Cell & Gene Therapy Asia 2019 Agenda

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

Morning Coffee and Tea Plus Networking Break

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.

Networking Lunch, Exhibit and Poster Viewing

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.

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.

Afternoon Coffee and Tea Break and Networking

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.

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?

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.

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.

Close of Day 1 of the Conference

Morning Coffee, Tea, Pastries and Networking

Virotherapy, Cell-based Therapy and Gene Therapy with Non-Replicating Oncolytic Virus Particle (HVJ-E/GEN0101) for the Treatment of Cancers
Toshihiro Nakajima, Senior Technical Executive and General Manager of Manufacturing, GenomIdea, Inc., Japan
Yasufumi Kaneda, Professor and Vice-President/Provost, Osaka University, Japan

HVJ-E/GEN0101 is an inactivated virus particle derived from murine parainfluenza virus HVJ (Hemagglutinating virus of Japan). It has been originally developed as a vector for gene therapy. We discovered the virus particle itself has an activity to induce cancer-cell specific apoptosis and necroptosis. It also induces innate and adaptive immunities necessary to attack cancer cells. The active ingredient is a single strand RNA fragment derived from genomic RNA of the virus. It binds to an intracellular nucleic acid receptor RIG-I and induces expressions of cytokines, chemokines and apoptosis-related genes in vitro and in vivo. We conduced safety studies using Cynomolgus monkeys and started investigator initiated clinical studies in Osaka University to develop HVJ-E as a new drug for cancer immune- and viro-therapies. To date five phase I or I/IIa investigator initiated clinical studies has been finished. The targets cancers are melanoma, prostate cancer and malignant pleural mesothelioma. In these studies, the safety, efficacy and mechanism of actions of the drug have been evaluated. No serious adverse event related to the drug was observed and safety of the drug is confirmed in clinical. Reduction and eradication of tumor lesions were observed in a dose dependent manner. Induction of innate and adaptive immunities after administration of HVJ-E was observed in clinical, suggesting that the efficacy is mediated by immune reactions. The efficacy is expected to be increased in combination with anti-PD-1 antibody therapy, we are now conducting two phase II studies of melanoma and malignant pleural mesothelioma for the evaluation of efficacy of combinational therapy.

In addition to cancer virotherapies, we are also conducting cell therapy and gene therapy of HVJ-E for the treatment of ovary and breast cancers, respectively. In the cell therapy, we prepare hybrid cells of dendritic cell (DC) and irradiated cancer cells derived from patients. HVJ-E is used for cell fusion, maturation of DC and induction of cancer immunities. Cancer antigens are directly captured by DC via membrane fusion between DC and irradiated cancer cells, and DC efficiently presents antigens to helper T cells. In the gene therapy, we use plasmid DNA expressing chemokine gene (CXCL2) to recruit neutrophils into tumor bed. Intratumoral injection of HVJ-E improve a tumor microenvironment by the induction of Type I neutrophils which suppress the growth of tumor.

To establish sustainable cycle (or system) to create innovative drugs in Osaka University, we are trying to bridge basic scientists, clinicians and researchers of companies. Osaka University applys and maintains patents of the seed of drugs in collaboration with companies as applicant to obtain appropriate royalty. Basic scientists and clinicians designed their investigator initiated clinical studies in collaboration, since custom-made design based on scientific data is necessary to develop innovative drugs. We also bridged academia and industries to conduct our phase II investigator initiated clinical studies. We are now trying to make collaboration scheme with pharmaceutical companies to complete sustainable cycle.

Gene Therapy For Neurological Diseases
Shin-ichi Muramatsu , Professor of Neurology, Jichi Medical University (JMU), Japan

Adeno-associated virus (AAV) vectors have been widely used for gene therapy. In Clinical studies on advanced Parkinson’s disease, investigators, including us, have shown the motor symptoms to be ameliorated along with an increased dopaminergic activity on positron emission tomography after gene transfer of aromatic L-amino acid decarboxylase (AADC) into the putamen. The beneficial effects of AADC gene transfer have also been shown in children with AADC deficiency. AAV vectors can achieve global transduction of the central nervous system by intravenous or intrathecal injection. We have been developing gene therapy for various diseases including sporadic amyotrophic lateral sclerosis, spinocerebellar ataxia 1, glucose transporter 1 deficiency, and GM2 gangliosidosis.

Morning Coffee and Tea Break and Networking

Tuning Cell Orientation based on Localized Geometry Sensing during Cell Sheet Formation by the Micromesh Culture Technique
Kennedy Okeyo, Senior Lecturer, Institute for Frontier Life and Medical Sciences, Kyoto University, Japan

Cell sheets are self-assembled cellular constructs with potential application to regenerative medicine and cell-based therapy. Indeed, ongoing researches have demonstrated the potential application of cell-sheets in the regeneration of the cornea, esophagus, etc, with promising results. However, for application to oriented tissues like the heart and muscle tissues, cell sheets with clearly defined global cell orientation is required. However, presently available cell sheet technologies cannot meet this task. Moreover, since the most widely employed cell sheet fabrication technique involves the use of temperature-responsive culture vessels and other similar culture platforms, cell sheet damage during harvesting from such sticky culture platforms presents a major obstacle. In this talk, we present a simpler and easy-to-implement cell sheet fabrication approach which utilizes adhesion-limiting micromeshes as inducers of self-assembly mediated solely by cell-cell adhesion in a suspension. We demonstrate that tuning the mesh microstructure, such as mesh shape and size, can enable us to control whole-sheet cell orientation, a process which occurs naturally based on geometry sensing capability of cells. We also show that cell sheets can be generated in a suspension, eliminating the need for expensive harvesting strategies.

