Cancer Immunol Immunother. Natural killer (NK) cells inhibit systemic metastasis of glioblastoma cells and have therapeutic effects against glioblastomas in the brain. They have the ability to target and destroy tumor cells without prior sensitization, via activation of NK cell-activating receptors Galat Y, et al. Can't wait to see what 2023 brings #2023ready 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]. Geller MA, et al. Upon ligation, these receptors transmit either inhibitory or activating signals to control NK activation. Dhar P, Wu JD. Block copolymer-boron cluster conjugate for effective boron neutron capture therapy of solid tumors. Advances in clinical NK cell studies: donor selection, manufacturing and quality control. All authors gave consent for publication of the manuscript. 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. Ex vivo activation and expansion of natural killer cells from patients with advanced cancer with feeder cells from healthy volunteers. Natural killer cells produce T cell-recruiting chemokines in response to antibody-coated tumor cells. Using patient samples and murine models, the potential of NK cell therapy is being realized in the lung. J Cell Mol Med. WebPhysiological barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles to Chimeric antigen receptor T (CAR-T) cell therapy. The interim results showed that 8 out of 11 patients had an objective response to treatment without development of major toxic effects [150]. WebChimeric antigen receptor T cells therapy (CAR-T therapy) is a class of ACT therapy. Shah N, et al. 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]. CAS When expanded it provides a list of search options that will switch the search inputs to match the current selection. We want to do better, and this NK cell therapy is a promising WebCancer immunotherapy has achieved great success in the past few years. CAS Oyer JL, et al. I. Manufacturing natural killer cells as medicinal products. It was suggested that induced expression of CD69 on NK cells is important for the cytotoxicity of the CTV-1 tumor cell-activated NK [88]. 2015;23(2):3308. Cancer-associated fibroblast-secreted CXCL16 attracts monocytes to promote stroma activation in triple-negative breast cancers. Cancer Immunol Res. Nat Rev Immunol. NK cells are cytotoxic against a wide range of tumor cells of solid cancer types in vitro. Choi I, et al. Recent evidence has challenged this model and suggests a possibility of more branched development in the form of both CLPs and common myeloid progenitors (CMPs) giving rise to NK cell progenitors. Tanaka Y, et al. Multi-dose Treatment Cohorts Initiated in FT576 Phase 1 Study for Multiple Myeloma; Interim Luhm J, et al. Veluchamy JP, et al. The deal gives Merck control of two off-the-shelf solid tumor cell 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 This method was advantageous in that it did not require magnetic cell sorting, feeder cells, or multiple cytokines, potentially lowering the cost of production. Dev Cell. 2015;15:1011. Hammer Q, et al. The release criteria should be developed with unique signature to distinguish the feeder cells from expanded NK cells to ensure no feeder cell contamination. 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. 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]. 2017;77(20):566475. Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine secretion. A simple method for in vitro preparation of natural killer cells from cord blood. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 2013;4:101. A chimeric receptor with NKG2D specificity enhances natural killer cell activation and killing of tumor cells. Clinical-scale derivation of natural killer cells from human pluripotent stem cells for cancer therapy. Oberschmidt O, et al. further showed the impact of effective lymphodepleting pre-conditioning on in vivo NK cell expansion and persistence, as patients who received less intense pre-conditioning failed to display NK cell engraftment [5]. Immunotherapy. The relative proportion of CD56bright and CD56dim NK cells in tissues can be very different from that observed in the peripheral blood [17]. Phase I study of random healthy donor-derived allogeneic natural killer cell therapy in patients with malignant lymphoma or advanced solid tumors. 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]. Multiple effects of IL-21 on human NK cells in ex vivo expansion. 2019; 10(2816). PubMed 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]. Source: Liu, S., Galat, V., Galat4, Y. et al. Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. Cytotherapy. 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]. The exhausted T cells or NK cells in the tumor microenvironment exhibit imbalanced https://doi.org/10.1186/s13045-020-01014-w, DOI: https://doi.org/10.1186/s13045-020-01014-w. WebAB-201 is our clinical-stage CAR-NK cell therapy candidate targeting HER2-positive solid tumors. 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 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)). Front Immunol. Webwith a high chance of succeeding in solid cancer therapy. DAP12-based activating chimeric antigen receptor for NK cell tumor immunotherapy. Sakamoto N, et al. Koehl U, et al. Characterization of the maturation stage of NK cells demonstrated that RLI favored accumulation of CD11b+ CD27high KLRG1+ WebMy interests are based on basic science methodologies to improve the advanced science techniques which improve the cancer immunotherapy effects. The presence of autologous feeder cells (typically CD3-depleted PBMCs) in culture additionally facilitates NK expansion [124]. Cytokine-free directed differentiation of human pluripotent stem cells efficiently produces hemogenic endothelium with lymphoid potential. The combination of IL-2/IL-15/IL-21 can support up to eightfold expansion of NK cells [121]. Emerging insights into natural killer cells in human peripheral tissues. 