08:00 | Conference Registration, Materials Pick-Up, Morning Coffee and Tea |
| Session Title: Conference Opening Session -- Emerging Trends and Themes in Cell & Gene Therapy |
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08:45 | | Conference Chair Chairman's Welcome and Introduction to the Conference Norio Nakatsuji, Chief Advisor, Stem Cell & Device Laboratory, Inc. (SCAD); Professor Emeritus, Kyoto University, Japan
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09:00 | | Keynote Presentation Current Status and Future Directions of CAR-T Cell Therapy Keiya Ozawa, Professor Emeritus and Visiting Professor of the Division of Immuno-Gene & Cell Therapy, Jichi Medical University, Japan
Adoptive immunotherapy with CAR (chimeric antigen receptor)-T cells is a promising cell-based anticancer therapy for hematological malignancies. CARs are hybrid proteins consisting of an extracellular single chain fragment of variable region (scFv) fused to intracellular lymphocyte signaling domains CD28 or 4-1BB, coupled with CD3 to mediate T cell activation. CD19-targeted CAR-T cell therapy showed surprising clinical efficacy against relapsed/refractory acute lymphoblastic leukemia and malignant lymphoma. In 2017, this novel treatment was approved by FDA in USA. Cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and tumor lysis syndrome (TLS) are adverse effects that appear at an early stage following the infusion of CAR-T cells. Delayed onset toxicity of CD19-CAR-T cell therapy is the serum immunoglobulin deficiency due to destruction of normal B cells (on-target, off-tumor reaction). A next promising target antigen is considered to be BCMA (B cell maturation antigen), and BCMA-CAR-T cell therapy has been shown to be effective against multiple myeloma. On the other hand, the efficacy of CAR-T cell therapy for solid tumors has been unclear. There are several issues to be solved, and CAR-T for solid tumors should be combined with other therapeutic technologies. Currently, genome editing technology is rapidly progressing, and its application to gene-modified T cell therapy is being conducted; e.g. 1) TCR gene knockout for allogeneic (universal) CAR-T cell therapy and 2) PD-1 gene knockout of CAR-T cells (immune checkpoint blockade) to increase its cytotoxic activity. Another major issue is that gene therapies recently approved in Europe and the U.S. are extremely expensive. |
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09:40 | | Keynote Presentation Development of an Allogeneic iPSC-derived Cell Therapy Product Ross Macdonald, Chief Executive Officer and Managing Director, Cynata Therapeutics Ltd, Australia
From the first description of reprogramming methods able to generate pluripotent cells from adult somatic tissues in the middle of the last decade, the science and clinical potential of induced pluripotent stem cells – iPSCs – has taken many important steps forward. The use of iPSCs in modelling and investigating human diseases, as well as for screening drugs, has already been enormously enlightening. But it is perhaps their use in the development of therapeutic products where the greatest opportunity for iPSCs arises. Notably iPSCs share many properties with embryonic stem cells (ESCs) but because iPSCs are not derived from embryos they are not associated with the substantial ethical controversies that have overshadowed ESC research and which will most certainly influence commercial development of ESC-derived therapeutic products. iPSCs are now being used to develop a broad range of cell therapy products, including myocardial tissue for potential use to effect recovery post-myocardial infarction, retinal pigmented epithelium for potential use in age-related macular degeneration and mesenchymal stem cells (MSCs) for a broad range of disease targets. The latter cell type is the most advanced, with Cynata Therapeutics Ltd, an Australian biotechnology company, completing in 2018 a Phase 1 clinical trial in acute steroid resistant graft-versus-host disease (GvHD) with a unique allogeneic iPSC-derived MSC cell therapy product. This clinical trial, the first in the world using an allogeneic iPSC derived product, demonstrated very encouraging safety and efficacy, paving the way for a Phase 2 trial in this and further indications. The trial confirms a viable and clinically relevant process for large scale manufacture of a highly consistent cell therapy product without the challenges presented by requiring multiple donors and massive expansion of the finished product. Data from the Cynata trial in GvHD and the pathway to trial approval and beyond will be discussed. |
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10:20 | | Keynote Presentation Optimizing the Delivery of Anticancer Immune Response-Inducing Oncolytic Adenovirus and Adjuvant Immunotherapeutic Chae-Ok Yun, Professor, Department of Bioengineering, Hanyang University, Korea South
