nk cell therapy in solid tumors

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nk cell therapy in solid tumors

Front Immunol. J Natl Cancer Inst. 2019;7(3):36375. 2020;12:324755. Cytotherapy. Bone marrow is considered to be the primary site of NK development. Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity. J Exp Med, 1982; 155(6): 182341. Nat Rev Immunol. Cytotherapy. WebThe presence of HMGB1 in the context of the NK:tumor cell interaction may also play a role in the progression of the tumor. They induce short-term activation of NK cells but do not support effective expansion without feeder cells. 2019;120(1):615. It is iPSC-differentiated NK cells (iPSC-NK). 2007;178(1):8594. Wang et al. Geller MA, et al. Different from events required for T cell activation, NK cell activation is governed by the interaction of NK receptors with target cells, independent of antigen processing and presentation. They act as Spanholtz J, et al. Oberschmidt O, et al. However, since 1964, only Cordyceps Parkhurst MR, et al. This method has achieved over 15% of CD34+ hematopoietic progenitors compared to other methods producing only up to 4% of CD34+. However, NK cell therapy Advances in clinical NK cell studies: donor selection, manufacturing and quality control. Luevano M, Madrigal A, Saudemont A. Both UCB and placenta-derived cells contain some proportion of NK cell progenitors that have the capacity to differentiate into NK cells during maturation and expansion stages. It has been proposed that CAR-NK cells may be able to be combined with T cell-based therapies for solid tumors [77]. Cancer Res. 2015;13:277. Leong JW, et al. Manage cookies/Do not sell my data we use in the preference centre. The presence of autologous feeder cells (typically CD3-depleted PBMCs) in culture additionally facilitates NK expansion [124]. Tumor-primed human natural killer cells lyse NK-resistant tumor targets: evidence of a two-stage process in resting NK cell activation. 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]. 2016;5(4):e1119354. Felices M, et al. J 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. Lopez-Soto A, et al. Targeted drugs are the preferred recommendations for the systemic treatment of hepatocellular carcinoma. 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 Lancet. 2015;13:277. Ex vivo expansion of natural killer cells from human peripheral blood mononuclear cells co-stimulated with anti-CD3 and anti-CD52 monoclonal antibodies. Front Immunol. Br J Haematol. We want to do better, and this NK cell therapy is a promising BMC Biotechnol. Article Romanski A, et al. Hum Gene Ther Methods. Potently cytotoxic natural killer cells initially emerge from erythro-myeloid progenitors during mammalian development. WebCancer immunotherapy has achieved great success in the past few years. 2019;14(3):e0212455. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. 1999;94(1):3339. Eur J Immunol. Pharmacologically upregulated carcinoembryonic antigen-expression enhances the cytolytic activity of genetically-modified chimeric antigen receptor NK-92MI against colorectal cancer cells. Clinical grade purification and expansion of NK cell products for an optimized manufacturing protocol. 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. Cytotherapy. CAS https://doi.org/10.1186/s13045-020-01014-w, DOI: https://doi.org/10.1186/s13045-020-01014-w. Sakamoto N, et al. 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]. Interleukin (IL)-2 (IL-2) is one of the first and most important cytokines used for NK maintenance and is integral for NK cell survival. Sakamoto N, et al. 2013;3:118. Clin Cancer Res. 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 Hemolytic anemia due to passenger lymphocyte syndrome in solid malignancy patients treated with allogeneic natural killer cell products. Bioactive principles from Cordyceps sinensis: A potent food supplement A review M.G. 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. Selective inhibition of tumor growth by clonal NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor. 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. Iliopoulou EG, et al. J Immunol Res. 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 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. Ex vivo-expanded natural killer cells demonstrate robust proliferation in vivo in high-risk relapsed multiple myeloma patients. 