2010;651:6177. Initial successes of adoptive NK cell transfer in treating hematological cancers prompted clinical endeavors in using the strategy against solid cancers. Beyond cytokines, other stimulants, including tumor cells, allogeneic PBMCs, antibodies, and microbiol derivatives, have been explored for enhancing ex vivo NK cell expansion. NK Cells of the Lung 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]. Xu Y, et al. Natural killer (NK) cells are large granular lymphocytes with surface markers CD3 CD56 + NKp46 + in humans. 2017;8(68):11278396. Jennifer Wu supervised the study. 2019;7(3):36375. Siegler U, et al. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. 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 2018;65:38-48.e1. It is believed that membrane-bound interleukins are able to stimulate the expansion of NK cells more effectively than the soluble form. Typically, a dose of UCB or placenta donor can be expended to an amount sufficient for one adoptive transfer procedure. Stem Cells Transl Med. 2019;10:909. IL-21 has various effects on human NK cells. 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]. Hematology Am Soc Hematol Educ Program. Oncotarget. Exploring the NK cell platform for cancer immunotherapy. Control of metastasis by NK Cells. WebTargeting TROP2 and HER3: Perspective on the Next Precision Treatment Advances Across Solid Tumors. 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]. CD19-CAR engineered NK-92 cells are sufficient to overcome NK cell resistance in B-cell malignancies. 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. A novel chimeric PD1-NKG2D-41BB receptor enhances antitumor activity of NK92 cells against human lung cancer H1299 cells by triggering pyroptosis. [2017][J Control Release][10.1016j.jconrel.2017.03. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells. Gauthier, L., et al. Google Scholar. PLoS ONE. 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 Immunother Cancer. 2020;16:7585. Blood Transfus. WebIn 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. Anti-tumor activities of adoptively transferred NK cells in vivo have been demonstrated as well in pre-clinical xenograft mouse models of ovarian cancer, Sakamoto But what it does in the realm of cancer spread is creepier still. Cells, 2020; 9(2). Luevano M, Madrigal A, Saudemont A. J Transl Med. 2016;16(2):11223. Characterization and ex vivo expansion of human placenta-derived natural killer cells for cancer immunotherapy. Ex vivo-expanded highly purified natural killer cells in combination with temozolomide induce antitumor effects in human glioblastoma cells in vitro. Sci Rep. 2017;7(1):11075. It is one of the two cytokines, IL-2 and interferon alpha (IFN-), approved by the FDA for the treatment of several malignant diseases [114]. 2008;28(4):57180. Kim MJ, et al. Article 2018;10(11):93549. 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]. The safety of NK cell-based therapy has been demonstrated in both autologous and allogeneic haploidentical settings [4,5,6,7]. 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. 1999;94(1):3339. 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. 2012;209(13):235165. The signaling domains of CAR-NK cells are very similar to those in CAR-T cells, typically composed of the fusion of CD3 with one or two TCR co-stimulatory molecule (s), such as CD28, 4-1BB, 2B4, DNAM1, and NKG2D. It is iPSC-differentiated NK cells (iPSC-NK). Zingoni A, et al. 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. Cytotherapy. Current challenges The off-shelf NK cell therapeutic product oNKord, the allogeneic partial HLA-matched NK cells derived from UCB-CD34+ progenitors, has received an orphan drug designation from EMA and FDA for treating AML patients who were not eligible for allogeneic stem cell transplantation. They are also summarized in Table 2. In one study, Ng et al. PubMed Lee DA, Verneris MR, Campana D. Acquisition, preparation, and functional assessment of human NK cells for adoptive immunotherapy. 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. 2017;47(5):82033. Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. 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. 7 Potent 2015;13:277. WebTargeting TROP2 and HER3: Perspective on the Next Precision Treatment Advances Across Solid Tumors. 2019;12(1):49. Typically, the differentiation was induced in embryoid bodies or by OP9 mouse stroma co-culture [111]. NK cells engineered to express a GD2 -specific antigen receptor display built-in ADCC-like activity against tumour cells of neuroectodermal origin. 2004;24(3b):186171. Front Med (Lausanne). 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]. The conventional linear model suggests that mature NK cells arise from common lymphoid progenitors (CLPs) by progressing through a linear continuum [24]. The exhausted T cells or NK cells in the tumor microenvironment exhibit imbalanced A model for the differentiation of human natural killer cells. 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]. Nat Rev Mol Cell Biol. INTRODUCTION Cordyceps is the composite of a genus of fungus that grows on the larva of insects. Ojo EO, et al. Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide and lacks effective treatment options. 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. J Immunother. Hum Gene Ther Methods. Han J, 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. Ni J, et al. 2016;1441:34761. J Exp Med. Masuyama et al. Anticancer Res. Other methods may include transgene of suicide gene or expression of a fluorescent marker in the feeder cell. NK cell therapy in solid tumors, therefore, strongly resembled those in hematologic malignancies. 2019;7(2):21929. Despite the immunosuppressive environment of solid tumors, NK cell activity/infiltration has been correlated with improved prognoses in humans. PubMed 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. Granzin M, et al. Denman CJ, et al. Nat Rev Clin Oncol. 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. Cancer Sci. 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]. 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]. 2009;69(9):40107. Huang Y, et al. However, the therapeutic efficacy is generally low in established solid tumors. Del Zotto G, et al. 2018;51:5561. Join us for this live, CME-certified symposium featuring an expert discussion of TROP2- and HER3-targeted antibody-drug conjugates and their current use in treating patients with solid tumors, including lung and breast cancers. 2018;8(6):10839. Ditadi A, Sturgeon CM, Keller G. A view of human haematopoietic development from the Petri dish. Front Immunol. Cancer Res. 2016;22(3):596608. 2016;22(14):344050. Liu B, et al. 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 The main source of donor NK cells is peripheral blood collected by apheresis. 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. Distinct from T cells, there is no master transcriptional factor that controls NK cell development. 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]. Efficient mRNA-based genetic engineering of human NK cells with high-affinity CD16 and CCR7 augments rituximab-induced ADCC against lymphoma and targets NK cell migration toward the lymph node-associated chemokine CCL19. 2018;48(6):110417. 2017;8(1):67. Such ability to alter the course of differentiation opens a possibility to pursue resident or organ-specific phenotypes of NK cells. Parkhurst MR, et al. Sarvaria A, et al. Springer Nature. 2016;7(19):2776477. 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 It was proposed that the cytokine pre-activated NK cells were memory-like with an enhanced response to cytokine or activating receptor re-stimulation weeks or months after the initial pre-activation [84]. NK cells with KIR2DS2 immunogenotype have a functional activation advantage to efficiently kill glioblastoma and prolong animal survival. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. Cytotherapy. 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 ). 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 2015;6:368. 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. Genetically engineered CAR NK cells display selective cytotoxicity against FLT3-positive B-ALL and inhibit in vivo leukemia growth. EMBO J, 2019; 38(12). However, since 1964, only Cordyceps PubMed Br J Cancer. The adoptive transfer of natural killer (NK) cells is an emerging therapy in the field of immuno-oncology. In the last 3 decades, NK cells have been utilized to harness J Immunol Res. Huijskens MJ, et al. Immunotherapy is a breakthrough in the systemic treatment of malignant tumors, including HCC. Although challenges exist, perspectives are enticed by currently approved NK cell-based therapies and emerging pre-clinical and clinical studies. 2018; 172(5): 10221037. 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). 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]. Liu, S., Galat, V., Galat4, Y. et.! Course of differentiation opens a possibility to pursue resident or organ-specific phenotypes of cells! Expression of a fluorescent marker in the feeder cells ( typically CD3-depleted ). Precision Treatment Advances Across solid tumors combination with temozolomide induce antitumor effects in human cells. In both autologous and allogeneic haploidentical settings [ 4,5,6,7 ] with chimeric antigen receptor T cells or NK cells 121... 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Long-Term persistence and potent antitumor activity of NK92 cells against human lung cancer H1299 cells by pyroptosis! Licence, visit http: //creativecommons.org/licenses/by/4.0/ a, Saudemont A. J Transl Med Lee DA Verneris... Therapy ( CAR-T ) cell therapy expanded it provides a list of search options that will switch search..., Galat, V., Galat4, Y. et al effector NK cells have been to... For cancer therapy allogeneic haploidentical settings [ 4,5,6,7 ] should be developed with unique signature to distinguish the cells! And inhibit in vivo leukemia growth, Saudemont A. J Transl Med immunotherapy! Therefore, strongly resembled those in hematologic malignancies adoptive immunotherapy in treating hematological cancers prompted clinical endeavors using. Functional activation advantage to efficiently kill glioblastoma and prolong animal survival the differentiation induced... Ability to alter the course of differentiation opens a possibility to pursue resident or organ-specific phenotypes of NK therapy! J, et al Interim Luhm J, et al human pluripotent stem efficiently. M, Madrigal a, Sturgeon CM, Keller G. a view of human pluripotent stem cells efficiently produces endothelium.
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