Currently, intratumoral injection of an oncolytic adenovirus (Ad) remains the conventional administration route in clinical trials. Nonetheless, the locally administered Ad disseminates to the surrounding nontarget tissues and has short biological activity due to immunogenicity of Ad, which inadvertently promotes rapid clearance and insufficient intratumoral retainment of therapeutics. To this end, we developed biocompatible and biodegradable hydrogels to enhance the therapeutic efficacy of oncolytic Ads via single intratumoral administration. A hydrogel-based intratumoral delivery of oncolytic Ads led to prolonged viral retainment within tumor tissues and restricted nonspecific shedding to normal tissues (up to 161.4-fold higher retainment than naked oncolytic Ad). Notably, hydrogel systems attenuated oncolytic Ad-mediated antiviral immune response, which can cause adverse inflammatory response, while preserving the viruses’ ability to induce robust antitumor immune response. One of the hydrogel was capable of efficiently co-delivering and protecting both therapeutic dendritic cells and oncolytic Ad in tumor tissues, thus potentiating the robust antitumor immune response by combination therapy regimen. Collectively, hydrogel-based delivery system enables biological activity of both immunotherapeutic agents could be preserved over a considerable time period in immunosuppressive and hostile tumor microenvironment that significantly diminishes the efficacy of immunotherapeutics. A delivery system, which simultaneously modulates both antiviral and antitumor immune response in a favorable manner to the potency and safety of oncolytic virotherapy in a complex immunological microenvironment of tumors, is of great importance as it may finally enable oncolytic virotherapy to reach its full potential and achieve optimal therapeutic outcome against clinical cancer. |
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11:00 | Morning Coffee and Tea Plus Networking Break |
11:30 | First Commercial Available Gene Therapy Drug “Collategen” in Cardiovascular Disease Ryuichi Morishita, Professor of Clinical Gene Therapy, Osaka University School of Medicine, Japan
Gene therapy has emerged as a novel therapy to promote angiogenesis in patients with critical limb ischemia (CLI) caused by peripheral artery disease. We have focused on hepatocyte growth factor (HGF) as pro-angiogenic factors. In the clinical trials of phase III, the naked plasmid DNA encoding HGF showed the safety and their potential for symptomatic improvement in CLI patients. Improvement rate was 70.4 % in HGF and 30.8% in placebo in Fontaine III patients (P=0.014). HGF gene therapy achieved a significantly higher improvement rate of ischemic ulcers compared with placebo (100% vs. 40%, P=0.018). No major safety problems were observed. Based on phase III data, in this year, HGF will be launched in Japan market as the first gene therapy drug. |
12:00 | | Keynote Presentation Exosome-based Cell Free Therapy Takahiro Ochiya, Professor, Tokyo Medical University, Japan
Extracellular vesicles (EVs) play important roles in intercellular communications via their content molecules, and mimic, at least in part, the roles that are played by their originating cells. Consistent with this notion, an increasing number of reports have suggested that EVs including exosomes derived from mesenchymal stem cells (MSCs), which are therapeutically beneficial to a wide range of diseases, can serve as drugs to treat multiple diseases. EVs contain a variety of molecules, including proteins, microRNAs, and mRNAs, and are associated with biological processes in a content molecule-dependent manner. In this presentation, it will be reviewed the latest reports regarding the therapeutic potential of MSC-EVs by focusing on the underlying molecular mechanisms of their effects. Specifically, it will be notified the effects of MSC-EVs in terms of their content molecules and of the tissue recovery processes endowed by these molecules for exosome-based cell-free therapy. |
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12:40 | Networking Lunch, Exhibit and Poster Viewing |
| Session Title: Advances in Cell Therapy |
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13:30 | | Keynote Presentation Preclinical Transplantation Study of iPS Cell-Derived Cardiomyocytes in Non-Human Primate Yuji Shiba, Professor, Department of Regenerative Science and Medicine, Shinshu University, Japan