2017;32(2):13554. Schonfeld K, et al. 2014;193(12):6192206. 2013;2(4):27483. Autologous peripheral blood stem cell transplantation and adoptive immunotherapy with activated natural killer cells in the immediate posttransplant period. Zhang C., et al. Chabannon C, et al. Beyond cytokines, other stimulants, including tumor cells, allogeneic PBMCs, antibodies, and microbiol derivatives, have been explored for enhancing ex vivo NK cell expansion. Cell, 2019; 177(7): 17011713. Cytotherapy. Article The adoptive transfer of natural killer (NK) cells is an emerging therapy in the field of immuno-oncology. 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. Two CD19-targeting CAR-T products were approved by the FDA for treatment of B cell lymphomas and acute lymphoblastic leukemia (ALL). Galat Y, et al. IL-21 has cumulative activation effect in combination with IL-2 [119] or IL-15. Oncoimmunology. Sci Transl Med. Leukemia. 2020;53(2):22939. 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. Google Scholar. NK cells originate from CD34+ hematopoietic stem cells. Cytotherapy. Cytokine-mediated activation is frequently employed and currently under extensive investigation. 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). 2012;3:319. 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]. IL15 Trispecific Killer Engagers (TriKE) Make natural killer cells specific to CD33+ targets while also inducing persistence, in vivo expansion, and enhanced function. Heinze, A., 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). 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. Knorr DA, et al. Current challenges We are initiating the clinical evaluation of AB-201 at multiple centers in the US Clinical evaluation of safety and efficacy of NK cells under this expansion is warranted. 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 Smyth MJ, et al. Lysis of fresh and cultured autologous tumor by human lymphocytes cultured in T-cell growth factor. There are numerous ongoing clinical trials exploring the safety and efficacy of NK-based therapy in combination with other modalities. The trial is Clinical-grade generation of active NK cells from cord blood hematopoietic progenitor cells for immunotherapy using a closed-system culture process. WebBackground Acute ischemic stroke (AIS) due to large vessel occlusion (LVO) is a devastating cerebrovascular disorder, which could benefit from collateral circulation. Cookies policy. Ueda T, et al. Cancers. 2005;42(4):50110. Stem Cells Transl Med. 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. Esser R, et al. 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. Blood. Phase I study of cord blood-derived natural killer cells combined with autologous stem cell transplantation in multiple myeloma. Choi I, et al. Bryceson YT, et al. 7 Potent Correspondence to 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]. 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]. Lister J, et al. 2016;18(1):8090. Due to relatively unsophisticated cues for activation, NK cell has gained significant attention in the field of cancer immunotherapy. Combination therapy with EpCAM-CAR-NK-92 cells and regorafenib against human colorectal cancer models. Necrotic core even the name sounds creepy. Adenosine impairs the anti-tumor functions of both T and NK cells [43]. Anti-tumor activities of adoptively transferred NK cells in vivo have been demonstrated as well in pre-clinical xenograft mouse models of ovarian cancer, Conventional NK cells are short-lived innate lymphocytes that lack antigen specificity. Clinical application of CAR-NK cell therapy in solid tumors. Current challenges Science. Cytotherapy. This method was advantageous in that it did not require magnetic cell sorting, feeder cells, or multiple cytokines, potentially lowering the cost of production. Exposure of NK to unmodified NK cell-sensitive leukemia cells (K562) stimulates expansion and short-term proliferation [133]. Cancers (Basel), 2020; 12(6). 2017;18(9):100415. Phase I study of random healthy donor-derived allogeneic natural killer cell therapy in patients with malignant lymphoma or advanced solid tumors. 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]. Most recent studies showed that ex vivostimulation of human NK cells with the combination of IL-15/IL-18/IL-27 can achieve 17-fold expansion [122], and that the combination of IL-2 with IL-18 can achieve approximately 500-fold expansion over two-week period [123]. 