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1
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Miroshnichenko S, Pykhtina M, Kotliarova A, Chepurnov A, Beklemishev A. Engineering a New IFN-ApoA-I Fusion Protein with Low Toxicity and Prolonged Action. Molecules 2023; 28:8014. [PMID: 38138504 PMCID: PMC10745500 DOI: 10.3390/molecules28248014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 11/29/2023] [Accepted: 12/04/2023] [Indexed: 12/24/2023] Open
Abstract
Recombinant human interferon alpha-2b (rIFN) is widely used in antiviral and anticancer immunotherapy. However, the high efficiency of interferon therapy is accompanied by a number of side effects; this problem requires the design of a new class of interferon molecules with reduced cytotoxicity. In this work, IFN was modified via genetic engineering methods by merging it with the blood plasma protein apolipoprotein A-I in order to reduce acute toxicity and improve the pharmacokinetics of IFN. The chimeric protein was obtained via biosynthesis in the yeast P. pastoris. The yield of ryIFN-ApoA-I protein when cultivated on a shaker in flasks was 30 mg/L; protein purification was carried out using reverse-phase chromatography to a purity of 95-97%. The chimeric protein demonstrated complete preservation of the biological activity of IFN in the model of vesicular stomatitis virus and SARS-CoV-2. In addition, the chimeric form had reduced cytotoxicity towards Vero cells and increased cell viability under viral load conditions compared with commercial IFN-a2b preparations. Analysis of the pharmacokinetic profile of ryIFN-ApoA-I after a single subcutaneous injection in mice showed a 1.8-fold increased half-life of the chimeric protein compared with ryIFN.
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Affiliation(s)
- Svetlana Miroshnichenko
- Federal Research Center of Fundamental and Translational Medicine (FRC FTM), Timakova str., 2, 630117 Novosibirsk, Russia; (S.M.); (A.C.); (A.B.)
| | - Mariya Pykhtina
- Federal Research Center of Fundamental and Translational Medicine (FRC FTM), Timakova str., 2, 630117 Novosibirsk, Russia; (S.M.); (A.C.); (A.B.)
| | - Anastasiia Kotliarova
- N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry SB RAS, Lavrentiev Ave., 9, 630090 Novosibirsk, Russia;
| | - Alexander Chepurnov
- Federal Research Center of Fundamental and Translational Medicine (FRC FTM), Timakova str., 2, 630117 Novosibirsk, Russia; (S.M.); (A.C.); (A.B.)
| | - Anatoly Beklemishev
- Federal Research Center of Fundamental and Translational Medicine (FRC FTM), Timakova str., 2, 630117 Novosibirsk, Russia; (S.M.); (A.C.); (A.B.)
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2
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Suda T, Yokoo T, Kanefuji T, Kamimura K, Zhang G, Liu D. Hydrodynamic Delivery: Characteristics, Applications, and Technological Advances. Pharmaceutics 2023; 15:1111. [PMID: 37111597 PMCID: PMC10141091 DOI: 10.3390/pharmaceutics15041111] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 03/20/2023] [Accepted: 03/23/2023] [Indexed: 04/03/2023] Open
Abstract
The principle of hydrodynamic delivery was initially used to develop a method for the delivery of plasmids into mouse hepatocytes through tail vein injection and has been expanded for use in the delivery of various biologically active materials to cells in various organs in a variety of animal species through systemic or local injection, resulting in significant advances in new applications and technological development. The development of regional hydrodynamic delivery directly supports successful gene delivery in large animals, including humans. This review summarizes the fundamentals of hydrodynamic delivery and the progress that has been made in its application. Recent progress in this field offers tantalizing prospects for the development of a new generation of technologies for broader application of hydrodynamic delivery.
