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SELECTBIO Conferences EV-based Diagnostics, Delivery & Therapeutics

EV-based Diagnostics, Delivery & Therapeutics Agenda

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Circulating Biomarkers World Congress 2020 | EV-based Diagnostics, Delivery & Therapeutics | 

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Monday, 17 February 2020


Conference Registration, Materials Pick-Up, Morning Coffee and Pastries

Session Title: Conference Opening Session -- Emerging Themes in Circulating Biomarkers and Exosomes/EVs


Michael GranerConference Chair

Welcome and Introduction to the Conference
Michael Graner, Associate Professor, Dept of Neurosurgery, University of Colorado Anschutz School of Medicine, United States of America


Steve SoperKeynote Presentation

Integrated Microfluidic Systems for the Efficient Isolation of Circulating Leukemia Cells and Circulating Plasma Cells
Steve Soper, Foundation Distinguished Professor, Director, Center of BioModular Multi-scale System for Precision Medicine, The University of Kansas, Adjunct Professor, Ulsan National Institute of Science & Technology, United States of America

Liquid biopsies are generating great interest within the biomedical community due to the simplicity for securing important biomarkers to manage complex diseases. We are developing a suite of microfluidic devices that can process whole blood directly and engineered to efficiently search for a variety of disease-associated liquid biopsy markers and their subsequent molecular analysis. One microfluidic device can isolate targets with recovery >90% and high purity (>80%) to enable downstream analysis of the particular biomarker without requiring single cell picking. We have also developed a microfluidic device for imaging single cells. The aforementioned microfluidic devices can be interfaced to a fluidic motherboard to allow for full process automation, including cell selection from blood and then, immunophenotyping and/or FISH of the isolated cells. In this presentation, information will be shared on the operational parameters of these devices for the selection of liquid biopsy markers, and the downstream molecular information that can be garnered from the isolated markers in acute myeloid / acute lymphoblastic leukemia (circulating leukemia cells) and multiple myeloma (circulating plasma cells). The attractive nature of using liquid biopsy markers for these two diseases is that it circumvents the need for a patient to undergo a painful bone marrow biopsy. Information will be provided as to the use of these liquid biopsy markers to monitor relapse from minimum residual disease, and stage patients for directing therapy.


Daniel ChiuKeynote Presentation

New Flow-Based Technologies for the High-Sensitivity and High-Resolution Analysis of CTCs and Exosomes
Daniel Chiu, A. Bruce Montgomery Professor of Chemistry, University of Washington, United States of America

This presentation will describe two flow-based technologies we developed for the analysis of single rare cells and individual extracellular vesicles. The first flow platform is a rare-cell isolation instrument we call eDAR (ensemble decision aliquot ranking), which is capable of operating in a rapid sequential sorting mode for isolating single rare cells with exceptionally high sensitivity and purity. The second flow instrument is a single-vesicle sorter, capable of high-sensitivity analysis of individual extracellular vesicles. I will outline the workings of these new tools, describe their performance, and discuss the clinical questions we are addressing with these next-generation technologies.


Min YuKeynote Presentation

Circulating Tumor Cells Inform Mechanism of Breast Cancer Metastasis
Min Yu, Assistant Professor, University of Southern California, United States of America

Circulating tumor cells (CTCs) are expected to contain metastasis-initiating cells that can shed light on the mechanisms of cancer metastasis. However, due to limited patient-derived material, the metastatic capability of CTCs has yet to be proved. Using our recently established patient-derived CTC lines, we found that different patient CTC lines demonstrated distinct metastatic tissue tropisms in immunodeficient mice and identified associated pathways to specific organs via RNA-seq and ATAC-seq analysis.


Morning Coffee Break and Networking in the Exhibit Hall


Biofluid Biomarkers for the Brain
Kendall Van Keuren-Jensen, Professor and Deputy Director, Translational Genomics Research Institute, United States of America

We will describe some of our efforts in using exRNAs as diagnostics for central nervous system injury and disease.


