Hammer Q, et al. Br J Cancer. 2012;14(7):83040. Cancer Immunol Res. Stem Cells Transl Med. NK cells are mounted with a repertoire of inhibitory and activating surface receptors (Table 1) [25,26,27,28,29]. 2018;32(2):52031. Perform PBMCs apheresis from the patient and isolate NK cells, transfect the NK cells with Claudin6 targeting CAR, amplify the number of transfected NK cells as On the one hand, it was shown to enhance interferon gamma (IFN-) production, cytotoxic functions, and antibody-dependent cellular cytotoxicity(ADCC) responses [117]. J Immunother Cancer. Galat Y, et al. Shah N, et al. Li Q, et al. NK cell infiltration Pinz KG, et al. The mechanism of CTV-1-mediated NK priming is unclear. Oncotarget. 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. WebValuable industry experience focuses on understanding NK cells biology and contributing to develop an immuno oncology platform based on off the shelf products. Cells, 2020; 9(2). In order to avoid critical side effects, such as GVHD caused by alloreactive T cells [98] or a passenger lymphocyte syndrome caused by donor-derived B cells [99], purification is recommended for allogeneic NK cells before the expansion to restrict contaminating total T cells to less than 15105/Kg. PubMed Sci Transl Med. Cytotherapy. 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. Kim EK, et al. 2013;2013(1):23446. 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 PubMed Central 2010;651:6177. Sci Rep. 2017;7(1):11075. Shaping of natural killer cell antitumor activity by ex vivo cultivation. Non-viral vector-based delivery methods such as transposon systems and electroporation of mRNA have been used as well [41, 43,44,45]. The NKG2D-2B4 containing CAR-NK had elevated Syk and Erk1/2 phosphorylation [42]. Cancer Immunol Immunother. 2015;38(5):197210. Vallera et al. Several groups have demonstrated in vitro derivation of functional NK cells from human embryonic stem cells (hESCs) and iPSCs [108,109,110]. Lee HR, et al. The main source of donor NK cells is peripheral blood collected by apheresis. 2017;25(8):176981. This successful immunotherapy has led to a more complete view of cancer that now considers not only the cancer cells to be targeted and destroyed but also the immune environment of the cancer cells. 2006;66(1):51726. 2013;13(2):1459. 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]. WebArtivas NK cells engineered to express chimeric antigen receptors, or CARs, have the potential to enhance the targeting and activity of the NK cells against either hematologic Distinctly different from T cell receptors, NK cell receptors are germline-encoded and hard-wired receptors without a requirement for V(D)J recombination. 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. 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]. WebNK cell-mediated control of large solid tumors is usually not efficient, although tumors often express high amounts of activating ligands and low levels of inhibitory ligands, 2012;3:408. In mouse, the lack of CD3 and the presence of NK1.1 are canonical criterion for distinguishing NK cells. Carlsten M, et al. Cancer-associated fibroblast-secreted CXCL16 attracts monocytes to promote stroma activation in triple-negative breast cancers. observed in CAR NK cell therapy in liquid tumors have not yet been seen in NK cells are cytotoxic against a wide range of tumor cells of solid cancer types in vitro. Mol Ther. further pioneered the use of NK cells in non-transplant settings. Cytotherapy. Manufacturing natural killer cells as medicinal products. Mehta RS, Shpall EJ, Rezvani K. Cord blood as a source of natural killer cells. Article Hassan R, Ho M. Mesothelin targeted cancer immunotherapy. This TriKE design (GTB-3550) is currently in clinical trial for treating high-risk hematological malignancies (NCT03214666). Eur J Immunol. Zhang P, et al. 2018;2018:4263520. Phase I study of cord blood-derived natural killer cells combined with autologous stem cell transplantation in multiple myeloma. Blood. 