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Affiliation(s)
- Takeshi Suda
- Department of Gastroenterology and Hepatology, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Minamiuonuma 949-7302, Niigata, Japan
| | - Takeshi Yokoo
- Department of Preemptive Medicine for Digestive Diseases and Healthy Active Life, School of Medicine, Niigata University, Niigata 951-8510, Niigata, Japan
| | - Tsutomu Kanefuji
- Department of Gastroenterology and Hepatology, Tsubame Rosai Hospital, Tsubame 959-1228, Niigata, Japan
| | - Kenya Kamimura
- Department of General Medicine, School of Medicine, Niigata University, Niigata 951-8510, Niigata, Japan
| | - Guisheng Zhang
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 30602, USA
| | - Dexi Liu
- Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 30602, USA
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3
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Mendoza-Valderrey A, Alvarez M, De Maria A, Margolin K, Melero I, Ascierto ML. Next Generation Immuno-Oncology Strategies: Unleashing NK Cells Activity. Cells 2022; 11:3147. [PMID: 36231109 PMCID: PMC9562848 DOI: 10.3390/cells11193147] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 09/06/2022] [Accepted: 10/02/2022] [Indexed: 11/19/2022] Open
Abstract
In recent years, immunotherapy has become a powerful therapeutic option against multiple malignancies. The unique capacity of natural killer (NK) cells to attack cancer cells without antigen specificity makes them an optimal immunotherapeutic tool for targeting tumors. Several approaches are currently being pursued to maximize the anti-tumor properties of NK cells in the clinic, including the development of NK cell expansion protocols for adoptive transfer, the establishment of a favorable microenvironment for NK cell activity, the redirection of NK cell activity against tumor cells, and the blockage of inhibitory mechanisms that constrain NK cell function. We here summarize the recent strategies in NK cell-based immunotherapies and discuss the requirement to further optimize these approaches for enhancement of the clinical outcome of NK cell-based immunotherapy targeting tumors.
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Affiliation(s)
- Alberto Mendoza-Valderrey
- Rosalie and Harold Rae Brown Cancer Immunotherapy Research Program, Borstein Family Melanoma Program, Translational Immunology Department, Saint John’s Cancer Institute, Santa Monica, CA 90404, USA
| | - Maite Alvarez
- Program for Immunology and Immunotherapy, CIMA, Universidad de Navarra, 31008 Pamplona, Spain
- Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
| | - Andrea De Maria
- Department of Health Sciences, University of Genoa, 16126 Genova, Italy
- IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy
| | - Kim Margolin
- Borstein Family Melanoma Program, Saint John’s Cancer Institute, Santa Monica, CA 90404, USA
| | - Ignacio Melero
- Program for Immunology and Immunotherapy, CIMA, Universidad de Navarra, 31008 Pamplona, Spain
- Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
- Department of Immunology and Immunotherapy, Clínica Universidad de Navarra, 31008 Pamplona, Spain
| | - Maria Libera Ascierto
- Rosalie and Harold Rae Brown Cancer Immunotherapy Research Program, Borstein Family Melanoma Program, Translational Immunology Department, Saint John’s Cancer Institute, Santa Monica, CA 90404, USA
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Schramme F, Crosignani S, Frederix K, Hoffmann D, Pilotte L, Stroobant V, Preillon J, Driessens G, Van den Eynde BJ. Inhibition of Tryptophan-Dioxygenase Activity Increases the Antitumor Efficacy of Immune Checkpoint Inhibitors. Cancer Immunol Res 2019; 8:32-45. [PMID: 31806638 DOI: 10.1158/2326-6066.cir-19-0041] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 06/27/2019] [Accepted: 11/15/2019] [Indexed: 11/16/2022]
Abstract
