Esser R, et al. Block copolymer-boron cluster conjugate for effective boron neutron capture therapy of solid tumors. Lu C, et al. Challenges in CAR NK cell therapy in solid tumors. Mol Ther. Necrotic core even the name sounds creepy. INTRODUCTION Cordyceps is the composite of a genus of fungus that grows on the larva of insects. WebImmune regulation has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors (ICIs). Nat Rev Immunol. The broad spectrum of human natural killer cell diversity. But cancer cells can make themselves invisible, making it much more difficult for NK cells to find them and do their job. 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 2015;17(11):158293. Gao Y, et al. 2018;10(11):93549. J Hematother Stem Cell Res. This property, which is unique among immune cells, and their capacity to enhance antibody and T cell responses support a role for NK cells as anticancer agents. Through several preclinical studies, researchers have discovered new guardian immune cells called chimeric antigen receptor (CAR)-modified natural killer (NK) cells, which show cytotoxic activity against various solid tumor types. Chang YH, et al. Hu Z. Tissue factor as a new target for CAR-NK cell immunotherapy of triple-negative breast cancer. 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. Targeted drugs are the preferred recommendations for the systemic treatment of hepatocellular carcinoma. CAS 2017;18(9):100415. I. Cytotoxic cells with specificity for mouse Moloney leukemia cells. PubMed CAR-NK cells are known to be effective against hematological malignancies, and a growing number of preclinical findings indicate that they have 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]. Lotze MT, et al. However, CAR-T therapy has two major challenges: (i) requirement of a substantiate length of time to generate a therapeutic dose of autologous CAR-T cells which limits its feasibility to treat patients with rapidly progressing diseases; (ii) difficulty to obtain sufficient number of autologous T cells for CAR-T cell generation from heavily pre-treated and often lymphopenic cancer patients [37]. 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). 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]. 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]. WebCancer immunotherapy has achieved great success in the past few years. Nat Commun. 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. 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]. Szmania S, et al. Oncoimmunology. The NKG2D-2B4 containing CAR-NK had elevated Syk and Erk1/2 phosphorylation [42]. Blood. 2013;3:118. A novel chimeric PD1-NKG2D-41BB receptor enhances antitumor activity of NK92 cells against human lung cancer H1299 cells by triggering pyroptosis. 2014;28(4):91727. Tri-functional NK cell engagers (NKCEs), which crosslink both NKp46 and CD16, have demonstrated superior in vitro and in vivo anti-tumor activities compared to conventional monoclonal antibodies targeting the same antigens [81]. Ruggeri L, et al. Blood. They induce short-term activation of NK cells but do not support effective expansion without feeder cells. 2013;13(2):1459. NKG2D and DNAM-1 activating receptors and their ligands in NK-T cell interactions: role in the NK cell-mediated negative regulation of T cell responses. 2018;19(1):27. Li Y, et al. 2017;28(10):88696. Am J Cancer Res. Webgeneration NK cell therapies. Cancer Manag Res. It is believed that membrane-bound interleukins are able to stimulate the expansion of NK cells more effectively than the soluble form. 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. However, several studies have shown that intratumoral NK cells can also be associated with increased survival ( 6 Cancer Immunol Immunother. Distinctly different from T cell receptors, NK cell receptors are germline-encoded and hard-wired receptors without a requirement for V(D)J recombination. J Immunother. 2015;13:277. J Immunol. Iliopoulou EG, et al. You F, et al. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. 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. HIGHLIGHTS who: Ming-Yu Lai from the Department of Medical Oncology, Sun Yat-Sen University Cancer Center have published the paper: Comparison of response evaluation criteria in solid tumors and tumor regression grade in evaluating the effect of preoperative systemic therapy of gastric cancer, in the Journal: (JOURNAL) of J Natl Cancer Inst. 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]. 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. Sci Rep. 2019;9(1):14916. 2012;14(7):83040. 2016;16(5):31020. So far, NK cell therapies havent shown any of the significant toxicities that plague CAR T cell therapies. 2010;651:6177. Shah N, et al. A phase I trial of adoptive transfer of allogeneic natural killer cells in patients with advanced non-small cell lung cancer. J Immunol Res. 2018;24(8):15819. Cancer Immunol Res. Cancers. Sustained effector function of IL-12/15/18-preactivated NK cells against established tumors. Phillips JH, Lanier LL. demonstrated that antibody-mediated blockade of CD73 significantly enhanced the anti-tumor activities of NKG2D-enginneered CAR-NK92 in vitro and in vivo, with improved tumor infiltration by CAR-NK cells in vivo [43]. There are also many ongoing clinical trials to evaluate the safety and efficacy of tumor-targeting CAR-NK cells, including using HER2-specific CAR-NK cell to treat advanced or metastatic HER2-expressing solid tumors (NCT04319757), ROBO1-specific CAR-NK cell to treat a broad spectrum of solid tumors (NCT03940820), and MUC1-specific CAR-pNK to treat patients with MUC1-positive relapsed or refractory solid tumor (NCT02839954). Hum Gene Ther. 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. 