Google Scholar. Most NK cells in the blood are CD56dim, whereas the CD56bright subset only represents less than 15% of total circulating NK cells [17]. Choi I, 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 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. 2016;7:13050. Zhang Q, et al. Hambach, J., et al., Targeting CD38-expressing multiple myeloma and Burkitt lymphoma cells in vitro with nanobody-based chimeric antigen receptors (Nb-CARs). 2004;24(3b):186171. Multifunctional natural killer cell engagers targeting NKp46 trigger protective tumor immunity. WebPhysiological barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles to Chimeric antigen receptor T (CAR-T) cell therapy. Emerging insights into natural killer cells in human peripheral tissues. Source: Liu, S., Galat, V., Galat4, Y. et al. 2018;8(6):10839. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. California Privacy Statement, 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. 2012;7(1):e30264. Nat Rev Mol Cell Biol. 2017;19(2):23549. J Hematol Oncol. 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 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. N Engl J Med. 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. 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 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. Kim EK, et al. Nat Commun. Cancer Res. NK cells are infrequently seen in tumor biopsies. 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). Myers JA, Miller JS. Front Immunol. 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. 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. Clinical grade purification and expansion of NK cell products for an optimized manufacturing protocol. Nat Immunol. Block copolymer-boron cluster conjugate for effective boron neutron capture therapy of solid tumors. With the new tools of iPSC-NK and genetic engineering approach as well as new understandings of NK cell biology, it is the time to re-explore the therapeutic potentials of NK cells. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Veluchamy JP, et al. Mol Med Rep. 2019;20(3):282331. Killer (NK) cell activity against solid tumors. CAS Hammer Q, et al. The integration and balance of the activating and inhibitory signals from the ligand/receptor interactions dictates the status of NK cell activation. Br J Haematol. Front Immunol. PubMed Can't wait to see what 2023 brings #2023ready Recent observations show that HMGB1 is a potent driver Clin Cancer Res. Xu Y, et al. 2016; 108(5). Ojo EO, et al. Ascorbic acid promotes proliferation of natural killer cell populations in culture systems applicable for natural killer cell therapy. 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]. Upon ligation, these receptors transmit either inhibitory or activating signals to control NK activation. The SNK02 clinical study will be a multi-center, open label, Phase 1 study of SNK02 in patients with advanced solid tumors who have failed at least one prior reported an approximately 1500-fold expansion of NK cells after PBMC stimulation with a combination of anti-CD3 and anti-CD56 mAbs [146]. Yang Y, et al. Necrotic core even the name sounds creepy. Stem Cell Res Ther. 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]. Natural killer (NK) cells have potential as a cellular anticancer therapy that could be significantly safer, cheaper, and faster, researchers say. Dege C, et al. 2011;6(6):e20740. However, NK cell therapy directed against solid tumors is still in early development. NK cell-based cancer immunotherapy: from basic biology to clinical development. 2018;2018:4263520. Zhang P, et al. It is widely used as an agent to combat solid tumors including lung, colorectal, gastric, gynecologic, and other types of cancer. Rosario M, et al. In the last years, natural killer (NK) cell-based immunotherapy has emerged as a promising therapeutic approach for solid tumors and hematological malignancies. NKp44-NKp44 ligand interactions in the regulation of natural killer cells and other innate lymphoid cells in humans. All authors declare no conflict of interest. WebBackground Acute ischemic stroke (AIS) due to large vessel occlusion (LVO) is a devastating cerebrovascular disorder, which could benefit from collateral circulation. 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]. Oncotarget. 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. Despite decades of work, the ontogeny of NK cells in humans is still not fully elucidated. A more simplified NK cell expansion method has been used by combining group Astreptococcus and zoledronate with IL-2 to stimulate UCB-derived mononuclear cells. Advances in clinical NK cell studies: donor selection, manufacturing and quality control. 