Tryptophan 2,3-dioxygenase (TDO) is an enzyme that degrades tryptophan into kynurenine and thereby induces immunosuppression. Like indoleamine 2,3-dioxygenase (IDO1), TDO is considered as a relevant drug target to improve the efficacy of cancer immunotherapy. However, its role in various immunotherapy settings has not been fully characterized. Here, we described a new small-molecule inhibitor of TDO that can modulate kynurenine and tryptophan in plasma, liver, and tumor tissue upon oral administration. We showed that this compound improved the ability of anti-CTLA4 to induce rejection of CT26 tumors expressing TDO. To better characterize TDO as a therapeutic target, we used TDO-KO mice and found that anti-CTLA4 or anti-PD1 induced rejection of MC38 tumors in TDO-KO, but not in wild-type mice. As MC38 tumors did not express TDO, we related this result to the high systemic tryptophan levels in TDO-KO mice, which lack the hepatic TDO needed to contain blood tryptophan. The antitumor effectiveness of anti-PD1 was abolished in TDO-KO mice fed on a tryptophan-low diet that normalized their blood tryptophan level. MC38 tumors expressed IDO1, which could have limited the efficacy of anti-PD1 in wild-type mice and could have been overcome in TDO-KO mice due to the high levels of tryptophan. Accordingly, treatment of mice with an IDO1 inhibitor improved the efficacy of anti-PD1 in wild-type, but not in TDO-KO, mice. These results support the clinical development of TDO inhibitors to increase the efficacy of immunotherapy of TDO-expressing tumors and suggest their effectiveness even in the absence of tumoral TDO expression.See article by Hoffmann et al., p. 19.
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Affiliation(s)
- Florence Schramme
- Ludwig Institute for Cancer Research, Brussels, Belgium.,de Duve Institute, UCLouvain, Brussels, Belgium
| | | | | | - Delia Hoffmann
- Ludwig Institute for Cancer Research, Brussels, Belgium.,de Duve Institute, UCLouvain, Brussels, Belgium
| | - Luc Pilotte
- Ludwig Institute for Cancer Research, Brussels, Belgium.,de Duve Institute, UCLouvain, Brussels, Belgium
| | - Vincent Stroobant
- Ludwig Institute for Cancer Research, Brussels, Belgium.,de Duve Institute, UCLouvain, Brussels, Belgium
| | | | | | - Benoit J Van den Eynde
- Ludwig Institute for Cancer Research, Brussels, Belgium. .,de Duve Institute, UCLouvain, Brussels, Belgium.,Walloon Excellence in Life Sciences and Biotechnology, Brussels, Belgium
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5
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Translational Advances of Hydrofection by Hydrodynamic Injection. Genes (Basel) 2018; 9:genes9030136. [PMID: 29494564 PMCID: PMC5867857 DOI: 10.3390/genes9030136] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Revised: 02/20/2018] [Accepted: 02/21/2018] [Indexed: 12/11/2022] Open
Abstract
Hydrodynamic gene delivery has proven to be a safe and efficient procedure for gene transfer, able to mediate, in murine model, therapeutic levels of proteins encoded by the transfected gene. In different disease models and targeting distinct organs, it has been demonstrated to revert the pathologic symptoms and signs. The therapeutic potential of hydrofection led different groups to work on the clinical translation of the procedure. In order to prevent the hemodynamic side effects derived from the rapid injection of a large volume, the conditions had to be moderated to make them compatible with its use in mid-size animal models such as rat, hamster and rabbit and large animals as dog, pig and primates. Despite the different approaches performed to adapt the conditions of gene delivery, the results obtained in any of these mid-size and large animals have been poorer than those obtained in murine model. Among these different strategies to reduce the volume employed, the most effective one has been to exclude the vasculature of the target organ and inject the solution directly. This procedure has permitted, by catheterization and surgical procedures in large animals, achieving protein expression levels in tissue close to those achieved in gold standard models. These promising results and the possibility of employing these strategies to transfer gene constructs able to edit genes, such as CRISPR, have renewed the clinical interest of this procedure of gene transfer. In order to translate the hydrodynamic gene delivery to human use, it is demanding the standardization of the procedure conditions and the molecular parameters of evaluation in order to be able to compare the results and establish a homogeneous manner of expressing the data obtained, as ‘classic’ drugs.