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 NKG2D, an activating NK cell receptor, can bind to eight different stress-induced ligands that are naturally expressed on 80% of hematological and solid cancer All authors gave consent for publication of the manuscript. Lanier LL, et al. Ex vivo-expanded natural killer cells demonstrate robust proliferation in vivo in high-risk relapsed multiple myeloma patients. Ruggeri L, et al. Due to their innate ability to eliminate tumor cells, NK cell-based immunotherapies against cancer have been investigated for decades. WebPhysiological barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles to Chimeric antigen receptor T (CAR-T) cell therapy. Generation of BiKEs and TriKEs to improve NK cell-mediated targeting of tumor cells. CAR-NK is one of the approaches in development to overcome this limitation. However, NK cell therapy 2017;8:87. NK cells are infrequently seen in tumor biopsies. 2017;8:329. Romanski A, et al. Using allogeneic NKs for adoptive transfer without expansion after a short overnight incubation with cytokines was shown to be sufficient to activate NK cells and enhance their cell cytotoxicity against tumor targets [86]. Granzin M, et al. 2013;4:101. Development of automated separation, expansion, and quality control protocols for clinical-scale manufacturing of primary human NK cells and alpharetroviral chimeric antigen receptor engineering. Beyond directing CAR-NK cytotoxicity against tumor cells by targeting tumor antigens, it has been proposed that CAR-NK cells can be used to eliminate immunosuppressive immune cells in the tumor microenvironment that include myeloid-derived suppressor cells (MDSCs) and M2 tumor-associated macrophages (TAMs) [77, 78]. Front Immunol. Google Scholar. Anti-tumor activities of adoptively transferred NK cells in vivo have been demonstrated as well in pre-clinical xenograft mouse models of ovarian cancer, Over 100-fold expansion was achieved with Wilms tumor HFWT [134] and immortalized T lymphocyte Jurkat cell lines [135]. 2018;19(5):45363. Correspondence to Blood. 2015;2:93. Combination therapy with EpCAM-CAR-NK-92 cells and regorafenib against human colorectal cancer models. PubMed NK cells are cytotoxic against a wide range of tumor cells of solid cancer types in vitro. Ex vivo expansion of natural killer cells from human peripheral blood mononuclear cells co-stimulated with anti-CD3 and anti-CD52 monoclonal antibodies. Potently cytotoxic natural killer cells initially emerge from erythro-myeloid progenitors during mammalian development. Lee SJ, et al. Ruggeri L, et al. IL15 Trispecific Killer Engagers (TriKE) Make natural killer cells specific to CD33+ targets while also inducing persistence, in vivo expansion, and enhanced function. Parihar and colleagues designed CAR-NK cells expressing the activating receptor NKG2D as the antigen recognition to target human MDSCs. Imai K, et al. Lee et al. The deal gives Merck control of two off-the-shelf solid tumor cell Genssler S, et al. Sizhe Liu, Vasiliy Galat, Yekaterina Galat, Yoo Kyung Annie Lee, Derek Wainwright, and Jennifer Wu wrote and reviewed the manuscript. 2018;24(8):15819. 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. Effects of CSF1R-targeted chimeric antigen receptor-modified NK92MI & T cells on tumor-associated macrophages. Stem Cell Res Ther. 2023 BioMed Central Ltd unless otherwise stated. 2012;7(1):e30264. Cerwenka A, Lanier LL. Despite promising results shown in hematologic tumors, immunotherapies for the treatment of solid tumors have mostly failed so far. EMBO J, 2019; 38(12). Kim MJ, 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]. J High cytotoxic efficiency of lentivirally and alpharetrovirally engineered CD19-specific chimeric antigen receptor natural killer cells against acute lymphoblastic leukemia. When expanded it provides a list of search options that will switch the search inputs to match the current selection. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. Targeting T-cell malignancies using anti-CD4 CAR NK-92 cells. Noteworthy, IL-2 primarily activates NK cytotoxicity, while supporting proliferation of both NK and T cells. 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. Gauthier, L., et al. Most NK cells in the blood are CD56dim, whereas the CD56bright subset only represents less than 15% of total circulating NK cells [17]. Engineering natural killer cells for cancer immunotherapy. Front Immunol. 2015;6:368. J Hematother Stem Cell Res. Production Process of CAR-NK Childs RW, Berg M. Bringing natural killer cells to the clinic: ex vivo manipulation. 2015;220(7):87688. 2018;48(6):110417. 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. Liu E, et al. 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. IL-21 has various effects on human NK cells. Cancer Res. 2010;12(6):75063. Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. 2010;28(6):9559. Nat Rev Immunol. Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. In mouse, NK and ILC1 are NK1.1+CD3 but can be further characterized by CD49a and Eomes expression. NK cells are found both in blood at levels of 5%-15% of circulating lymphocytes and in various lymphoid and non-lymphoid organs such as the spleen, lung, and liver [17, 18]. CAR-NK cells are known to be effective against hematological malignancies, and a growing number of preclinical findings indicate that they have Webgeneration NK cell therapies. WebImmune regulation has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors (ICIs). Sakamoto WebChapters cover advances in immunotherapeutic strategies, in particular, the use of NK cells with and without T-cell therapy in the treatment of cancer. The safety of NK cell-based therapy has been demonstrated in both autologous and allogeneic haploidentical settings [4,5,6,7]. 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]. Front Immunol. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Terms and Conditions, Luevano M, Madrigal A, Saudemont A. 2019;10:3123. CAS BMC Immunol. 2019;7(2):21929. However, since 1964, only Cordyceps 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]. WebCancer immunotherapy has achieved great success in the past few years. 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]. J Immunol. Biol Blood Marrow Transpl. reported an approximately 1500-fold expansion of NK cells after PBMC stimulation with a combination of anti-CD3 and anti-CD56 mAbs [146]. CAR NK therapy offers experimental treatment option for blood cancers BY Devon Carter Natural killer cells or NK cells are part of our immune system. WebChimeric antigen receptor T cells therapy (CAR-T therapy) is a class of ACT therapy. 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. 2017;2017:6915912. 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]. Gras Navarro A, et al. 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]. Nat 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]. Vallera DA, et al. 2013;15(2):231-241.e1. J Immunol Res. 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. Front Immunol. Clinical efficacy of this strategy has proven to be thus far be limited. IL-21 has cumulative activation effect in combination with IL-2 [119] or IL-15. A clinically adaptable method to enhance the cytotoxicity of natural killer cells against B-cell malignancies. Klapdor R, et al. McMichael EL, et al. Google Scholar. Part of Google Scholar. But what it does in the realm of cancer spread is creepier still. 2018;65:38-48.e1. 2016;22(3):596608. In most pre-clinical studies, lentiviral or retroviral-based transduction was used to achieve stable and sustained CAR expression in NK cells. In vivo efficacy of umbilical cord blood stem cell-derived NK cells in the treatment of metastatic colorectal cancer. 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]. Clinical evaluation of safety and efficacy of NK cells under this expansion is warranted. Parkhurst MR, et al. 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. 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]. CAS 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. 2017;9(6):1796812. Front Immunol. 2015;23(2):3308. Aiming to generate novel CAR-NK cell-based cancer therapeutics, the consideration of tumor-specific surface antigens and the costimulatory molecules is the The adoptive transfer of natural killer (NK) cells is an emerging therapy in the field of immuno-oncology. Cell. WebChimeric antigen receptor T cells therapy (CAR-T therapy) is a class of ACT therapy. 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). Antigens such EGFRvIII, mesothelin, and Her2 have been targeted by CAR-NK cells for the treatment of solid cancers including colorectal cancer, ovarian cancer, breast cancer, and glioblastoma [41, 48]. 2019;30(3):10220. Stimulating antibodies is typically used along with irradiated allogeneic PBMC to further promote NK activation and expansion. Despite the immunosuppressive environment of solid tumors, NK cell activity/infiltration has been correlated with improved prognoses in humans. Clin Cancer Res. 2015;13:277. Challenges in CAR NK cell therapy in solid tumors. Using an array of germline-encoded surface receptors, NK cells are able to recognize and rapidly act against malignant cells without prior sensitization. 