Jennifer JonesKeynote Presentation

Liquid Biopsies Using EVs: Promise and Peril on the Frontiers of a New Field
Jennifer Jones, NIH Stadtman Investigator, Head of Transnational Nanobiology, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, United States of America


Randolph CortelingKeynote Presentation

An Exosome-based Drug Delivery Platform Derived From an Immortalized Human Neural Stem Cell (hNSC) Line
Randolph Corteling, Head of Research, ReNeuron Ltd., United Kingdom

To ensure the scale required for clinical research and commercialization producer cell immortalization and clonal isolation is a practical strategy to produce consistent, functionally bioactive exosomes for use as therapeutic agents. Immortalization ensures production stability and reduces the need for equivalence testing.

CTX0E03 is a conditionally immortalised human neural stem cell line that has been manufactured to clinical-grade (GMP) standards, using a 3-tier banking strategy and is currently in Phase IIb clinical evaluation for disability after stroke. Using the conditioned media produced during GMP manufacture, we have shown that CTX0E03 is an abundant producer of exosomes that can be readily isolated and purified at scale. The CTX cell line can also be rapidly and efficiently modified to direct the expression of a variety of cargoes within the secreted EV population, whilst maintaining the key immortalised stem cell characteristics of the parental cell line.  The natural tissue tropism of CTX-derived exosomes can then be exploited to deliver loaded cargoes to target cells.


Susanne GabrielssonKeynote Presentation

Optimizing Dendritic Cell-Derived Exosomes For Cancer Immunotherapy
Susanne Gabrielsson, Professor, Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Sweden

Peptide loaded exosomes are promising cancer treatment vehicles, however, low T cell responses in human clinical trials indicate a need to further understand exosome-induced immunity. We previously demonstrated that antigen-loaded exosomes carry whole protein antigens and require B cells for induction of antigen-specific T cells. I will discuss our latest data where we investigated the need for different immune related molecules on exosomes to induce T cell responses and tumor rejection in the B16 mouse melanoma model. Our data demonstrate ways to increase the feasibility of exosome-based therapeutic approaches in cancer.


Networking Lunch in the Exhibit Hall, Exhibits and Poster Viewing

Session Title: Exosomes and Extracellular Vesicles (EVs) -- Research, Biomarkers, Delivery and Therapeutics Arenas

Session Chairperson: Professor Lucia Languino, Thomas Jefferson University


A Multi-Dimensional Approach to EV Flow Cytometry
Andries Zijlstra, Associate Professor of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center, United States of America

Flow cytometry has proven to be very promising method for Single-EV analysis. Unfortunately, the heterogeneity of EV populations prevents the application of the single-particle classification strategy derived from conventional flow cytometry of intact cells fails in our attempts to resolve distinct classes of EVs. In simple terms, the small size of most EVs prevents the incorporation of all protein markers that define a uniform class of EVs. Consequently, EVs generated through the same biogenesis pathway from the same donor cells, could contain vastly different cargo. Conversely, restricting EV classification only to a size range is equally limiting. To improve EV sub-classification and enable the identification of biologically-significant alterations in EV populations in response to alterations in physiological or pathological states of the donor cell/tissue, we have developed a multi-dimensional approach to EV flow cytometry that attempts to cluster EVs into subpopulations on the basis of many, rather than single parameters.


GE Healthcare Life SciencesIsolation and Purification of Extracellular Vesicles: Current Directions
William Whitford, Strategic Solutions Leader, GE Healthcare Life Sciences

When isolating vesicles for therapeutic applications, it’s advantageous to have a very good understanding of diverse individual characteristics of the target subpopulation. There are many reasons for this, including that the three major groups of EVs have been described (and even defined) according to their mechanism of generation: macrovesicles, apoptotic bodies and exosomes. While the latter are often assumed to represent a homogenous population, significant work on exosomes has revealed distinct subpopulations of differing properties.  These properties include physical behaviors in manipulation, and such molecular composition as proteomic and nucleic acid repertoires.  Significantly, these subpopulations have also been reported to mediate differential effects upon recipient cells and tissues. All-in-all, it has been reported that different populations of exosome types may be generated from differing cell and tissue types, culture techniques, isolation strategies, and even the scale of an identified isolation technology.  
Furthermore, it has been reported that no individual isolation technique will exquisitely separate any subpopulation from all others.  This is because each characteristic is presented by more than one sub-type. For example, separation based on size solely cannot isolate any of the three major EV groups, since they significantly overlap in size.  For similar reasons no single technology can even isolate any particular sub-type of exosomes.
Finally, the impurities to be removed in the production of EV-based pharmaceutical ingredients are primarily free proteins and host cell DNA– but virus and endotoxin must also be considered.  Many isolation and purification process have been described, and the study points to the value of including some sort of specific capture step.  Approaches to this type of purification will be reviewed.


