♢ 中國醫藥大學副校長♢ 中國醫藥大學附設醫院 癌症中心院長
♢ 萬寶祿生技新藥公司總經理♢ 中央研究院農業生物科技研究中心客座講座
13:00 – 13:10
13:10 – 13:50
The future of cord blood transplantation and cellular therapy
Elizabeth Shpall, MD
♢ Professor, Howard and Lee Smith Chair in Cancer Research
♢ Director, Cell Therapy Laboratory and Cord Blood Bank
♢ Deputy Chair, Department of Stem Cell Transplantation and Cellular Therapy
♢ The University of Texas MD Anderson Cancer Center
Wider use of cord blood transplantation (CBT) has been limited by the low dose of hematopoietic stem and progenitor cells (HSPCs) in CB units, with resultant delays in engraftment and a substantial rate of engraftment failure. Our laboratory has developed a bone marrow-derived mesenchymal stromal cell (MSC)-CB coculture system that proved safe and able to accelerate time to engraftment, compared with results of double unmanipulated CBT (de Lima et al, NEJM, 2012). Our results also showed that ex vivo cell-surface fucosylation of CB using the α(1,3)-fucosyltransferase (FT) known as FT-6 with GDP-fucose (the donor sugar) boosted engraftment to a similar level by promoting CB homing to the marrow (Popat et al, Blood 2015). Thus, we are now investigating another, more physiologic, fucosyltransferase enzyme, FT-7, and have evidence that it could be more effective than FT-6 at enhancing CB engraftment to the marrow. Given this progress, are now embarking on a series of studies designed to bring the results of CBT in line with those of G-CSF-mobilized peripheral blood progenitor cells by further enhancing engraftment with the combination of MSC-expansion of CB cells followed by exofucosylation with FT-7. Moreover, graft-versus-host disease (aGVHD) continues to restrict the utility of CBT, and are associated with significant morbidity and mortality in all stem cell transplant settings. MSCs have been used over the past decade for the treatment of aGVHD with variable results. In our patients, those with liver and gastrointestinal aGVHD have significantly benefited from MSC treatment. In a xenogenic model, we have observed that fucosylated MSCs can enhance homing to sites of inflammation, resulting in a striking survival benefit compared with the outcome of unmanipulated MSC treatment. We have also recently observed that CB tissue-derived MSCs are logistically easier to obtain and expand much more rapidly than marrow-derived MSCs. We therefore will examine whether fucosylated CB tissue-MSCs can eliminate aGVHD in preclinical models; if successful, this approach will be tested in a clinical trial.
13:50 – 14:10
Development of cellular reprogramming and iPSC technology as personalized medicine-based platform: from bench to clinic bedside
Shih-Hwa Chiou, MD, PhD
♢ Section Chair, Basic Research, Department of Medical Research, Taipei Veterans General Hospital
♢ Distinguished Professor, The Institute of Pharmacology / The Institute of Clinical Medicine & Genomic Center, National Yang-Ming University, Taiwan
♢ Appointment Researcher, Genomics Research Center, Academia Sinica, Taiwan
The development of induced pluripotent stem cells (iPSCs) has opened a new era for stem cell research. How to quickly, efficiently, and safely produce specific-lineage differentiation from pluripotent-state cells and iPSCs is still an open question. To overcome this critical obstacle, we performed proteomic analysis to find that Parp1, a key factor for DNA repair, plays a crucial role in regulating the efficiency of cellular reprogramming. Furthermore, the generation of patient- or disease-specific iPSCs therefore holds promising potential for the drug industry and regenerative medicine. Following this concept with using iPSC technology, we have reprogrammed T cells from patients with dry type aged macular degeneration (AMD) into induced pluripotent stem cells (iPSCs) via integration-free episomal vectors and differentiated them into RPE cells that were used as an expandable platform for investigating pathogenesis of the AMD and in-vitro drug screening. Moreover, we demonstrated a plasma treated and laminin coated PDMS film that can enhance the attachment, sustain the survival, and facilitate the functional maturation of iPSC-differentiated retinal pigment epithelial cells (dRPE) seeded on it. The dRPE/PDMS-PmL implant was able to enhance the response to light stimuli in vivo. Taken together, our findings provide the pre-clinical examinations for the prospective clinical application of Human iPSCs, including dRPE/PDMS-PmL subretinal implant, in treating aging degeneration diseases like AMD.
14:10 – 14:30
Recent regulatory innovation in cell therapy in Taiwan: from a global perspective
I-Ning Tang, MD
♢ Medical Reviewer, Center for Drug Evaluation (CDE), Taiwan
In today's presentation, I will introduce the global regulations regarding cell therapy and the history of cell therapy medicinal products in Taiwan, then I will provide the audience with statistics regarding the current status of cell therapy clinical trials. Also, I will talk about the recent regulatory innovative measures in order to reduce the regulatory burden and facilitate the approval process of clinical trials and market authorizations.
14:30 – 14:40
Coffee Break, 10 minutes
14:40 – 15:20
Immune Cell- and Signaling-Specific Effects of Phytomedicines as Cell-based Therapeutic Approaches for Anti-cancer Metastasis
Ning-Sun Yang, Ph.D.
♢ Chief Scientific Officer, One Power Innovative Phytomedicine Inc., Taiwan.
♢ Visiting Chair Professor, Academia Sinica, Taiwan.