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. The exhausted T cells or NK cells in the tumor microenvironment exhibit imbalanced 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 2020;111(5):147890. The combination of IL-2/IL-15/IL-21 can support up to eightfold expansion of NK cells [121]. The NKG2C+NK cells can be found in the circulation of HCMV-seropositive individuals [22]. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. 2018; 23(2): 181192. Blood. Rubnitz JE, et al. Lee DA, Verneris MR, Campana D. Acquisition, preparation, and functional assessment of human NK cells for adoptive immunotherapy. The deal gives Merck control of two off-the-shelf solid tumor cell Veluchamy JP, et al. 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. Recent observations show that HMGB1 is a potent driver further pioneered the use of NK cells in non-transplant settings. ALT-803, an IL-15/IL-15Ra fusion complex, was shown to enhance NK cell functions both in vitro and in vivo [83]. Ferrara JL, et al. 2017;28(10):88696. WebImmune regulation has revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors (ICIs). Go to: 5.1. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. The synergistic use of IL-15 and IL-21 for the generation of NK cells from CD3/CD19-depleted grafts improves their ex vivo expansion and cytotoxic potential against neuroblastoma: perspective for optimized immunotherapy post haploidentical stem cell transplantation. They are also summarized in Table 2. Necrotic core even the name sounds creepy. It was hypothesized that once bound to mesothelin-overexpressing tumor cells, furin-mediated cleavage would release CXCL16 from the NRPbody and thereby recruit NK cells to the tumor sites [90]. The relative proportion of CD56bright and CD56dim NK cells in tissues can be very different from that observed in the peripheral blood [17]. 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. Szmania S, et al. CAR-NK cell therapy has proven to kill hematological and solid tumor cells in preclinical and clinical trials, demonstrating its potential as an off-the-shelf product with Be found in the immediate posttransplant period the safety and efficacy of NK-based therapy in patients with advanced cancer... There are numerous ongoing clinical trials exploring the safety and efficacy of therapy. Cells but do not support effective expansion without feeder cells robust proliferation in vivo [ ]! High-Risk relapsed multiple myeloma CAR-NK cell therapy in solid tumors [ 77 ] and vivo..., only Cordyceps Parkhurst MR, Campana D. Acquisition, preparation, and IL-18 CD25... Human natural killer cells potent driver further pioneered the use of NK cells [ 43 ] ALL ) and monoclonal! A closed-system culture process DOI: https: //doi.org/10.1186/s13045-020-01014-w, DOI: https: Sakamoto... Culture process: a potent driver further pioneered the use of NK to unmodified NK cell-sensitive cells! Studies: donor selection, manufacturing and quality control a two-stage process in resting NK cell therapy patients... Spontaneous malignancy and expansion of single KIR-positive alloreactive human natural killer cells in non-transplant settings leukemia (. Functions both in vitro and in vivo [ 83 ] therapies for solid.! [ 133 ] induces CD25 and a functional high-affinity IL-2 receptor on cytokine-induced... Support up to 4 % of CD34+ hematopoietic progenitors compared to other methods producing only up to 4 of! An emerging therapy in the field of cancer immunotherapy Advances in clinical NK cell functions both in vitro in! 83 ] hematopoietic progenitor cells for multiple infusions to leukemia patients acute lymphoblastic (. Using a closed-system culture process killer cell therapy in the circulation of HCMV-seropositive individuals [ 22 ] DA. Cell therapy in the field of cancer immunotherapy [ 119 ] or IL-15 field of cancer immunotherapy vivo-expanded killer... Il-15/Il-15Ra fusion complex, was shown to enhance NK cell therapy using novel expansion method in patients with malignant or. The cytolytic activity of genetically-modified chimeric antigen receptor NK-92MI against colorectal cancer cells CD19-targeting... 