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      Applying extracellular vesicles based therapeutics in clinical trials – an ISEV position paper

      1 , 2 , 1 , 2 , 1 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 3 , 21 , 22 , 23 , 24 , 25 , 26 , 3 , 27 , 28 , 29 , 30 , 1 , 2 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 32 , 8 , 9 , 45 , 46 , 47 , 1 , 2 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 52 , 55 , 7 , 56 , 1 , 2 , * , 3 , *

      Journal of Extracellular Vesicles

      Co-Action Publishing

      immunology, neurobiology, haematology, stem cells, tissue regeneration, tumour vaccination, regulation

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          Extracellular vesicles (EVs), such as exosomes and microvesicles, are released by different cell types and participate in physiological and pathophysiological processes. EVs mediate intercellular communication as cell-derived extracellular signalling organelles that transmit specific information from their cell of origin to their target cells. As a result of these properties, EVs of defined cell types may serve as novel tools for various therapeutic approaches, including (a) anti-tumour therapy, (b) pathogen vaccination, (c) immune-modulatory and regenerative therapies and (d) drug delivery. The translation of EVs into clinical therapies requires the categorization of EV-based therapeutics in compliance with existing regulatory frameworks. As the classification defines subsequent requirements for manufacturing, quality control and clinical investigation, it is of major importance to define whether EVs are considered the active drug components or primarily serve as drug delivery vehicles. For an effective and particularly safe translation of EV-based therapies into clinical practice, a high level of cooperation between researchers, clinicians and competent authorities is essential. In this position statement, basic and clinical scientists, as members of the International Society for Extracellular Vesicles (ISEV) and of the European Cooperation in Science and Technology (COST) program of the European Union, namely European Network on Microvesicles and Exosomes in Health and Disease (ME-HaD), summarize recent developments and the current knowledge of EV-based therapies. Aspects of safety and regulatory requirements that must be considered for pharmaceutical manufacturing and clinical application are highlighted. Production and quality control processes are discussed. Strategies to promote the therapeutic application of EVs in future clinical studies are addressed.

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          Most cited references 203

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          Circulating endothelial progenitor cells, vascular function, and cardiovascular risk.

          Cardiovascular risk factors contribute to atherogenesis by inducing endothelial-cell injury and dysfunction. We hypothesized that endothelial progenitor cells derived from bone marrow have a role in ongoing endothelial repair and that impaired mobilization or depletion of these cells contributes to endothelial dysfunction and cardiovascular disease progression. We measured the number of colony-forming units of endothelial progenitor cells in peripheral-blood samples from 45 men (mean [+/-SE] age, 50+/-2 years). The subjects had various degrees of cardiovascular risk but no history of cardiovascular disease. Endothelium-dependent and endothelium-independent function was assessed by high-resolution ultrasonography of the brachial artery. We observed a strong correlation between the number of circulating endothelial progenitor cells and the subjects' combined Framingham risk factor score (r=-0.47, P=0.001). Measurement of flow-mediated brachial-artery reactivity also revealed a significant relation between endothelial function and the number of progenitor cells (r=0.59, P<0.001). Indeed, the levels of circulating endothelial progenitor cells were a better predictor of vascular reactivity than was the presence or absence of conventional risk factors. In addition, endothelial progenitor cells from subjects at high risk for cardiovascular events had higher rates of in vitro senescence than cells from subjects at low risk. In healthy men, levels of endothelial progenitor cells may be a surrogate biologic marker for vascular function and cumulative cardiovascular risk. These findings suggest that endothelial injury in the absence of sufficient circulating progenitor cells may affect the progression of cardiovascular disease. Copyright 2003 Massachusetts Medical Society
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            Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells.

            Adult bone-marrow-derived mesenchymal stem cells are immunosuppressive and prolong the rejection of mismatched skin grafts in animals. We transplanted haploidentical mesenchymal stem cells in a patient with severe treatment-resistant grade IV acute graft-versus-host disease of the gut and liver. Clinical response was striking. The patient is now well after 1 year. We postulate that mesenchymal stem cells have a potent immunosuppressive effect in vivo.
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              Tumor-derived exosomes are a source of shared tumor rejection antigens for CTL cross-priming.

              The initiation of T-cell-mediated antitumor immune responses requires the uptake and processing of tumor antigens by dendritic cells and their presentation on MHC-I molecules. Here we show in a human in vitro model system that exosomes, a population of small membrane vesicles secreted by living tumor cells, contain and transfer tumor antigens to dendritic cells. After mouse tumor exosome uptake, dendritic cells induce potent CD8+ T-cell-dependent antitumor effects on syngeneic and allogeneic established mouse tumors. Therefore, exosomes represent a novel source of tumor-rejection antigens for T-cell cross priming, relevant for immunointerventions.