Dominique PV de KleijnKeynote Presentation

Plasma Extracellular Vesicle Sub-fractions as Biomarker Source For Cardiovascular Disease
Dominique PV de Kleijn, Professor Experimental Vascular Surgery, Professor Netherlands Heart Institute, University Medical Center Utrecht, The Netherlands, Netherlands

Cardiovascular Disease (CVD) is with the cardiovascular events of Ischemic Heart Disease and Stroke, the number 1 and 2 cause of death in the world and expect to increase especially in Asia. Ischemic heart disease (IHD) comprises 3 entities: stable coronary artery disease (SCAD), unstable angina (UA) and myocardial infarction (MI). Because IHD is associated with an increased risk of adverse clinical events such as heart failure and death, early recognition of IHD is of utmost importance. However, to diagnosis SCAD is challenging, as many patients present with atypical symptoms. Troponins are the main diagnostic tool for detection of MI. Blood biomarkers for SCAD (typically causing stable angina) and UA, however, are not available. These diagnoses frequently require hospital visits/admissions for time-consuming and costly (non)invasive tests. We use plasma extracellular vesicle protein content of vesicles from plasma sub-fractions as an accurate source for early diagnosis of SCAD. This plasma sub-fraction technology is also used for prognosis of a second MI or stroke to identify the high risk patient that can be treated with more intensive and often more costly medication.


Afternoon Coffee and Tea Break and Networking


Dana LaroccaKeynote Presentation

Extracellular Vesicles as Reprogramming Reagents for induced Tissue Regeneration (iTR)
Dana Larocca, VP Discovery Research, AgeX Therapeutics, United States of America

The global demographic shift toward an older population has created an urgent unmet medical need for effective therapeutics to treat chronic diseases of aging.  Our somatic restriction model views aging as a progressive loss of robust replicative and regenerative potential, initially observed in the developing embryo, that leads to the eventual loss of tissue homeostasis associated with aging.  We are currently assessing the ability of natural and engineered EVs to restore aging adult cells to a younger more regenerative state.  Accordingly, we hypothesized that EVs from young highly regenerative embryonic progenitor cell lines could potentially act as reprogramming reagents to induce regeneration in aging adult cells and tissues.  Toward this end, we have been mining our PureStem library of over 200 highly scalable and clonally pure embryonic progenitor cell lines to identify cellular sources of EVs capable of induced Tissue Regeneration (iTR). Using angiogenesis as a model system of vascular regeneration, we identified embryonic progenitor cell lines that produce EVs capable of stimulating adult endothelial cell migration and tube formation with increased potency compared to EVs from adult cell lines.  We are using comparative transcriptomic analysis of our PureStem library to identify additional candidate cell lines that produce angiogenic EVs. In addition, we identified miRNA cargo associated with increased angiogenic activity that we are currently loading into native exosomes to determine whether they can enhance therapeutic potency. Our data indicate the potential of embryonic progenitor cell lines as a source of natural and engineered EVs for treating cardiovascular disease as well as other degenerative diseases of aging.