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Ochoa MC, Minute L, López A, Pérez-Ruiz E, Gomar C, Vasquez M, Inoges S, Etxeberria I, Rodriguez I, Garasa S, Mayer JPA, Wirtz P, Melero I, Berraondo P. Enhancement of antibody-dependent cellular cytotoxicity of cetuximab by a chimeric protein encompassing interleukin-15. Oncoimmunology 2017; 7:e1393597. [PMID: 29308327 DOI: 10.1080/2162402x.2017.1393597] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Revised: 10/13/2017] [Accepted: 10/13/2017] [Indexed: 12/13/2022] Open
Abstract
Enhancement of antibody-dependent cellular cytotoxicity (ADCC) may potentiate the antitumor efficacy of tumor-targeted monoclonal antibodies. Increasing the numbers and antitumor activity of NK cells is a promising strategy to maximize the ADCC of standard-of-care tumor-targeted antibodies. For this purpose, we have preclinically tested a recombinant chimeric protein encompassing the sushi domain of the IL15Rα, IL-15, and apolipoprotein A-I (Sushi-IL15-Apo) as produced in CHO cells. The size-exclusion purified monomeric fraction of this chimeric protein was stable and retained the IL-15 and the sushi domain bioactivity as measured by CTLL-2 and Mo-7e cell proliferation and STAT5 phosphorylation in freshly isolated human NK and CD8+ T cells. On cell cultures, Sushi-IL15-Apo increases NK cell proliferation and survival as well as spontaneous and antibody-mediated cytotoxicity. Scavenger receptor class B type I (SR-B1) is the receptor for ApoA-I and is expressed on the surface of tumor cells. SR-B1 can adsorb the chimeric protein on tumor cells and can transpresent IL-15 to NK and CD8+ T cells. A transient NK-humanized murine model was developed to test the increase of ADCC attained by the chimeric protein in vivo. The EGFR+ human colon cancer cell line HT-29 was intraperitoneally inoculated in immune-deficient Rag2-/-γc-/- mice that were reconstituted with freshly isolated PBMCs and treated with the anti-EGFR mAb cetuximab. The combination of the Sushi-IL15-Apo protein and cetuximab reduced the number of remaining tumor cells in the peritoneal cavity and delayed tumor engraftment in the peritoneum. Furthermore, Sushi-IL15-Apo increased the anti-tumor effect of a murine anti-EGFR mAb in Rag1-/- mice bearing subcutaneous MC38 colon cancer transfected to express EGFR. Thus, Sushi-IL15-Apo is a potent tool to increase the number and the activation of NK cells to promote the ADCC activity of antibodies targeting tumor antigens.
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Affiliation(s)
- Maria Carmen Ochoa
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain.,Navarra Institute for Health Research (IDISNA), Pamplona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Spain
| | - Luna Minute
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain.,Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Ascensión López
- Servicio de Inmunología e Inmunoterapia, Clínica Universidad de Navarra, Pamplona, Spain.,Hematología y Área de Terapia Celular, Clínica Universidad de Navarra, Pamplona, Spain
| | - Elisabeth Pérez-Ruiz
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain.,Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Celia Gomar
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain.,Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Marcos Vasquez
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain.,Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Susana Inoges
- Servicio de Inmunología e Inmunoterapia, Clínica Universidad de Navarra, Pamplona, Spain.,Hematología y Área de Terapia Celular, Clínica Universidad de Navarra, Pamplona, Spain
| | - Iñaki Etxeberria
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain.,Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | - Inmaculada Rodriguez
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain.,Navarra Institute for Health Research (IDISNA), Pamplona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Spain
| | - Saray Garasa
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain.,Navarra Institute for Health Research (IDISNA), Pamplona, Spain
| | | | | | - Ignacio Melero
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain.,Navarra Institute for Health Research (IDISNA), Pamplona, Spain.,Servicio de Inmunología e Inmunoterapia, Clínica Universidad de Navarra, Pamplona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Spain