                Author and article information

                J Extracell Vesicles
                J Extracell Vesicles
                Journal of Extracellular Vesicles
                Co-Action Publishing
                31 December 2015
                : 4
                [1 ]Spinal Cord Injury & Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University (PMU), Salzburg, Austria
                [2 ]Department of Blood Group Serology and Transfusion Medicine, University Hospital, Salzburger Landeskliniken GesmbH (SALK), Salzburg, Austria
                [3 ]Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
                [4 ]Department of Genetics, Cell- and Immunobiology, Semmelweis University, Budapest, Hungary
                [5 ]Molecular Biotechnology Center, Department of Medical Sciences, University of Turin, Turin, Italy
                [6 ]Laboratory of Immunomonitoring in Oncology, UMS 3655 CNRS/US23 Inserm, Villejuif, France
                [7 ]Centre of Clinical Investigation in Biotherapy CICBT 1248, Institut Gustave Roussy, Villejuif, France
                [8 ]Division of Hematology & Oncology, Rhode Island Hospital, Providence, RI, USA
                [9 ]The Alpert Medical School of Brown University, Providence, RI, USA
                [10 ]Department of Physiology, Faculty of Biology, Pontificia-Universidad Católica de Chile, Santiago, Chile
                [11 ]ICREA at Barcelona Centre for International Health Research (CRESIB), Hospital Clínic – Universitat de Barcelona, Barcelona, Spain
                [12 ]Institut d'Investigació Germans Trias i Pujol (IGTP), Badalona, Spain
                [13 ]School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin 2, Ireland;
                [14 ]Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
                [15 ]Anti-Tumor Drugs Section, Department of Therapeutic Research and Medicines Evaluation, National Institute of Health (ISS), Rome, Italy
                [16 ]Metabolomics Unit, CIC bioGUNE, CIBERehd, Bizkaia Technology Park, Derio, Spain
                [17 ]IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
                [18 ]Department of Paediatrics I, Neonatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
                [19 ]Departament de Producció Animal, ETSEA, Universitat de Lleida, Lleida, Spain
                [20 ]Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea
                [21 ]Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA
                [22 ]James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
                [23 ]Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Ghent University Hospital, Ghent, Belgium
                [24 ]Department of Neurology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
                [25 ]Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Australia
                [26 ]Massachusetts General Hospital, Boston, MA, USA
                [27 ]Department of Surgery, YLL School of Medicine, NUS, Singapore, Singapore
                [28 ]Department of Bone Marrow Transplantation, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
                [29 ]Experimental Perinatology/Neonatology, School of Mental Health and Neuroscience, School of Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
                [30 ]Molecular Cell Biology and Focus Program Translational Neurosciences, University of Mainz, Mainz, Germany
                [31 ]Research and Cell Services, Finnish Red Cross Blood Service, Helsinki, Finland
                [32 ]Division of Stem Cell Neurobiology, Department of Clinical Neurosciences, Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK
                [33 ]European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Cambridge, UK
                [34 ]Department of Cell Biology, Center for Molecular Medicine, University Medical Center, Utrecht, The Netherlands
                [35 ]Institute of Medical Biology, Agency for Science Technology and Research (A*STAR), Singapore, Singapore
                [36 ]Krefting Research Centre, Institute of Medicine, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
                [37 ]Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA
                [38 ]Dpto. Biología Celular y Parasitologia, Facultat de Farmacia, Universitat de Valencia, Valencia, Spain
                [39 ]Joint Research Unit on Endocrinology, Nutrition and Clinical Dietetics, Universitat de València-Health Research Institute La Fe, Valencia, Spain
                [40 ]Institute for Environmental Health Sciences and Hospital Infection Control Medical Center, University of Freiburg, Freiburg im Breisgau, Germany
                [41 ]Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, Tokyo, Japan
                [42 ]Departments of Transplantation and Cancer Biology, Mayo Clinic, Jacksonville, FL, USA
                [43 ]Centre for Cardiovascular Research, Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg University, Aalborg, Denmark
                [44 ]Mass Spectrometry and Proteomics, Institute of Biosciences and BioResources, National Research Council of Italy, Naples, Italy
                [45 ]BASG – Bundesamt für Sicherheit im Gesundheitswesen – Federal Office for Safety in Health Care, AGES – Agentur für Gesundheit und Ernährungssicherheit – Austrian Agency for Health and Food Safety, Institut Überwachung – Institute Surveillance, Wien, Austria
                [46 ]Institute of Molecular Regenerative Medicine, Spinal Cord Injury & Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University (PMU), Salzburg, Austria;
                [47 ]Ralf Sanzenbacher, Paul-Ehrlich-Institut, Bundesinstitut für Impfstoffe und biomedizinische Arzneimittel, Federal Institute for Vaccines and Biomedicines, Langen, Germany
                [48 ]Cell Therapy Facility, Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands
                [49 ]Experimental & Clinical Cell Therapy Institute, Spinal Cord Injury & Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria
                [50 ]Institute for Transfusion Medicine Dresden, German Red Cross Blood Donation Service North-East, Dresden, Germany
                [51 ]Laboratory of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, The Netherlands
                [52 ]Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
                [53 ]Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands
                [54 ]Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
                [55 ]Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
                [56 ]INSERM U932, Institut Curie, Paris, France
                Author notes
                [* ]Correspondence to: Eva Rohde, Spinal Cord Injury & Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University (PMU), AT-5020 Salzburg, Austria; Department of Blood Group Serology and Transfusion Medicine, University Hospital, Salzburger Landeskliniken GesmbH (SALK), Lindhofstraße 20-22, AT-5020 Salzburg, Austria, Email e.rohde@ ; Bernd Giebel, Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Virchowstr. 179, 45147 Essen, Germany, Email: bernd.giebel@
                © 2015 Thomas Lener et al.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Position Paper


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