Chulhee ChoiKeynote Presentation

Development of Therapeutic Exosomes: Principles and Applications
Chulhee Choi, Professor and Chair, BioMedical Imaging Center, Korea Advanced Institute of Science and Technology (KAIST), President, ILIAS Biologics Incorporated, Korea South

Our group has recently developed an opto-genetically engineered exosome system, named "exosomes for protein loading via optically reversible protein–protein interaction” (EXPLOR) that can deliver soluble proteins into the cytosol of target cells via controlled, reversible protein–protein interactions (PPI). By integrating a reversible PPI module controlled by specific wavelength of light with the endogenous process of exosome biogenesis, cargo proteins of our interest can be loaded into newly generated exosomes. Protein-loaded exosomes were shown to significantly increase intracellular levels of cargo proteins and their function in recipient cells in both a time- and dose-dependent manner. In this presentation, I will introduce the basic principles of EXPLOR technology and follow-up studies for therapeutic applications.


Paul RobbinsKeynote Presentation

Therapeutic Applications of Extracellular Vesicles for Extending Healthspan
Paul Robbins, Professor, Department of Biochemistry, Molecular Biology, and Biophysics, and the Institute on the Biology of Aging and Metabolism, University of Minnesota Medical School, United States of America

A universal characteristic of aging is loss of tissue regenerative potential due to stem cell dysfunction, contributing to the dramatic increase in the risk of morbidity and mortality. We have used both naturally-aged mice and mouse models of accelerated aging to demonstrate that transplantation of young, functional adult stem cells results in an extension of healthspan. In addition, we have demonstrated that stem cell-derived EVs are a key mediator for conferring the observed extension of healthspan by young stem cells.   Progress towards developing clinically-relevant approaches using adult stem cell-derived extracellular vesicles to treat age-related pathologies and extend healthspan will be presented.


Lorraine O’DriscollKeynote Presentation

The Hopes and Hypes of EV-based Diagnostics, Therapeutics and Delivery in Cancer
Lorraine O’Driscoll, Professor in Pharmacology, Trinity College Dublin, Ireland

Increasing evidence indicates that substantial "cargos of information" involved in cell-to-cell communication are transported out of cells and into body fluids via membrane-surrounded vesicles that are then termed extracellular vesicles (EVs). EVs content seems to include proteins, RNAs and DNA. These -collectively termed extracellular vesicles (EVs)- released from cells were originally considered as junk but are now considered to be mini-maps of their cells of origin.

Some EVs are released from healthy cells and are associated with a range of physiological functions. In cancer, studies of cell lines, animal models and serum or plasma from patients and healthy individuals have advocated EVs in a positive light as minimally-invasive diagnostics and predictive biomarkers, based on relative EV quantitative and/or contents.


Lucia LanguinoKeynote Presentation

Extracellular Vesicles in Cancer Progression
Lucia Languino, Professor of Cancer Biology, Thomas Jefferson University, United States of America


Networking Reception with Beer, Wine and a Light Dinner in the Exhibit Hall


Close of Day 1 of the Conference

Tuesday, 18 February 2020


Morning Coffee, Tea and Pastries in the Exhibit Hall

Session Title: Exosomes and Extracellular Vesicles (EVs) -- Status of the Field 2020 and Emerging Directions

Session Chairperson: Professor Mei He, University of Kansas


Properties of Exosomes Derived from Primed Mesenchymal Stem Cells
Johnathon Anderson, Assistant Professor, University of California Davis Health, United States of America

Our work involves characterization of the composition of exosomes (pMEX) derived from primed MSCs. Our data indicate that pMEX possess functional in vitro and in vivo therapeutic properties in models of inflammation associated disease.


Macrophage Exosomes in Atherosclerosis Control
Robert Raffai, Professor, University of California-San Francisco, United States of America

Macrophages are a type of immune cell that display plasticity in inflammatory diseases including atherosclerosis. M1-macrophages contribute to inflammation and atherosclerosis acceleration while M2-macrophages display opposite effects to suppress and even regress atherosclerosis. More recently, macrophages have been shown to produce exosomes that can travel in the circulation and contribute to metabolic disorders including diabetes. But whether they impact atherosclerotic lesion dynamics is currently unknown. Our findings reveal that exosomes produced by M1-macropahges enhance inflammation and atherosclerosis acceleration while those produced by M2-like macrophages exert opposite effects. Thus, macrophage exosomes could serve as biomarkers and effectors of atherosclerosis disease severity and its resolution.