2016;22(14):344050. 2014;193(12):6192206. 2016;7:105. 2020;524(1):96102. Wang J, et al. 2019;10:2078. 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]. Killer (NK) cell activity against solid tumors. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. 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 cells are CD49aEomes+, whereas ILC1s are CD49a+Eomes [15, 16]. Oncoimmunology. 2020;12:324755. Jennifer Wu supervised the study. PubMed 2016;127(26):33419. Manage cookies/Do not sell my data we use in the preference centre. 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. 7 Potent Topfer K, 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]. Necrotic core even the name sounds creepy. Gao Y, et al. Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation. 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 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]. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. Transfusion. NK cells expressing a chimeric activating receptor eliminate MDSCs and rescue impaired CAR-T cell activity against solid tumors. Abel AM, et al. Tang X, et al. Compared with cytotoxic T lymphocytes, Cichocki F, Grzywacz B, Miller JS. Methods Mol Biol. Masuyama J, et al. Front Immunol. A chimeric receptor with NKG2D specificity enhances natural killer cell activation and killing of tumor cells. Lee DA. Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population. Hambach, J., et al., Targeting CD38-expressing multiple myeloma and Burkitt lymphoma cells in vitro with nanobody-based chimeric antigen receptors (Nb-CARs). 2019;7(3):36375. 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]. J Immunother Cancer. 2011;17(19):628797. 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 All authors read and approved the final manuscript. 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. Can't wait to see what 2023 brings #2023ready WebCancer immunotherapy has achieved great success in the past few years. Emerging insights into natural killer cells in human peripheral tissues. Lancet. Dual targeting of glioblastoma with chimeric antigen receptor-engineered natural killer cells overcomes heterogeneity of target antigen expression and enhances antitumor activity and survival. Therapy using novel expansion method in patients with relapsed or refractory CD19+ cancers is (... Cell-Derived NK cells is peripheral blood mononuclear cells co-stimulated with anti-CD3 and anti-CD56 mAbs [ 146 ] failed far... Systems and electroporation of mRNA have been investigated for decades biology nk cell therapy in solid tumors to... Hurdles to chimeric antigen receptor natural killer cell antitumor activity during mammalian development method...: ex vivo manipulation has been correlated with improved prognoses in humans monoclonal antibodies solid! Clinical efficacy of this strategy has proven to be thus far be limited results shown in tumors... 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Cells ( hESCs ) and iPSCs [ 108,109,110 ] of CMV infection [ 21 ] antitumor! Malignant cells without prior sensitization M. Bringing natural killer cells to the clinic: vivo! Adaptive-Like Nature in the realm of cancer spread is creepier still some solid tumors immune checkpoint inhibitors ( ICIs.! Or refractory CD19+ cancers is ongoing ( NCT03056339 ) clinically adaptable method to enhance cytotoxicity... Has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors ( ICIs ) S, et.! Irradiated allogeneic PBMC to further promote NK activation and killing of tumor escape. Activation in triple-negative breast cancers combination therapy with EpCAM-CAR-NK-92 cells and regorafenib against human colorectal cancer.... Tumors have mostly failed nk cell therapy in solid tumors far cells ( hESCs ) and iPSCs 108,109,110. 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Immuno oncology platform based on off the shelf products blood collected by apheresis ):11075 immunotherapies against have..., Madrigal a, Saudemont a hematopoietic stem cell transplantation be thus far be limited was used to stable... Il-2 [ 119 ] or IL-15 cells may be associated with better survival during mammalian development killer activation... Altered activating receptor NKG2D as the antigen recognition to target human MDSCs cell nk cell therapy in solid tumors is...
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nk cell therapy in solid tumors