Induced pluripotent stem cells (iPSCs) have promising potential as a source of autologous patient-specific cardiomyocytes for cardiac repair, obviously providing a major benefit in terms of immune rejection. However, autologous transplantation comes with substantial challenges related to manufacturing and regulation. Although major histocompatibility complex (MHC)-matched allogeneic transplantation is a promising alternative strategy, surprisingly few immunological studies have been carried out with iPSCs. Here, we established an allogeneic transplantation model using cynomolgus monkey, whose MHC structure is identical to that of humans. iPSCs were generated from fibroblasts from an animal with a homozygous MHC haplotype (HT4), and the cells were differentiated into cardiomyocytes (iPSC-CMs). Five HT4 heterozygous monkeys were subjected to myocardial infarction followed by direct intramyocardial injection of the iPSC-CMs. The grafted cardiomyocytes survived for 12 weeks with no evidence of immune rejection under treatment of clinically relevant doses of methylprednisolone and tacrolimus, and they showed indisputable electrical integration with host cardiomyocytes as assessed by use of our novel fluorescent calcium indicator, G-CaMP7.09. In addition, transplantation of the iPSC-CMs improved cardiac contractile function at 4 and 12 weeks post transplantation; however, the incidence of ventricular tachycardia was transiently but significantly increased when compared to the vehicle-treated control. MHC-matched allogeneic transplantation of iPSC-CMs regenerates infarcted non-human primate heart. Further research to control post-transplant arrhythmias is warranted. |
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14:10 | Clinical Application of iPS Cell Therapy For Parkinson’s Disease Asuka Morizane, Assistant Professor, Center for iPS Cell Research and Application (CiRA), Kyoto University, Japan Jun Takahashi, Professor, Kyoto University, Japan
The innovation of induced pluripotent stem cells (iPSCs) and previous embryonic stem cell (ESC) technologies are drawing attention to their application for regenerative medicine. Parkinson’s disease (PD) is one of the most promising target diseases based on the history of fetal nigral transplantation in clinics. The technology of iPSCs offers a limitless and more advantageous donor source than aborted tissue. One of the advantages is possibility of preparing immunologically compatible donor cells from self-derived or allogeneic iPSCs. We have successfully established a protocol for donor induction with clinically compatible grade and have transplanted these neurons into PD models of mice, rats, and cynomolgus monkeys as preclinical studies. Based on these research results, the clinical trial of cell therapy for PD with iPS cells started since 2018. The presentation will include the recent research results and the proceedings of the clinical trial. |
14:40 | Therapeutic Considerations of Mesenchymal Stromal Cells Ling-Mei Wang, President and COO, Steminent Biotherapeutics, Taiwan
Mesenchymal Stromal Cells (MSCs), with its unique anti-inflammatory and immunomodulatory functions, have been widely considered as a viable drug agent for many unmet or underserved disease indications. Anyhow challenges remain before we can see more popularized clinical applications. Some critical dimensions include the high level of biological complexities, regulatory requirements, and manufacturing scale-up. This presentation will have an overview of some essential issues to be considered, along with suggested approaches in developing viable clinical use of MSCs. Steminent Biotherapeutics, with its proprietary allogenic stem cell technologies, will present some of the key findings of utilizing MSC-based treatments on Spinocerebellar Ataxia (SCA) and Acute Liver Failures (ALF), both are debilitating medical needs without effective options. |
15:10 | Afternoon Coffee and Tea Break and Networking |
| Session Title: 3D-Culture, Organoids and 3D-Bioprinting -- An Emerging Toolbox |
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15:40 | Challenge and Solution of Cellular Pharmacokinetic Considerations For Cell Therapy Thai-Yen Ling, Associate Professor, National Taiwan University, Taiwan
In the field of cell therapy, application of cells is not only regarded as “a treatment protocol", but also to consider cells as a medical product: “the cell drugs". However, different to the drugs of small molecular, which have been regulated by well-established evaluation process of preclinical pharmacokinetic/pharmacodynamic (PK/PD) studies in order to apply for the investigational new drug application (IND) and new drug application (NDA), methods used to assess the bio-distribution of transplanted cells and related metabolic information and therapeutic effect mechanisms are still limited. Our study demonstrated that fluorescent nanodiamonds (FND) labeling techniques of cell toward accurate quantification and bio-distribution for cell-transplantation in PK/PD studies may substitute for radiographic calibration, Q-PCR and immunohistochemical analysis for PK/PD in preclinical animal studies. FND has the properties of high biocompatibility, non-toxicity, low chemical activity and stable optical properties. The technique can be applied to different kind of immune cells, stem cells, and any other cells using for cell therapy. Taken altogether, transplanted cells by FND labeling could be accurately located and quantified for the distribution of experimental animals in vivo, and the techniques will provide the essential information of cellular PK/PD evaluation in preclinical studies of cell therapy to assist IND process for cell drug development. |