Engineering Stem Cell-derived EVs For Local Delivery and Therapeutic Applications
Aijun Wang, Associate Professor, Director of Translational Research, Innovation and Entrepreneurship, University of California-Davis, United States of America

Extracellular vesicles (EVs) play a significant role in cell-to-cell communication. In our previous studies, we have confirmed that EVs secreted by placental mesenchymal stem cells (PMSC-EVs) exert significant neuroprotective functions similar in magnitude to live PMSCs. In this presentation, I will discuss what we have learned about PMSC-EVs and the potential mechanisms of action on how PMSC-EVs are protecting neurons. Recently, we have also developed various approaches to improve MSC-EV’s yield and efficacy, and designed biomaterials-based delivery vehicles to improve MSC-EVs stability, retention and targeted delivery. In summary, we are developing and engineering stem cell-derived EVs into a cell-free, off-the-shelf, and easy-to-use therapeutic modality for various disease treatment and regenerative medicine applications.


Pharmacoengineered Extracellular Vesicles for Therapeutic Applications
Juliane Nguyen, Associate Professor, University of North Carolina at Chapel Hill, United States of America

An increasing number of studies report that mesenchymal stem cell-derived exosomes have regenerative effects. However, the underlying molecular mechanisms of this are poorly characterized. Using microRNA profiling and network analysis, we identified the dominant biological processes and pathways modulated by exosomal miRNAs. Further, to improve upon the intrinsic biological effects of MSC exosomes, we have discovered novel biomaterials that allow highly efficient loading of exosomes with therapeutic cargoes including nucleic acids, paving the way for cell-free therapeutics in many diseases including cardiac regeneration after myocardial infarction.


Mei HeKeynote Presentation

High-Throughput Engineering Exosomes For Precision Immunotherapy
Mei He, Assistant Professor, University of Kansas and Chief Science Officer of Clara Biotech, United States of America

Studying extracellular vesicles (EV), particularly exosomes, is holding great promise. With intrinsic molecular payload and biodegradability, molecular engineering of exosomes opens new avenues for mediating cellular responses and developing novel nano-delivery systems in precision immunotherapy. We will report several novel approaches including microfluidic technology and nanotechnology developed in our research group for engineering exosomes as nanodelivery system employed in advancing precision immunotherapy.


Networking Coffee Break in the Exhibit Hall -- Visit Exhibitors and View Posters


Steven SticeKeynote Presentation

Neural Exosomes - Therapeutic and Drug Delivery Potential in the Treatment of Neurodegenerative Diseases and Stroke
Steven Stice, Co-Founder and Chief Scientific Officer, Aruna Bio; DW Brook Distinguished Professor and Director of the Regenerative Bioscience Center, Georgia Research Alliance Eminent Scholar, University of Georgia, United States of America

Exosomes represent a promising approach to the future treatment of a number of disease states.  Aruna Bio is utilizing the power of exosomes, or nano-sized extracellular vesicles, to target diseased neural cells and facilitate their repair. The company’s lead exosome product, AB126, is derived from a proprietary neural stem cell line. AB126 crosses the blood-brain barrier and harbors unique neurogenic and angiogenic cargos (mRNA, miRNA, and protein), which have anti-inflammatory, neuroregenerative, and neuroprotective effects in multiple models of neurological disease.  Presentation will review data on neural stem cell derived exosomes and their potential both as a therapeutic and as a delivery vehicle.


The Use of Vesicles from Cow Milk for Oral Drug Delivery
Tom Anchordoquy, Professor, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, United States of America

Many pharmaceuticals must be administered intravenously due to their poor oral bioavailability.  In addition to issues associated with sterility and inconvenience, the cost of repeated infusion over a six-week course of therapy costs the healthcare system tens of billions of dollars per year.  Attempts to improve oral bioavailability have traditionally focused on enhancing drug solubility and membrane permeability, and the use of synthetic nanoparticles has also been investigated.  As an alternative strategy, some reports have clearly demonstrated that exosomes from cow milk are absorbed from the gastrointestinal tract in humans, and could potentially be used for oral delivery of drugs that are traditionally administered intravenously.  Our results demonstrate that milk exosomes are absorbed from the gut as intact particles that can be modified with ligands to promote retention in target tissues.