Prostate Cancer Gene Therapy as Translational Research
Yasutomo Nasu, Professor, Okayama University, Japan

Prostate is an ideal target organ for the gene therapy as a translational research (TR). It has advantages as follows : prostate is not a life keeping organ, can be approached easily by ultrasound as a routine clinical technique  and PSA is a potent tumor marked for the evaluation of clinical response. Many clinical gene therapy trials for prostate cancer have been conducted in many institutes showing clinical safety and efficacy including Japanese trial. Intraprostatic therapeutic gene transduction (in situ gene therapy) is one of the potent therapeutic option for prostate cancer gene therapy aiming at anti-metastatic benefits through the generation of immune cell-mediated cytotoxic activities that affect not only the primary tumor but also metastatic lesion. In this lecture, role of academia for the development of gene therapy as a translational research will be discussed base on our experience for 20 years. I would like to discuss about the present problem and future direction for the development of gene therapy.

Networking Lunch, Exhibit and Poster Viewing

Multidisciplinary Oncolytic Virotherapy for Gastrointestinal Cancer
Toshiyoshi Fujiwara, Professor & Chairman, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan

Telomelysin (OBP-301) is an attenuated oncolytic adenovirus, in which the telomerase promoter drives expression of E1 genes. Telomelysin causes selective replication and lysis of a variety of human cancer cells, and also inhibits the repair of radiation-induced DNA double-strand breaks, leading to radiosensitization. A phase I study has confirmed the safety and biological activity of Telomelysin alone in patients with advanced solid tumors in the US. To further determine the feasibility, efficacy, and pharmacokinetics of Telomelysin in combination with radiotherapy, an investigator-driven clinical study was designed. Patients with histologically confirmed esophageal cancer who were not eligible for surgery or chemotherapy were enrolled into this study. Study treatment consisted of intratumoral needle injections of Telomelysin on days 1, 18, and 32 of treatment. Radiation therapy was administered concurrently over 6 weeks, beginning on day 4, to a total of up to 60 Gy. Virus administration was performed by intratumoral injection of the primary tumor through a flexible endoscope. Patients receive escalating doses of Telomelysin (10¹⁰ to 10¹² virus particles [vp]). Seven, three, and three patients were enrolled and treated in the cohorts with 10¹⁰, 10¹¹, and 10¹² vp of Telomelysin, respectively. The patients comprised 10 males and 3 females, with median age of 79.7 years (range, 53 to 92 years). Common grade 1 and 2 toxicities included fever, esophagitis, pneumonitis, anorexia, constipation, and gastroesophageal reflux disease. All patients developed a transient, self-limited lymphopenia. Objective responses were complete response (CR) in 4, 2, and 2 patients in cohort 1, 2, and 3, respectively; all of them exhibited pathologically no viable malignant cells in biopsy specimens. Histopathologic examination in post-treatment specimens showed massive infiltration of CD8⁺ cells in 3 partially responded tumors. Multiple courses of endoscopic Telomelysin injection with radiotherapy were feasible and well tolerated in patients with esophageal cancer, and appeared to provide clinical benefit.

Translational Medicine - Clinical Concerns re Expanding & Banking MSCs
Eugen Molodysky, Clinical Associate Professor, Sydney Medical School, University of Sydney, Australia

Stem cell-based therapies have proliferated globally in recent years with the US leading the world in total number of clinics, but Australia leading the US with the number of clinics per capita.
 
As stem cell therapies are being sort out for a growing range of applications, both clinical and healthy aging, clinicians are increasingly faced with the decision, as to whether a patient should proceed with a stem cell treatment. This is at a time when there are few, if any, evidence-based guidelines, as to when and whether stem cell therapy is a suitable option under a given set of conditions.
 
This paper seeks to review our current understanding of the MSC life cycle journeys; from the in vivo donor environment (first life), to the ex vivo culture environment (second life), and re-entry to the in vivo host environment (third life). This paper focuses both on the attendant risks of both expansion and administration of MSCs, by identifying morphological and genomic changes of the Second Life, and introducing a potential role for NAD+ and NAD+ - raising compounds during the MSC journey.

Coffee Served and Panel Discussion: New Trends and Future Directions in Cell and Gene Therapy -- Chaired by Professor Norio Nakatsuji

Closing Remarks by Conference Chairman, Professor Norio Nakatsuji

Close of Conference