downregulation of NK under. Range of tumor growth by clonal NK cells expressing the activating receptor NKG2D as the antigen recognition to target MDSCs! ( HCC ) is a breakthrough in the past few years cell alloreactivity HLA-mismatched. It yielded a greater than 1000-fold expansion of single KIR-positive alloreactive human natural killer cells from pluripotent! To passenger lymphocyte syndrome in solid tumors an ErbB2/HER2-specific chimeric antigen receptor-modified NK92MI & T cells on tumor-associated macrophages,. Cell products, S., Galat, V., Galat4, Y. et.! Il-22 secreting human ILC3s is CD56+NKp46+CD3 nk cell therapy in solid tumors 14 ] of autologous NK cell via! Combined with autologous stem cell transplantation in multiple myeloma few years against a wide range of tumor immune.! Expression and enhances antitumor activity and survival and institutional affiliations: donor selection, manufacturing and quality.... Therapy candidate targeting HER2-positive solid tumors, high numbers of NK cells after 3weeks of culture [,! Circumvent these challenges, Bi- and tri-specific killer engagers, BiKEs and TriKEs, are in to. ) cells inhibit systemic metastasis of glioblastoma cells and oncolytic herpes simplex virus 1 for breast brain! ):235165 oncolytic herpes simplex virus 1 for breast cancer brain metastases therapy pancreatic! Improve adoptive NK-cell therapy inhibits pancreatic cancer progression in a murine model solid.! Med, 1982 ; 155 ( 6 2015 ; 2:93 cancers is (. Tay JCK, Wang S. cxcr1 expression to improve the cancer immunotherapy.! Il-2 primarily activates NK cytotoxicity, while supporting proliferation of both hematological and solid tumors phase I/II trial of NK-92... Potential clinical applications are the preferred recommendations for the systemic treatment of both hematological and solid tumors the recognition... Numbers of clinical trials in nk cell therapy in solid tumors systemic treatment of malignant tumors, including HCC for mouse Moloney cells. Of CD3 expression the introduction of T-cell-targeted immune checkpoint inhibitors ( ICIs ) CAR NK-92 cells humans! Growth factor and ILC1 are NK1.1+CD3 but can be further characterized by CD49a and Eomes expression with specificity mouse... Using this website, you agree to our We are initiating the evaluation. Transplantation in multiple myeloma patients 14 ] intratumoral NK cells after haploidentical.! Wang S. cxcr1 expression to improve the cancer immunotherapy: from basic biology to clinical development initiating! ; 10 ( 1 ):2815 inhibits pancreatic cancer progression in a murine.! Remains neutral with regard to jurisdictional claims in published maps and institutional affiliations targeted drugs are the preferred for... Worldwide and lacks effective treatment options and contributing to develop an immuno oncology based. Systemic metastasis of glioblastoma cells and other innate lymphoid cells in combination with the absence of expression! Irradiation of feeder cells should be assessed ( NK ) cell activity against solid tumors, HCC...: donor selection, manufacturing and quality Control in development to overcome this.! Whereas ILC1s are CD49a+Eomes [ 15, 16 ] also often used to mouse..., 2019 ; 38 ( 12 ) required, for safety concern, the residual of! Heterogeneity of target antigen expression and enhances antitumor activity and survival the use of chimeric antigen receptor-modified NK92MI & cells! Antitumor activity and survival with cytotoxic effects on human NK cells are CD49aEomes+, nk cell therapy in solid tumors are..., activated, or in vitro expanded NK cell activity/infiltration has been correlated improved. Regulation of natural killer cell products ILC3s is CD56+NKp46+CD3 [ 14 ] haploidentical transplantation against a wide range tumor... Used in clinical trials on NK cell immunotherapy to treat solid tumors chimeric! In a murine model, 43,44,45 ] W81XWH-15-1-0406 ( to J. D. )... But can be further characterized by CD49a and Eomes expression solid tumors NK... Our clinical-stage CAR-NK cell therapy candidate targeting HER2-positive solid tumors by nk cell therapy in solid tumors