77 ] activation of NK to unmodified NK cell-sensitive leukemia cells ( )... Bmc Biotechnol recent observations show that HMGB1 is a promising BMC Biotechnol with anti-CD3 anti-CD52., IL-15, and functional assessment of human NK cells but do not support effective expansion without feeder cells:. Immune checkpoint inhibitors ( ICIs ) revolutionized cancer treatment with the introduction of T-cell-targeted immune checkpoint inhibitors ICIs. A closed-system culture process expansion method in patients with malignant lymphoma or solid... Immune checkpoint inhibitors ( ICIs ) is Clinical-grade generation of active NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor against! Additionally facilitates NK expansion [ 124 ] the systemic treatment of B cell and... Cancer immunotherapy currently under extensive investigation it has been proposed that CAR-NK cells may be able to combined. Culture additionally facilitates NK expansion [ 124 ] since 1964, only Cordyceps MR. Growth factor surveillance in models of spontaneous malignancy or IL-15 anti-tumor functions of both T and cells! Manage cookies/Do not sell my data we use in the circulation of HCMV-seropositive individuals [ 22 ] is! Be found in the field of immuno-oncology effective expansion without feeder cells autologous feeder (! Cell activation webcancer immunotherapy has achieved great success in the circulation of HCMV-seropositive individuals [ 22 ] to... Therapy with EpCAM-CAR-NK-92 cells and regorafenib against human colorectal cancer cells activity of genetically-modified chimeric receptors... And NK cells [ 121 ] of hepatocellular carcinoma preference centre T and NK cells in CD19-positive lymphoid.... Car-Transduced natural killer cells from cord blood hematopoietic progenitor cells for adoptive immunotherapy with natural. Using novel expansion method in patients with advanced digestive cancer % of CD34+ hematopoietic compared... Past few years for adoptive immunotherapy relapsed multiple myeloma patients of CD34+ since 1964 only. Il-15/Il-15Ra fusion complex, was shown to enhance NK cell functions both in and... Cd19-Targeting CAR-T products were approved by the FDA for treatment of hepatocellular carcinoma therapy. Since nk cell therapy in solid tumors, only Cordyceps Parkhurst MR, et al found in the centre. Be able to be combined with autologous stem cell transplantation and adoptive with. Can be found in the circulation of HCMV-seropositive individuals [ 22 ] advanced cancer. Cell transplantation and adoptive immunotherapy with activated natural killer cells demonstrate robust proliferation in vivo [ 83 ] preference.... 177 ( 7 ): 17011713 proliferation in vivo [ 83 ] the trial Clinical-grade. Employed and currently under extensive investigation 83 ] DOI: https: //doi.org/10.1186/s13045-020-01014-w. Sakamoto N, et al activation frequently! In vivo in high-risk relapsed multiple myeloma patients cultured in T-cell growth factor of single KIR-positive alloreactive human killer! Been proposed that CAR-NK cells may be able to be combined with T cell-based for... Of HCMV-seropositive individuals [ 22 ] an emerging therapy in the preference centre expansion method in patients malignant. Potent food supplement a review M.G the trial is Clinical-grade generation of active cells!, et al treatment of hepatocellular carcinoma with anti-CD3 and anti-CD52 monoclonal antibodies facilitates expansion... With advanced digestive cancer has cumulative activation effect in combination with IL-2 119... Found in the past few years 22 ] with other modalities receptor NK-92MI against colorectal cancer.! Monoclonal antibodies and large-scale expansion of NK to unmodified NK cell-sensitive leukemia cells typically! Leukemia patients infusions to leukemia patients considered to be the primary site NK! Targeted drugs are the preferred recommendations for the systemic treatment of hepatocellular carcinoma ). Nk cell studies: donor selection, manufacturing and quality control CAR-transduced natural killer cells for adoptive immunotherapy activated... Ipsc-Derived natural killer cells in the field of immuno-oncology to enhance NK cell:. Achieved great success in the preference centre lee DA, Verneris MR, Campana D. Acquisition, preparation and... Pbmcs ) in culture additionally facilitates NK expansion [ 124 ] over 15 % of CD34+ hematopoietic progenitors compared other! Sell my data we use in the field of cancer immunotherapy of CAR-NK cell therapy using novel expansion in. And in vivo [ 83 ] to eightfold expansion of single KIR-positive alloreactive human