| | - Pedro Berraondo
- Program of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), Pamplona, Spain.,Navarra Institute for Health Research (IDISNA), Pamplona, Spain.,Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Spain
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7
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Yokoo T, Kamimura K, Abe H, Kobayashi Y, Kanefuji T, Ogawa K, Goto R, Oda M, Suda T, Terai S. Liver-targeted hydrodynamic gene therapy: Recent advances in the technique. World J Gastroenterol 2016; 22:8862-8868. [PMID: 27833377 PMCID: PMC5083791 DOI: 10.3748/wjg.v22.i40.8862] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2016] [Revised: 08/03/2016] [Accepted: 08/23/2016] [Indexed: 02/06/2023] Open
Abstract
One of the major research focuses in the field of gene therapy is the development of clinically applicable, safe, and effective gene-delivery methods. Since the first case of human gene therapy was performed in 1990, a number of gene-delivery methods have been developed, evaluated for efficacy and safety, and modified for human application. To date, viral-vector-mediated deliveries have shown effective therapeutic results. However, the risk of lethal immune response and carcinogenesis have been reported, and it is still controversial to be applied as a standard therapeutic option. On the other hand, delivery methods for nonviral vector systems have been developed, extensively studied, and utilized in in vivo gene-transfer studies. Compared to viral-vector mediated gene transfer, nonviral systems have less risk of biological reactions. However, the lower gene-transfer efficiency was a critical hurdle for applying them to human gene therapy. Among a number of nonviral vector systems, our studies focus on hydrodynamic gene delivery to utilize physical force to deliver naked DNA into the cells in the living animals. This method achieves a high gene-transfer level by DNA solution injections into the tail vein of rodents, especially in the liver. With the development of genome editing methods, in vivo gene-transfer therapy using this method is currently the focus in this research field. This review explains the method principle, efficiency, safety, and procedural modifications to achieve a high level of reproducibility in large-animal models.
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8
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Alfaro C, Teijeira A, Oñate C, Pérez G, Sanmamed MF, Andueza MP, Alignani D, Labiano S, Azpilikueta A, Rodriguez-Paulete A, Garasa S, Fusco JP, Aznar A, Inogés S, De Pizzol M, Allegretti M, Medina-Echeverz J, Berraondo P, Perez-Gracia JL, Melero I. Tumor-Produced Interleukin-8 Attracts Human Myeloid-Derived Suppressor Cells and Elicits Extrusion of Neutrophil Extracellular Traps (NETs). Clin Cancer Res 2016; 22:3924-36. [PMID: 26957562 DOI: 10.1158/1078-0432.ccr-15-2463] [Citation(s) in RCA: 307] [Impact Index Per Article: 34.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2015] [Accepted: 02/03/2016] [Indexed: 12/17/2022]
Abstract
PURPOSE Myeloid-derived suppressor cells (MDSC) are considered an important T-cell immunosuppressive component in cancer-bearing hosts. The factors that attract these cells to the tumor microenvironment are poorly understood. IL8 (CXCL8) is a potent chemotactic factor for neutrophils and monocytes. EXPERIMENTAL DESIGN MDSC were characterized and sorted by multicolor flow cytometry on ficoll-gradient isolated blood leucokytes from healthy volunteers (n = 10) and advanced cancer patients (n = 28). In chemotaxis assays, sorted granulocytic and monocytic MDSC were tested in response to recombinant IL8, IL8 derived from cancer cell lines, and patient sera. Neutrophil extracellular traps (NETs) formation was assessed by confocal microscopy, fluorimetry, and time-lapse fluorescence confocal microscopy on short-term MDSC cultures. RESULTS IL8 chemoattracts both granulocytic (GrMDSC) and monocytic (MoMDSC) human MDSC. Monocytic but not granulocytic MDSC exerted a suppressor activity on the proliferation of autologous T cells isolated from the circulation of cancer patients. IL8 did not modify the T-cell suppressor activity of human MDSC. However, IL8 induced the formation of NETs in the GrMDSC subset. CONCLUSIONS IL8 derived from tumors contributes to the chemotactic recruitment of MDSC and to their functional control. Clin Cancer Res; 22(15); 3924-36. ©2016 AACR.