16:10 | | Keynote Presentation Cell Fiber Technology for Cell Therapy Shoji Takeuchi, Professor, Center For International Research on Integrative Biomedical Systems (CIBiS), Institute of Industrial Science, The University of Tokyo, Japan
The cell fiber was produced in a double coaxial laminar flow microfluidic device. The core stream of cells suspended in ECM sol and the shell stream of sodium alginate sol form a core-shell laminar co-flow in the device; the flow of Na-alginate sol becomes a gel at the point where it merges with the sheath stream of calcium chloride solution. As a result, a Ca-alginate shell with the cells and ECM sol in the core can be continuously generated on a meter-length scale. The three-dimensionally cultured cells in the fiber show excellent intrinsic functions. When with myocytes, endothelial, and nerve cells, they showed the contractile motion of the myocyte cell fiber, the tube formation of the endothelial cell fibers and the synaptic connections of the nerve cell fiber, respectively. By using microfluidic handling, higher-order assembly of fiber-shaped 3D cellular constructs can be performed; in particular, mechanical weaving of cell fibers with our lab-made microfluidic weaving machine provides a woven "cell fabric" composed of three different cell fibers. As the practical application, the fiber encapsulating beta-cells is used for the implantation of diabetic mice, and succeeded in normalizing the blood glucose level. |
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16:50 | How 3D Bioprinting Begins To Take Shape In Industry Brian Ikeda, Sales Director, Allevi
3D bioprinting has been a very promising technology to allow more and more research to be published and new discoveries made. However, how does bioprinting begin to penetrate the industrial sector? What specific areas should the field focus on? How can we measure impact? |
17:20 | Recent Advancements in Research Based on 3D Bioprinting Technology – From Single Cells to Miniature Organs Haruka Yoshie, Application Specialist, CELLINK
Additive manufacturing has made a resounding impact on many traditional manufacturing industries, allowing for custom and free-form manufacturing of parts. This has overlapped to the biomedical space for implants and prosthetics with large-scale metal and plastic printers gaining traction as custom solutions to patient-specific implants.
Despite growth in traditional sectors and the emerging market for 3D bioprinting, the use of 3D bioprinting as a custom solution for bio-applications in the pharmaceutical and bio-manufacturing industries has not yet been achieved. Many problems stem from low throughput of manufactured materials, lack of education in additive manufacturing, and the elusiveness of single-micron manufacturing.
While technology for additive fabrications has been used extensively in the research space, this talk will focus on the future role of additive manufacturing within biological industries, and the technology being developed that will drive it. |
17:50 | The Biologicalisation of Medicine and Manufacturing William G Whitford, Life Science Strategic Solutions Leader, DPS Group
The biologicalization (or the biological transformation) of manufacturing is essentially the use of digital manufacturing approaches (Industry 4.0) with biological and bio-inspired principles to support more efficient and sustainable manufacturing. It creates a biomimetic design – from reactions, equipment, and assemblies to materials, processes, and facilities. For example, Nobel Prize winner Frances H. Arnold invented systems directing the evolution of enzymes now routinely used in development catalysts in manufacturing. This approach to biologicalisation of processes is dependent upon advances in biochemistry, many of the ‘omics, as well as genetic engineering. From another direction, advances in fermentation and cell-culture technologies is supplying a cell-based biologicalisation of processes. Harmonization of digital principals with bio-integrated systems supports processes composed not only of biological chemistries, but of engineered organoids, tissues and cells. As supported by nano/micro-technology, cell-based systems can enable the goals of sustainability, economy and efficiency in research and therapeutics. |
18:20 | Close of Day 1 of the Conference |