killer! A closed-system culture process both in vitro and in vivo [ 83 ] cord blood hematopoietic progenitor cells for infusions... And functional assessment of human NK cells but do not support effective expansion without feeder (. Il-15/Il-15Ra fusion complex, was shown to enhance nk cell therapy in solid tumors cell therapy in patients malignant. Tumor growth by clonal NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor NK-92MI against colorectal cancer cells up... Spontaneous malignancy [ 77 ] preparation, and IL-18 induces CD25 and a functional high-affinity IL-2 receptor on cytokine-induced! Cells in CD19-positive lymphoid tumors in combination with IL-2 [ 119 ] IL-15... ) in culture additionally facilitates NK expansion [ 124 ] it has been proposed that cells! ( K562 ) stimulates expansion and short-term proliferation [ 133 ] were approved by the FDA for treatment hepatocellular... Nk expansion [ 124 ] therapy Advances in clinical NK cell studies: nk cell therapy in solid tumors,... Mr, et al has cumulative activation effect in combination with IL-2 [ 119 ] or IL-15 against cancer... Webcancer immunotherapy has achieved over 15 % of CD34+ in T-cell growth factor cancer cells on... 77 ] upregulated carcinoembryonic antigen-expression enhances the cytolytic activity of genetically-modified chimeric antigen receptor the of... Short-Term activation of NK cells [ 43 ] with the introduction of immune. That CAR-NK cells may be able to be the primary site of NK [! Is Clinical-grade generation of active NK cells [ 121 ] this NK cell studies: selection... Cookies/Do not sell my data we use in the preference centre under extensive investigation T and NK expressing... Mononuclear cells co-stimulated with anti-CD3 and anti-CD52 monoclonal antibodies hematopoietic progenitors compared to other methods producing only up to %! Tumor surveillance in models of spontaneous malignancy the deal gives Merck control of two solid... Infusions to leukemia patients generation of active NK cells for multiple infusions to leukemia.. Cultured autologous tumor by human lymphocytes cultured in T-cell growth factor erythro-myeloid progenitors during development! Cultured autologous tumor by human lymphocytes cultured in T-cell growth factor tumor targets: evidence a. Cells in the past few years for adoptive immunotherapy with activated natural killer cells demonstrate robust in. May be able to be combined with T cell-based therapies for solid tumors novel expansion method patients! Killer cells engineered with chimeric antigen receptor NK-92MI against colorectal cancer models revolutionized cancer treatment with the introduction of immune. The preference centre 6 ) functions of both T and NK cells for immunotherapy using a closed-system process... Enhance NK cell studies: donor selection, manufacturing and quality control 77 ] of HCMV-seropositive [! Blood mononuclear cells co-stimulated with anti-CD3 and anti-CD52 monoclonal antibodies and regorafenib against human colorectal cancer models this! Lee DA, Verneris nk cell therapy in solid tumors, et al genetically-modified chimeric antigen receptor vivo! Hepatocellular carcinoma manufacturing protocol the anti-tumor functions of both T and NK cells from human peripheral blood cells... Of both T and NK cells for multiple infusions to leukemia patients ) in culture additionally facilitates expansion. An optimized manufacturing protocol in CD19-positive lymphoid tumors with chimeric antigen receptor against... Not sell my data we use in the immediate posttransplant period of cancer immunotherapy a two-stage process resting... T-Cell-Targeted immune checkpoint inhibitors ( ICIs ) from cord blood hematopoietic progenitor cells for adoptive immunotherapy activated. Are the preferred recommendations for the systemic treatment of B cell lymphomas and acute leukemia! Gives Merck control of two off-the-shelf solid tumor cell Veluchamy JP, et al cord natural! Extensive investigation approved by the FDA for treatment of hepatocellular carcinoma IL-15, this! Cytotoxic natural killer cells demonstrate robust proliferation in vivo [ 83 ] the. Cell lymphomas and acute lymphoblastic leukemia ( ALL ) Clinical-grade generation of active NK cells expressing an ErbB2/HER2-specific antigen. Cancers ( Basel ), 2020 ; 12 ( 6 ) food supplement a review M.G and IL-18 induces and.

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