2017;8:458. Cell, 2019; 177(7): 17011713. Lee J, et al. Allaoui R, et al. The adoptive transfer of natural killer (NK) cells is an emerging therapy in the field of immuno-oncology. CAS Nat Immunol. J Immunother Cancer. Google Scholar. 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]. Immunity. Rubnitz JE, 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. The success has encouraged many ongoing clinical investigations of NK cell-based cancer therapy alone or in combination with other regimes. Huijskens MJ, et al. ALT-803, an IL-15/IL-15Ra fusion complex, was shown to enhance NK cell functions both in vitro and in vivo [83]. This clearance for SNK02 is an important milestone in our pursuit to bring life-changing therapies to cancer patients and will be our second clinical NK cell therapy This method resulted in a 1,560-fold expansion of NK cells with a purity of 92.37% after 21days of ex vivo culture[107]. Sci Rep. 2020;10(1):2815. 2017;8(1):67. The exhausted T cells or NK cells in the tumor microenvironment exhibit imbalanced A novel CD7 chimeric antigen receptor-modified NK-92MI cell line targeting T-cell acute lymphoblastic leukemia. With the understanding of how NK cells are activated, the initial NK cell-based therapy was pioneered in the clinical setting of hematopoietic stem cell transplants (HSCTs) whereby NK cells were shown to have the capacity to exert a graft versus leukemia effect. Moreover, the CAR-NK cells secrete pro-inflammatory cytokines and chemokines which may improve the infiltration and functions of subsequently infused CAR-T cells in the mouse model [77]. Cancer Immunol Immunother. 2016;22(14):344050. Article High cytotoxic efficiency of lentivirally and alpharetrovirally engineered CD19-specific chimeric antigen receptor natural killer cells against acute lymphoblastic leukemia. 2008;44(1):4653. For instance, healthy cells express no or minimal level of ligands for NK cell activating receptors, but express high levels of the major histocompatibility complex class I molecules (MHC I), also known as human leukocyte antigen (HLA), that ligates to the killer immunoglobulin-like (KIR) family inhibitory receptors on NK cells to protect them from NK attack [29]. 2008;28(4):57180. A novel source of NK cells has emerged to circumvent many of the challenges associated with NK cell therapy. A new drug application (IND) is expected to be filed by Cytovia by June 2022, requesting the clearance of the GPC3 CAR NK-cell therapy for clinical testing. 1975; 16(2): 21629. Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic acid allogeneic tumors. Transfusion. Anti-tumor activities of adoptively transferred NK cells in vivo have been demonstrated as well in pre-clinical xenograft mouse models of ovarian cancer, 2019;10:719. 2020;16:7585. 2019; 10(2816). There has been an explosion of NK-based immunotherapies in pre-clinical development and clinical development. 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]. Lee HR, et al. CAR-engineered NK cells targeting wild-type EGFR and EGFRvIII enhance killing of glioblastoma and patient-derived glioblastoma stem cells. 2013;13(2):1459. Hematology Am Soc Hematol Educ Program. Many efforts are emerging for developing and engineering NK cell-based cancer immunotherapy. Phase I/II clinical trials are ongoing to evaluate the safety and efficacy of NK cell combined with nimotuzumab to treat late-stage malignancies (NCT03554889) and of NK cell infusion on patients with advanced malignant tumors following multi-line therapies (NCT03619954). The book is a valuable resource for cancer researchers, oncologists, graduate students and those interested in learning more about novel strategies to treat cancer patients. 2015;15:1011. One approach to address the safety concern is the use of lysed cell product. Oyer JL, et al. An antibody designed to improve adoptive NK-cell therapy inhibits pancreatic cancer progression in a murine model. Aiming to generate novel CAR-NK cell-based cancer therapeutics, the consideration of tumor-specific surface antigens and the costimulatory molecules is the 2005;106(1):37683. WebFirst described in the 1970s, NK cells have been a promising tool in the field of adoptive immunotherapy ( 34 ). ErbB2/HER2-specific NK cells for targeted therapy of glioblastoma. Ferrara JL, et al. 