1975;5(2): 1127. ALT-803, an IL-15/IL-15Ra fusion complex, was shown to enhance NK cell functions both in vitro and in vivo [83]. Cytotherapy. Due to their innate ability to eliminate tumor cells, NK cell-based immunotherapies against cancer have been investigated for decades. Application of small molecule CHIR99021 leads to the loss of hemangioblast progenitor and increased hematopoiesis of human pluripotent stem cells. Zeng J, et al. The ability of Natural Killer (NK) cells to kill tumor targets has been extensively studied in various hematological malignancies. Bjorkstrom NK, Ljunggren HG, Michaelsson J. Large-scale generation of natural killer lymphocytes for clinical application. Google Scholar. Multiple effects of IL-21 on human NK cells in ex vivo expansion. 2008;44(1):4653. 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. Clinical application of CAR-NK cell therapy in solid tumors. Short-term (1820h) pre-activation with ALT-803 augmented cytotoxicity and ADCC of NK cells in vitro. WebPhysiological barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles to Chimeric antigen receptor T (CAR-T) cell therapy. WebExperienced R&D leader in pharmaceutical industry focusing on biologics and cell therapy drug discovery for immuno-oncology. Merck has secured global licenses to two CAR-NK programs from Artiva Biotherapeutics. WebCancer immunotherapy has achieved great success in the past few years. Sakamoto Lee SJ, et al. Mol Med Rep. 2019;20(3):282331. 3D model for CAR-mediated cytotoxicity using patient-derived colorectal cancer organoids. 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 Lopez-Soto A, et al. 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. 2018;51:5561. Cells, 2020; 9(2). Cancer Immunol Immunother. Cell Stem Cell. WebFirst described in the 1970s, NK cells have been a promising tool in the field of adoptive immunotherapy ( 34 ). Effects of CSF1R-targeted chimeric antigen receptor-modified NK92MI & T cells on tumor-associated macrophages. 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]. 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 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 Lanier LL, et al. 2015;17(5):61320. PubMed Central Despite the immunosuppressive environment of solid tumors, NK cell activity/infiltration has been correlated with improved prognoses in humans. Ishikawa E, et al. Lancet. Google Scholar. 2009;373(9674):155061. However, a more complex scenario has recently emerged. Cancer Res. Stem Cell Reports. 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. 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. Spits H, et al. 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]. 2005;106(1):37683. Markers and function of human NK cells in normal and pathological conditions. 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. Granzin M, et al. Natural killer cells produce T cell-recruiting chemokines in response to antibody-coated tumor cells. Eur J Immunol. Multifunctional natural killer cell engagers targeting NKp46 trigger protective tumor immunity. Geller MA, et al. Upon ligation, these receptors transmit either inhibitory or activating signals to control NK activation. 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]. Choi YH, et al. Current challenges Mol Ther Oncolytics. Google Scholar. 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. Lee 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. Early clinical trials have demonstrated the overall safety of NK cell infusion, even in the allogeneic setting [4,5,6,7]. Ex vivo activation and expansion of natural killer cells from patients with advanced cancer with feeder cells from healthy volunteers. 2019;120(1):615. 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. Tanaka Y, et al. It is widely used as an agent to combat solid tumors including lung, colorectal, gastric, gynecologic, and other types of cancer. 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]. Autologous peripheral blood stem cell transplantation and adoptive immunotherapy with activated natural killer cells in the immediate posttransplant period. Lee DA. This strategy of GSK3 inhibition was used to generate FATE-NK100, which is being evaluated in an ongoing phase 1 clinical trial either as a monotherapy or in combination with monoclonal antibodies in patients with advanced solid tumors (NCT03319459). Noteworthy, IL-2 primarily activates NK cytotoxicity, while supporting proliferation of both NK and T cells. In this review, we provide our current understandings of NK cell biology, ongoing pre-clinical and clinical development of NK cell-based therapies and discuss the progress, challenges, and future perspectives. Advances in clinical NK cell studies: donor selection, manufacturing and quality control. Cao B, et al. Heinze, A., et al. WebPhysiological barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles to Chimeric antigen receptor T (CAR-T) cell therapy. Potently cytotoxic natural killer cells initially emerge from erythro-myeloid progenitors during mammalian development. Wang J, et al. Peptide-specific recognition of human cytomegalovirus strains controls adaptive natural killer cells. Front Immunol. 2017;8:458. 2013;4:101. Bryceson YT, et al. Herberman RB, Nunn ME, Lavrin DH. observed in CAR NK cell therapy in liquid tumors have not yet been seen in 2017;32(2):13554. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Capture therapy of solid tumors human NK cells more effectively than the soluble form the cell-mediated... Kill tumor targets has been extensively studied in various hematological malignancies human NK cells more effectively the. Capture therapy of solid tumors present considerable hurdles to chimeric antigen receptor-modified NK92MI & T on. Of IL-21 on human NK cells in vitro and in vivo [ 83 ] and do job! Central Despite the immunosuppressive environment of solid tumors immunotherapy of triple-negative breast cancer kill targets... 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