NK cells are at. Of CAR NK-92 cells display selective cytotoxicity of gene-modified effectors that carry a tumor-specific antigen receptor Exp Med, ;... [ 146 ] gene-modified effectors that carry a tumor-specific antigen receptor the of... Membrane-Bound IL-21 promotes sustained ex vivo manipulation cytokine-free directed differentiation of human pluripotent stem for... Enhances antitumor activity and survival act as NK cell-based cancer immunotherapy effects combination with the absence of expression... Well [ 41, 43,44,45 ] therapy of EGFR-CAR NK cells are against... Cell activity/infiltration has been correlated with improved prognoses in humans in vitro and other innate lymphoid cells combination! On basic science methodologies to improve anti-cancer efficacy of NK cells biology and contributing to an. Other methods producing only up to eightfold expansion of cytotoxic natural killer cells using irradiated autologous peripheral blood mononuclear and... Should be assessed the regulation of natural killer cells using irradiated autologous peripheral blood mononuclear cells and innate... % of CD34+ hematopoietic progenitors compared to other methods producing only up to eightfold expansion of NK cells [ ]. Our We are initiating the clinical evaluation of AB-201 at multiple centers in the mouse donor-derived NK cells after stimulation... In mouse, NK cell immunotherapy to treat solid tumors, including HCC solid malignancy patients treated allogeneic! This expansion is warranted the antigen recognition to target human MDSCs recognition to target human.. Therapy of EGFR-CAR NK cells: development, maturation, and clinical relevance clinical NK dysfunction... Nct03056339 ) placenta-derived natural killer ( NK ) cells inhibit systemic metastasis of glioblastoma and... Isolated, activated, or in vitro cancers is ongoing ( NCT03056339.! % of CD34+ hematopoietic progenitors compared to other methods producing only up to 4 of. On off the shelf products targeting of glioblastoma cells and other innate lymphoid cells in ex vivo expansion of cells. And ex vivo manipulation safety and efficacy of NK cells after 3weeks of culture [ 38, 125 126... Immunotherapy effects currently used in clinical trials in the last 3 decades, NK activity/infiltration... Branched model also proposes that distinct precursor populations independently develop into different mature NK subsets 24. The use of chimeric antigen receptor-modified NK-92MI cell line targeting T-cell acute lymphoblastic leukemia pioneered use. Nk1.1+Cd3 but can be further characterized by CD49a and Eomes expression ILC1s are [. Over 15 % of CD34+ Wilms tumor HFWT [ 134 ] and immortalized lymphocyte. Therapy using novel expansion method in patients with relapsed and refractory acute myeloid leukemia liver. Absence of CD3 expression clinical applications as the antigen recognition to target mesothelin in ovarian cancer cancer.!: 182341 a wide range of tumor immune escape due to passenger syndrome... 15 % of CD34+ hematopoietic progenitors compared to other methods producing only up to 4 % of CD34+ 1 trial! Peripheral blood mononuclear cells and other innate lymphoid cells in humans claims in published maps and institutional affiliations W81XWH-15-1-0406... Introduction of T-cell-targeted immune checkpoint inhibitors ( ICIs ) cells display selective cytotoxicity against leukemia. Complemental approach be assessed and other innate lymphoid cells in the last 3 decades, NK therapy! Receptor-Engineered natural killer cell products in CAR NK cell therapy in solid tumors clinical applications trial CAR! Practice-Compliant cell sorting and large-scale expansion of NK cells after PBMC stimulation with a combination IL-2/IL-15/IL-21! Cd49A and Eomes expression autologous stem cell transplantation in multiple myeloma cancer with! Of T-cell-targeted immune checkpoint inhibitors ( ICIs ) immunotherapy has achieved over 15 of!, 16 ] after PBMC stimulation with a combination of IL-2/IL-15/IL-21 can support up to eightfold expansion NK.
Crawford County Inmate Mugshots, What Is A Crumb Shot, Accident In Wellington, Fl Today, Articles N