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Affiliation(s)
- Carlos Alfaro
- Division of Gene Therapy and Hepatology, Centre for Applied Medical Research (CIMA), Pamplona, Spain. Department of Oncology, University Clinic of Navarra, Pamplona, Spain. Department of Immunology, University Clinic of Navarra, Pamplona, Spain
| | - Alvaro Teijeira
- Division of Gene Therapy and Hepatology, Centre for Applied Medical Research (CIMA), Pamplona, Spain. Department of Oncology, University Clinic of Navarra, Pamplona, Spain. Department of Immunology, University Clinic of Navarra, Pamplona, Spain
| | - Carmen Oñate
- Division of Gene Therapy and Hepatology, Centre for Applied Medical Research (CIMA), Pamplona, Spain. Department of Oncology, University Clinic of Navarra, Pamplona, Spain. Department of Immunology, University Clinic of Navarra, Pamplona, Spain
| | - Guiomar Pérez
- Division of Gene Therapy and Hepatology, Centre for Applied Medical Research (CIMA), Pamplona, Spain. Department of Oncology, University Clinic of Navarra, Pamplona, Spain. Department of Immunology, University Clinic of Navarra, Pamplona, Spain
| | - Miguel F Sanmamed
- Department of Oncology, University Clinic of Navarra, Pamplona, Spain. Department of Immunology, University Clinic of Navarra, Pamplona, Spain
| | - Maria Pilar Andueza
- Department of Oncology, University Clinic of Navarra, Pamplona, Spain. Department of Immunology, University Clinic of Navarra, Pamplona, Spain
| | - Diego Alignani
- Cytometry Platform, Centre for Applied Medical Research (CIMA), Pamplona, Spain
| | - Sara Labiano
- Division of Gene Therapy and Hepatology, Centre for Applied Medical Research (CIMA), Pamplona, Spain
| | - Arantza Azpilikueta
- Division of Gene Therapy and Hepatology, Centre for Applied Medical Research (CIMA), Pamplona, Spain
| | - Alfonso Rodriguez-Paulete
- Division of Gene Therapy and Hepatology, Centre for Applied Medical Research (CIMA), Pamplona, Spain
| | - Saray Garasa
- Division of Gene Therapy and Hepatology, Centre for Applied Medical Research (CIMA), Pamplona, Spain
| | - Juan P Fusco
- Department of Oncology, University Clinic of Navarra, Pamplona, Spain. Department of Immunology, University Clinic of Navarra, Pamplona, Spain
| | - Angela Aznar
- Division of Gene Therapy and Hepatology, Centre for Applied Medical Research (CIMA), Pamplona, Spain
| | - Susana Inogés
- Department of Oncology, University Clinic of Navarra, Pamplona, Spain. Department of Immunology, University Clinic of Navarra, Pamplona, Spain
| | | | | | - Jose Medina-Echeverz
- Division of Gene Therapy and Hepatology, Centre for Applied Medical Research (CIMA), Pamplona, Spain
| | - Pedro Berraondo
- Division of Gene Therapy and Hepatology, Centre for Applied Medical Research (CIMA), Pamplona, Spain
| | - Jose L Perez-Gracia
- Department of Oncology, University Clinic of Navarra, Pamplona, Spain. Department of Immunology, University Clinic of Navarra, Pamplona, Spain
| | - Ignacio Melero
- Division of Gene Therapy and Hepatology, Centre for Applied Medical Research (CIMA), Pamplona, Spain. Department of Oncology, University Clinic of Navarra, Pamplona, Spain. Department of Immunology, University Clinic of Navarra, Pamplona, Spain.