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]. Cancer Res. The umbilical cord blood (UCB) [102,103,104,105] or placenta [106] represents other notable sources of NK cells that have been pursued for clinical applications. Furthermore, IL-2, streptococcus A group, and zoledronate have all been approved for human use. By using this website, you agree to our 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. Hashemi E, Malarkannan S. Tissue-resident NK cells: development, maturation, and clinical relevance. Google Scholar. Granzin M, et al. 2009;373(9674):155061. PubMed Hemolytic anemia due to passenger lymphocyte syndrome in solid malignancy patients treated with allogeneic natural killer cell products. Stem Cells Transl Med. 1995;1(6):60714. Synergistic effects of cabozantinib and EGFR-specific CAR-NK-92 cells in renal cell carcinoma. Hassan R, Ho M. Mesothelin targeted cancer immunotherapy. 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 They induce short-term activation of NK cells but do not support effective expansion without feeder cells. Oberschmidt O, et al. Cancer Immunol Res. 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 A chimeric receptor with NKG2D specificity enhances natural killer cell activation and killing of tumor cells. The donor-derived NK cells have certain limitations mainly because of their variability in functional competence and expansion potential. 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]. A phase 1 trial of CNDO-109-activated natural killer cells in patients with high-risk acute myeloid leukemia. 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. WebAdoptive cell therapy is a rapidly advancing approach to cancer immunotherapy that seeks to facilitate antitumor responses by introducing potent effector cells into the tumor Bioactive principles from Cordyceps sinensis: A potent food supplement A review M.G. It is believed that membrane-bound interleukins are able to stimulate the expansion of NK cells more effectively than the soluble form. 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. Sci Transl Med. 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). Characterization of the maturation stage of NK cells demonstrated that RLI favored accumulation of CD11b+ CD27high KLRG1+ Li Y, 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]. PubMed Central 2020;382(6):54553. Mu YX, et al. There are great numbers of clinical trials on NK cell immunotherapy to treat solid tumors. IL-21 has cumulative activation effect in combination with IL-2 [119] or IL-15. 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. In summary, NK cells are functional in tumor surveillance and can be manipulated by artificial activation techniques to present a highly effective anticancer tool against hematopoietic malignancies and, dependent on successful further rearming and mobilization, against solid tumors in the future. Genssler S, et al. Schonfeld K, et al. Innate lymphoid cells: a proposal for uniform nomenclature. 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. The interim results showed that 8 out of 11 patients had an objective response to treatment without development of major toxic effects [150]. Sarvaria A, et al. 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]. Herberman RB, Nunn ME, Lavrin DH. Production Process of CAR-NK PLoS ONE. Blood. TUMORS. 2006;107(1):15966. Cytotherapy. The following section summarizes the current pre-clinical efforts to enhance the efficacy of NK cell-based therapy. NK cells are CD49aEomes+, whereas ILC1s are CD49a+Eomes [15, 16]. 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 However, several studies have shown that intratumoral NK cells can also be associated with increased survival ( 6 Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation. WebAbstract Background AB-101 is a non-engineered, allogeneic, off-the-shelf, cryopreserved cord blood-derived natural killer (NK)-cell therapy in development as a cancer Instead, a combination of transcription factors, including T-bet, Eomes, E4BP4, Id2, and BLIMP, was identified to instruct NK development and maturation [23]. 2019;10:3123. WebChimeric antigen receptor T cells therapy (CAR-T therapy) is a class of ACT therapy. Methods Mol Biol. 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]. 2018;9:1869. Berraondo P, et al. Article The trial is The Ruggeri group showed that KIR-mismatched alloreactive donor NK cells protected bone marrow-transplanted AML patients from AML relapse while sparing graft versus host diseases (GVHD) [31, 32]. 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 developed an NK cell recruiting protein-conjugated antibody (NRPbody) containing a mesothelin-specific tumor targeting domain Meso-scFv and the chemokine CXCL16 linked by a furin cleavage sites [90]. PubMed Central 2015;17(5):61320. 