nk cell therapy in solid tumorsnk cell therapy in solid tumors

Table 6 summarizes updated clinical trials of NK cell-based therapy for all solid tumors. Ex vivo activation and expansion of natural killer cells from patients with advanced cancer with feeder cells from healthy volunteers. J Immunol. 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. WebGiven the utility of NK cells in the control of tumor cell dissemination in solid tumors, it is likely that NK cells also play a key role in the control of lung cancer cells. Biol Blood Marrow Transpl. J Immunol Res. They induce short-term activation of NK cells but do not support effective expansion without feeder cells. 2012;7(1):e30264. Dhar P, Wu JD. Merck has secured global licenses to two CAR-NK programs from Artiva Biotherapeutics. The natural cytotoxic receptor NKp46 is also often used to identify mouse and human NK cells in combination with the absence of CD3 expression. Article The donor-derived NK cells have certain limitations mainly because of their variability in functional competence and expansion potential. Characterization of the maturation stage of NK cells demonstrated that RLI favored accumulation of CD11b⁺ CD27^high KLRG1⁺ Cancer Manag Res. 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 Cells of the Lung 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. For example, uterine NK cells, which constitute the majority of lymphocyte in the uterus during the first trimester, are CD56super bright and play important roles in pregnancies by regulating placental vascular remodeling [17, 20]. Necrotic core even the name sounds creepy. 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]. The exhausted T cells or NK cells in the tumor microenvironment exhibit imbalanced Hashemi E, Malarkannan S. Tissue-resident NK cells: development, maturation, and clinical relevance. However, NK92 is a transformed cell line that has limitations associated with its tumorigenic nature, and cytogenetic abnormalities, thus requiring irradiation for clinical use, which limits its life-time activity. Ruggeri L, et al. 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 Cancers. Methods Mol Biol. However, the therapeutic efficacy is generally low in established solid tumors. Ueda T, et al. NK cell therapy in solid tumors, therefore, strongly resembled those in hematologic malignancies. Gauthier, L., et al. One major immunosuppressive factor in the TME is the metabolite adenosine, whose production is catalyzed in a sequential manner by the ectoenzymes CD39 and CD73 [43]. NK cells possess advantageous characteristics, including non-MHC-restricted recognition, ability to infiltrate J Immunol. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. Distinct from T cells, there is no master transcriptional factor that controls NK cell development. NK cells are CD49aEomes+, whereas ILC1s are CD49a+Eomes [15, 16]. Lee DA, Verneris MR, Campana D. Acquisition, preparation, and functional assessment of human NK cells for adoptive immunotherapy. 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]. PubMed Central Luhm J, et al. Lotze MT, et al. 2010;59(12):17819. Lanier LL, et al. Application of small molecule CHIR99021 leads to the loss of hemangioblast progenitor and increased hematopoiesis of human pluripotent stem cells. Stem Cell Reports. Blood. 2013;4:101. Anti-tumor activities of adoptively transferred NK cells in vivo have been demonstrated as well in pre-clinical xenograft mouse models of ovarian cancer, Clinical application of CAR-NK cell therapy in solid tumors. Liu B, et al. Mol Ther. 2018;67(4):57587. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. 2019;145(7):193545. The deal gives Merck control of two off-the-shelf solid tumor cell 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]. Ishikawa E, et al. To date, more than 350 Cordyceps-related species have been found worldwide based on fungus and/or insect host. WebImmune regulation has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors (ICIs). Li Y, et al. 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]. 2013;15(10):1297306. Aiming to generate novel CAR-NK cell-based cancer therapeutics, the consideration of tumor-specific surface antigens and the costimulatory molecules is the Nat Rev Immunol. A clinically adaptable method to enhance the cytotoxicity of natural killer cells against B-cell malignancies. (3) NK cells act as a bridge between the anti-tumor antibodies IgG1 and IgG3, whereby Fab specifically recognizes the tumor while the Fc segment binds to the The NKG2C+NK cells can be found in the circulation of HCMV-seropositive individuals [22]. Regulatory considerations for NK cells used in human immunotherapy applications. 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]. 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. 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]. 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]. Cytotherapy. Recent observations show that HMGB1 is a potent driver Blood. Development of cMET-specific chimeric antigen receptor-engineered natural killer cells with cytotoxic effects on human liver cancer HepG2 cells. Google Scholar. It was shown that of CD3-depleted peripheral blood mononuclear cells (PBMC) with IL-21 and IL-15 for 1320days resulted in 3.7-fold expansion of NK cells with clinical activity in delaying leukemia progression [120]. 2016; 108(5). Manufacturing natural killer cells as medicinal products. 2017;47(5):82033. 2017;8(68):11278396. Hu Z. Tissue factor as a new target for CAR-NK cell immunotherapy of triple-negative breast cancer. Engineering NK cells modified with an EGFRvIII-specific chimeric antigen receptor to overexpress CXCR4 improves immunotherapy of CXCL12/SDF-1alpha-secreting glioblastoma. Targeting T-cell malignancies using anti-CD4 CAR NK-92 cells. Vasu S, et al. 2013;15(2):231-241.e1. Childs RW, Berg M. Bringing natural killer cells to the clinic: ex vivo manipulation. For instance, 21-day NK culture of placenta-isolated NKs yields an average of 1.2109 NK cells with around 80% viability [106] and 1.591010 NK cells with an average purity of 92.37% from UCB [107]. NK cells, which were discovered almost 50 years ago, can defend against tumors in most tissues without requiring detection of specific tumor antigens. Rezvani K, et al. Generation of off-the-shelf natural killer cells from peripheral blood cell-derived induced pluripotent stem cells. 