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9
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Kamimura K, Yokoo T, Abe H, Kobayashi Y, Ogawa K, Shinagawa Y, Inoue R, Terai S. Image-Guided Hydrodynamic Gene Delivery: Current Status and Future Directions. Pharmaceutics 2015; 7:213-223. [PMID: 26308044 PMCID: PMC4588196 DOI: 10.3390/pharmaceutics7030213] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Revised: 08/13/2015] [Accepted: 08/18/2015] [Indexed: 12/13/2022] Open
Abstract
Hydrodynamics-based delivery has been used as an experimental tool to express transgene in small animals. This in vivo gene transfer method is useful for functional analysis of genetic elements, therapeutic effect of oligonucleotides, and cancer cells to establish the metastatic cancer animal model for experimental research. Recent progress in the development of image-guided procedure for hydrodynamics-based gene delivery in large animals directly supports the clinical applicability of this technique. This review summarizes the current status and recent progress in the development of hydrodynamics-based gene delivery and discusses the future directions for its clinical application.
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Affiliation(s)
- Kenya Kamimura
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan.
| | - Takeshi Yokoo
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan.
| | - Hiroyuki Abe
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan.
| | - Yuji Kobayashi
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan.
| | - Kohei Ogawa
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan.
| | - Yoko Shinagawa
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan.
| | - Ryosuke Inoue
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan.
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan.
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10
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Abstract
Hydrodynamic delivery (HD) is a broadly used procedure for DNA and RNA delivery in rodents, serving as a powerful tool for gene/protein drug discovery, gene function analysis, target validation, and identification of elements in regulating gene expression in vivo. HD involves a pressurized injection of a large volume of solution into a vasculature. New procedures are being developed to satisfy the need for a safe and efficient gene delivery in clinic. Here, we summarize the fundamentals of HD, its applications, and future perspectives for clinical use.
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Affiliation(s)
- Takeshi Suda
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Dexi Liu
- Department of Pharmaceutical and Biomedical Sciences, University of Georgia, School of Pharmacy, Athens, GA, USA
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Ochoa MC, Melero I, Berraondo P. High-density lipoproteins delivering interleukin-15. Oncoimmunology 2014; 2:e23410. [PMID: 23734302 PMCID: PMC3654572 DOI: 10.4161/onci.23410] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2012] [Accepted: 12/23/2012] [Indexed: 12/03/2022] Open
Abstract
Circulating lipoproteins may offer interesting properties as therapeutic carriers for cytokines and hormones, in terms of both stability and bio-distribution. The fusion of apolipoprotein A-I with interleukin-15 (IL-15) targets the latter to high-density lipoproteins (HDLs). The bioactivity of this chimera can be further enhanced by creating triple fusions with IL-15 receptor α domain involved in IL-15 trans-presentation.
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Affiliation(s)
- Maria C Ochoa
- Division of Hepatology and Gene Therapy; Center for Applied Medical Research, and University Clinic; University of Navarra, Pamplona; Navarra, Spain
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Zarogoulidis P, Lampaki S, Yarmus L, Kioumis I, Pitsiou G, Katsikogiannis N, Hohenforst-Schmidt W, Li Q, Huang H, Sakkas A, Organtzis J, Sakkas L, Mpoukovinas I, Tsakiridis K, Lazaridis G, Syrigos K, Zarogoulidis K. Interleukin-7 and interleukin-15 for cancer. J Cancer 2014; 5:765-73. [PMID: 25368677 PMCID: PMC4216801 DOI: 10.7150/jca.10471] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2014] [Accepted: 10/06/2014] [Indexed: 11/30/2022] Open
Abstract
Interleukin 7 and 15 are considered powerful pro-inflammatory cytokines, they have the ability to destabilize chromosomes and induce tumorigenesis. Additionally, they can control malignancy proliferation by influencing the tumor microenvironment and immune system. Immunotherapy has been proposed as a treatment modality for malignancy for over a decade; the exact mechanisms of action and pathways are still under investigation. Interleukin 7 and 15 have been extensively investigated in hematological malignancies since their mode of action influences the stimulation of the immune system in a more direct way than other malignancies such as lung, melanoma, and breast, renal and colorectal cancer.