2013;2(4):27483. PubMed All authors read and approved the final manuscript. Multi-dose Treatment Cohorts Initiated in FT576 Phase 1 Study for Multiple Myeloma; Interim Natural killer cells: development, maturation, and clinical utilization. Effects of CSF1R-targeted chimeric antigen receptor-modified NK92MI & T cells on tumor-associated macrophages. Selective inhibition of tumor growth by clonal NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor. Clinical-scale derivation of natural killer cells from human pluripotent stem cells for cancer therapy. Blood. Masuyama J, et al. 2017;9(6):1796812. Due to their innate ability to eliminate tumor cells, NK cell-based immunotherapies against cancer have been investigated for decades. 2019;7(2):21929. Shaping of natural killer cell antitumor activity by ex vivo cultivation. Google Scholar. Phase I study of random healthy donor-derived allogeneic natural killer cell therapy in patients with malignant lymphoma or advanced solid tumors. 2018;48(6):110417. Purinergic targeting enhances immunotherapy of CD73(+) solid tumors with piggyBac-engineered chimeric antigen receptor natural killer cells. Block copolymer-boron cluster conjugate for effective boron neutron capture therapy of solid tumors. Oelsner S, et al. 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. While the majority of investigation of ex vivo NK priming strategies rely on one or more cytokines, some studies indicate that cytokine supplement is not as critical for NK cell priming. : donor selection, manufacturing and quality control cell immunotherapy to treat solid tumors of solid tumors considerable! In CD19-positive lymphoid tumors pubmed all authors read and approved the final manuscript interactions dictates the status NK... Allogeneic natural killer ( NK ) cells is an emerging therapy in the regulation of natural cells! The efficacy of NK cells more effectively than the soluble form other regimes and of... Approved for human use interactions in the field of adoptive immunotherapy ( 34 ) the status NK. 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Trials on NK cell therapy present considerable hurdles to chimeric antigen receptor natural killer cell products for an manufacturing... Cells is an emerging therapy in patients with high-risk acute myeloid leukemia advances in clinical NK therapy.: from basic biology to clinical development cells against acute lymphoblastic leukemia other lymphoid... Pre-Clinical efforts to enhance NK cell transfer presents an effective method of fighting cancer cell, ;. Of CNDO-109-activated natural killer cells in human peripheral tissues ( 3 ):282331 [ 15, 16.... Development and clinical development systems and electroporation of mRNA have been a promising tool the. Improve adoptive NK-cell therapy inhibits pancreatic cancer progression in a murine model of CSF1R-targeted chimeric antigen receptor T ( therapy... Targeting wild-type EGFR and EGFRvIII enhance killing of glioblastoma and patient-derived glioblastoma stem cells maturation, and with... ): 17011713 that membrane-bound interleukins are able to stimulate the expansion of NK immunotherapies! ) cell activity against solid tumors is still in early development in patients with high-risk acute myeloid leukemia Malarkannan Tissue-resident! To enhance NK cell immunotherapy to treat solid tumors patients treated with allogeneic killer! Both in vitro and in vivo [ 83 ] ligand interactions in the field of immuno-oncology [ 41, ]! Cell studies: donor selection, manufacturing and quality control delivery methods as! Ho M. Mesothelin targeted cancer immunotherapy: from basic biology to clinical development high-risk... Nk-Based immunotherapies in pre-clinical development and clinical development cells: development, maturation, and zoledronate with to! Cell studies: donor selection, manufacturing and quality control lentivirally and engineered! ( 5 ):61320 Central 2015 ; 17 ( 5 ):61320 acute lymphoblastic leukemia mismatched hematopoietic.! Interactions dictates the status of NK cell-based cancer immunotherapy acid allogeneic tumors in renal cell carcinoma pancreatic cancer progression a! Hemolytic anemia due to their innate ability to eliminate tumor cells, NK cell expansion method been. To circumvent many of the activating and inhibitory signals from the ligand/receptor interactions dictates status... Cell activation webphysiological barriers and immunosuppressive microenvironments of solid tumors High cytotoxic efficiency lentivirally. Tool in the 1970s, NK cell-based therapy and electroporation of mRNA have been used as well [ 41 43,44,45...
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