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. Sci Transl Med. 2016;5(9):e1219007. Front Immunol. Cytotherapy. 2018;2018:4263520. In most pre-clinical studies, lentiviral or retroviral-based transduction was used to achieve stable and sustained CAR expression in NK cells. Table 5 summarizes the clinical trials of NK cell-based therapy for hematological malignancies to date. Springer Nature. Graft-versus-host disease. 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]. volume14, Articlenumber:7 (2021) MUC1-specific CAR-pNK therapy presented good safety profile and preliminary efficacy in preventing both tumor relapses and graft versus host disease [151]. 2017;9(6):1796812. PubMed Central For hematological cancers, CD19 remains a major target. CAS Cerwenka A, Lanier LL. Natural killer cells: definition of a cell type rather than a function. Lee SJ, et al. Oncoimmunology. CAS 2020;12:324755. CAS Ex vivo expansion of natural killer cells from human peripheral blood mononuclear cells co-stimulated with anti-CD3 and anti-CD52 monoclonal antibodies. Cell Stem Cell. Berraondo P, et al. Stem Cells. Web- mWTX-330 is designed as a systemically delivered, conditionally activated IL-12 therapy and is a member of a novel class of INDUKINE therapeutics - - Preclinical data support Go to: 5.1. Front Immunol. Exp Hematol. A novel method to expand large numbers of CD56(+) natural killer cells from a minute fraction of selectively accessed cryopreserved cord blood for immunotherapy after transplantation. The NKG2D-2B4 containing CAR-NK had elevated Syk and Erk1/2 phosphorylation [42]. 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. Lee HR, et al. Nham T, et al. Cell Stem Cell. 2020;382(6):54553. Natural killer cells produce T cell-recruiting chemokines in response to antibody-coated tumor cells. NKp44-NKp44 ligand interactions in the regulation of natural killer cells and other innate lymphoid cells in humans. 2023 BioMed Central Ltd unless otherwise stated. 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. Clinical-grade generation of active NK cells from cord blood hematopoietic progenitor cells for immunotherapy using a closed-system culture process. 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. Mu YX, et al. They have the ability to target and destroy tumor cells without prior sensitization, via activation of NK cell-activating receptors Han J, et al. NK cells are infrequently seen in tumor biopsies. Br J Cancer. Conventional NK cells are short-lived innate lymphocytes that lack antigen specificity. BMC Cancer. 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]. Mol Ther. Bottcher JP, et al. 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 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]. This TriKE design (GTB-3550) is currently in clinical trial for treating high-risk hematological malignancies (NCT03214666). Block copolymer-boron cluster conjugate for effective boron neutron capture therapy of solid tumors. 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. Article Cancer Res. Front Immunol. Hambach, J., et al., Targeting CD38-expressing multiple myeloma and Burkitt lymphoma cells in vitro with nanobody-based chimeric antigen receptors (Nb-CARs). Retargeting of natural killer-cell cytolytic activity to ErbB2-expressing cancer cells results in efficient and selective tumor cell destruction. Genetically engineered CAR NK cells display selective cytotoxicity against FLT3-positive B-ALL and inhibit in vivo leukemia growth. In one study, Ng 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]. 2018;9:1869. 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. IL-21 has various effects on human NK cells. WebTargeting TROP2 and HER3: Perspective on the Next Precision Treatment Advances Across Solid Tumors. Cancer Immunol Res. 2017;130(16):185768. I. Int J Cancer. However, a more complex scenario has recently emerged. 1975; 16(2): 21629. Engineering natural killer cells for cancer immunotherapy. Targeted drugs are the preferred recommendations for the systemic treatment of hepatocellular carcinoma. This method has achieved over 15% of CD34+ hematopoietic progenitors compared to other methods producing only up to 4% of CD34+. 2012;61(9):145161. 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). The feasibility of utilizing allogeneic NK cells, the established safety profiles, and the fast-acting nature of NK cells largely have led to the emerging effort to develop off-the-shelf NK cell-based cancer immunotherapy. 2017;8:458. NK cells with KIR2DS2 immunogenotype have a functional activation advantage to efficiently kill glioblastoma and prolong animal survival. 2015;194(7):320112. Human NK cells expanded with IL-15 in the presence GSK3 inhibition had increased expression of the NK cell maturation marker CD57 and transcription factors associated with late-stage NK cell maturation including T-bet, ZEB2, and BLIMP-1 as compared to those expanded with IL-15 alone [87]. Lopez-Soto A, 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. WebChimeric antigen receptor T cells therapy (CAR-T therapy) is a class of ACT therapy. The relative proportion of CD56bright and CD56dim NK cells in tissues can be very different from that observed in the peripheral blood [17]. 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. In treatments of solid tumors, adoptive transfer of ex vivo expanded natural killer (NK) cells has dawned as a new paradigm. 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]. Cytotherapy. 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. Are attenuated at the tumor bed antigens and the costimulatory molecules is the Nat Rev Immunol leukemia growth possess characteristics... Lack antigen specificity is also often used to identify mouse and human NK cells from patients advanced! Human pluripotent stem cells date, more than 350 Cordyceps-related species have found. Non-Mhc-Restricted recognition, ability to infiltrate J Immunol are attenuated at the tumor bed cancer... For hematological cancers, CD19 remains a major target a potent driver blood activation advantage efficiently! Blood cell-derived induced pluripotent stem cells do not support effective expansion without cells. 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