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Affiliation(s)
- Paul Zarogoulidis
- 1. Pulmonary Department-Oncology Unit, ``G. Papanikolaou`` General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Sofia Lampaki
- 1. Pulmonary Department-Oncology Unit, ``G. Papanikolaou`` General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Lonny Yarmus
- 2. Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, U.S.A
| | - Ioannis Kioumis
- 1. Pulmonary Department-Oncology Unit, ``G. Papanikolaou`` General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Georgia Pitsiou
- 1. Pulmonary Department-Oncology Unit, ``G. Papanikolaou`` General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Nikolaos Katsikogiannis
- 3. Surgery Department (NHS), University General Hospital of Alexandroupolis, Alexandroupolis, Greece
| | | | - Qiang Li
- 5. Department of Respiratory Diseases, Changhai Hospital/First Affiliated Hospital of the Second Military Medical University, Shanghai, China
| | - Haidong Huang
- 5. Department of Respiratory Diseases, Changhai Hospital/First Affiliated Hospital of the Second Military Medical University, Shanghai, China
| | - Antonios Sakkas
- 6. Pathology Department, ``G. Papanikolaou`` General Hospital, Thessaloniki, Greece
| | - John Organtzis
- 1. Pulmonary Department-Oncology Unit, ``G. Papanikolaou`` General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Leonidas Sakkas
- 6. Pathology Department, ``G. Papanikolaou`` General Hospital, Thessaloniki, Greece
| | - Ioannis Mpoukovinas
- 7. Oncology Department, ``BioMedicine`` Private Hospital, Thessaloniki, Greece
| | - Kosmas Tsakiridis
- 8. Cardiothoracic Surgery Department, ``Saint Luke`` Private Hospital, Thessaloniki, Greece
| | - George Lazaridis
- 9. Oncology Department, ``G. Papageorgiou`` University Hospital, Thessaloniki, Greece
| | - Konstantinos Syrigos
- 10. Oncology Department, ``Sotiria`` Hospital, University of Athens, Athens, Greece
| | - Konstantinos Zarogoulidis
- 1. Pulmonary Department-Oncology Unit, ``G. Papanikolaou`` General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
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Hernandez-Alcoceba R, Sangro B, Berraondo P, Gonzalez-Aseguinolaza G, Prieto J. Cytokines for the treatment of gastrointestinal cancers: clinical experience and new perspectives. Expert Opin Investig Drugs 2013; 22:827-41. [PMID: 23594171 DOI: 10.1517/13543784.2013.793307] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
INTRODUCTION Cytokines are key mediators of the immune system and have been proposed as therapeutic agents against cancer, either as recombinant proteins, or as transgenes in gene therapy approaches. Stimulation of immune responses against cancer cells is an appealing method to treat tumors with high risk of relapse and systemic dissemination. AREAS COVERED We provide a critical overview of clinical trials involving the use of cytokines for the treatment of liver, colon and pancreatic cancers. Special attention has been paid to advances in the field of gene therapy and oncolytic viruses. The potential of new developments still in a pre-clinical stage is also discussed. We have revised public sources of information (PubMed, US National Institutes of Health clinical trials database) up to January 2013. EXPERT OPINION The complexity of the immune system and the unfavorable pharmacokinetic properties of cytokines limit the efficacy of these molecules as single agents for the treatment of cancer. Expression from gene therapy vectors, together with new methods of targeting and stabilization, may overcome these hurdles. We believe cytokines will play a crucial role as part of combined approaches, enhancing the action of adoptive cell immunotherapy, oncolytic viruses or biological therapies.
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Affiliation(s)
- Ruben Hernandez-Alcoceba
- CIMA, University of Navarra, Division of Hepatology and Gene Therapy, Foundation for Applied Medical Research, Pamplona, Spain
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