Raghu KalluriKeynote Presentation

Basic and Applied Biology of Exosomes for Diagnosis and Treatment of Cancer
Raghu Kalluri, Professor & Chairman, Department of Cancer Biology; Olla S. Stribling Distinguished Chair for Cancer Research, MD Anderson Cancer Center, United States of America


Networking Lunch in the Exhibit Hall

Session Chairperson: Dr. John Ludlow, ZenBio


Jan LötvallKeynote Presentation

Clinical Translation of Extracellular Vesicle Research
Jan Lötvall, Professor, University of Gothenburg; Founding President of ISEV; Editor-in-Chief, Journal of Extracellular Vesicles, Sweden


My MahoneyKeynote Presentation

miRNA- and Cytokine-Associated Extracellular Vesicles Mediate Squamous Cell Carcinomas
My Mahoney, Professor and Vice Chair, Thomas Jefferson University, United States of America

Extracellular vesicles (EVs) serve as intercellular messengers carrying lipids, proteins, and genetic material that have been shown to play a significant role in many pathological conditions, including cancer. We recently demonstrated that the cadherin desmoglein 2 (Dsg2), a stem cell marker upregulated in many cancers, modulates EV biogenesis in squamous cell carcinomas (SCCs). Here, we show that this process occurs through the endocytic pathway and requires membrane association through protein palmitoylation. In SCC xenograft models, tumor size correlated with EV release and co-treatment with EVs increased xenograft size. To assess the molecular messengers contributing to the pathogenicity of Dsg2-mediated EVs, a cytokine antibody array was employed to show that Dsg2 stimulates release of multiple cytokines known to promote angiogenesis and inflammation, both of which enhance tumor growth. Profiling by RNAseq showed dramatic down-regulation of miRNAs that target those cytokines. These results suggest that intercellular communication through cell-cell adhesion, cytokine release, and secretion of extracellular vesicles are coordinated, critical for tumor growth and development.


Dolores Di VizioKeynote Presentation

Palmitoyl-Proteomics to Identify Protein Signatures For Large and Small Cancer-derived Extracellular Vesicles in Patient Plasma
Dolores Di Vizio, Professor, Cedars Sinai Medical Center, United States of America

Extracellular vesicles (EVs) are membrane-enclosed nano- and micro-particles that play an important role in cancer progression and have emerged as a promising source of circulating biomarkers. Historically called with various names, depending on the size, cargo, function and cellular and subcellular origin, they are currently categorized in large and small EVs. Our group and others have reported a cancer-specific population of EVs known as large oncosomes that is significantly larger than exosomes-like EVs, and is released by cancer cells during active metastatic migration. Protein S-acylation, also known as palmitoylation, has been proposed as a post-translational mechanism that modulates the dynamics of EV biogenesis and protein cargo sorting. However, technical challenges have limited large-scale profiling of the whole palmitoyl-proteins of EVs. We successfully employed a novel approach that combines low-background acyl-biotinyl exchange (LB-ABE) with label-free proteomics to analyze the palmitoyl proteome of large EVs (L-EVs) and small EVs (S-EVs) from prostate cancer cells and patient plasma. Here we report the first palmitoyl-protein signature of EVs, and demonstrate that L- and S-EVs harbor proteins associated with distinct biological processes and subcellular origin. We identified STEAP1, STEAP2, and ABBC4 as prostate cancer-specific palmitoyl proteins enriched in both EV populations in comparison with the originating cell lines. Importantly, the presence of the above proteins in EVs was significantly reduced upon inhibition of palmitoylation in the producing cells. We also performed additional experiments on a group of patients with metastatic prostate cancer and narrowed down a list of palmitoylated proteins that can be used as biomarkers in plasma. Finally, the palmitoyl-proteome of EVs in patient plasma significantly differed from the palmitoyl-proteome of whole plasma prior to purify EVs. These results suggest that palmitoylation may be involved in the differential sorting of proteins to distinct EV populations and allow for better detection of disease biomarkers.

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