We showed recently that a number of medicinal plant extracts and the derived phytochemicals can confer diverse pharmacological activities in suppressing tumor metastasis. These phytochemical activities can regulate specific immune cell systems or the stromal or non-malignant cells in a tumor tissue microenvironment under various in vivo conditions. Such cellular activities often cannot be effectively addressed by using the conventional monolayer cell culture systems in vitro. Hence a 3-dimensional (3D) cell culture assembly system was adapted. We then employed a strategy to investigate our study by using a combination of omics approaches and specified in vivo tumor model systems. Specifically, we first make predictions for candidate specific pharmacological activities according to the “omics screening” profile and data of specific, differential responsive genes, proteins or the involved metabolites. Then we made a preference of several hypothesis in a priority sequence. We evaluated subsequently, in well-designed tests the candidate mechanistic signaling cells/molecules systems, for suppression of tumor metastasis activity in representative and clinically relevant animal models. With this strategy, we have been successful in demonstrating a number of pharmacological effects of medicinal plant phytochemicals or their derivatives on specific and key immune cell systems or the surrounding stromal cells in defined tumor microenvironment.
With the above approach, we investigated a group of phytoextracts or the derived pure phytochemicals from specific TCM (traditional Chinese medicine) plants, and evaluated their effects, in vitro and in vivo, on various immune cells including dendritic cells, MDSCs, Th17, Tregs and others in 4T1 mouse tumor metastasis systems. For experimental approach, we employed functional genomics, proteomics, transgenic promoter analysis, cytokine/chemokine profiling, micro RNA array and signaling pathway analysis systems in a cross-examination fashion. Results and findings recently published in several key papers will be discussed and projected for future research directions and potential clinical applications.
15:20 – 16:00
The challenge and opportunity in adoptive T cell-mediated immune therapy
Xin Lin, PhD
♢ Professor and Chairman, the Department of Basic Medical Sciences
♢ Tsinghua University School of Medicine, Beijing, China
Recent success of immunotherapy by immune checkpoint inhibitors for many types of cancer has demonstrated that immunotherapy is the most promising approach to cure cancer. On the other hand, the adoptive T cell therapy, such as CAR-T/TCR-T method, is emerging as a complementary approach to the immune checkpoint inhibitors. Although this approach has a great potential for cancer therapy as well as for other diseases, many biological and technical problems remain to be solved. Understanding the biological mechanisms behind these problems and technical difficulties will provide the solution for the challenge faced in adoptive T cell therapy. During last few years, we have initiated several projects, including characterizing the fate of adoptively transduced T cells in tumor microenvironments and identification of tumor-specific antigens for T cell-mediated therapies, to tackle these problems. These lines of investigation will provide new therapeutic methods to improve the efficacy of adoptive T cell-mediated cancer immunotherapy.
16:00 – 16:20
Prognostic factors for autologous dendritic cell therapy in glioblastoma
Shao-Chih Chiu, PhD
♢ Deputy Director, Center for Cell Therapy, China Medical University Hospital, Taiwan
Autologous Dendritic Cell Vaccine (ADCV) therapy plus conventional treatments for glioblastoma multiforme (GBM) has demonstrated promising efficacy results in the previous clinical trial in our China Medical University Hospital (CMUH). However, some GBM patients responded well, while others not, to the add-on ADCV therapy, with increased survival rates, in comparison to GBM patients who received only conventional treatments. Thus, identifying biomarkers to select patients who respond better to dendritic cell (DC) vaccines is crucial for improving the treatment benefits and individualizing treatment strategies. In the current retrospective cohort study, 47 patients were selected according to diagnostic reports of primary GBM during the past 15 years and divided into two subgroups: one subgroup received post-surgical adjuvant ADCTA immunotherapy injection with the conventional treatment of concomitant chemoradiotherapy (CCRT) (ADCV group, n=27) and the other received conventional treatment without immunotherapy (reference group, n=20). Quantitative immunohistochemistry for CD4, CD8, and PD-1 was performed on patient tumor samples taken at initial resection/biopsy before treatment. Pearson’s correlation, Cox proportional hazard model, and Kaplan-Meier analyses were performed to examine the correlations between biomarker expression and survival response rates. In the ADCV group, patients with a low PD-1+/CD8+ ratio (≦ 0.21) on tumor infiltrating lymphocytes (TILs) had longer overall survival (median 60.97 months) than did patients with a high PD-1+/CD8+ ratio (median 20.07 months); 80% of the patients with a low PD-1+/CD8+ ratio survived longer than 2 years whereas only 20% of patients with a high PD-1+/CD8+ ratio. Similar results were seen for disease free survival time. GBM patients with low TIL PD-1+/CD8+ ratio may be suitable candidates and benefit from conventional multi-modal regimen plus ADCV immunotherapy.
16:20 – 16:40
Therapeutic use of multilineage human mesenchymal stem cells (MSCs) towards use towards inflammatory & immune-related diseases
B. Linju Yen, MD
♢ Deputy Director, Investigator & Attending Physician, Institute of Cellular & System Medicine, National Health Research Institutes (NHRI), Taiwan
Mesenchymal stem cells (MSCs) are the multilineage somatic progenitor cells for the paraxial mesodermal lineages of adipocytes, osteoblasts, and chondrocytes. Critically, MSCs possess strong immunomodulatory properties that appear increasingly relevant for clinical application. These immunomodulatory properties not only allow MSCs to be used as unmatched-3rd party cellular products, but also for direct application in immune-, including autoimmune, and inflammatory diseases. Our lab has demonstrated that diverse sources of MSCs—whether isolated from adult or fetal sources, and even if derived from pluripotent stem cells such has human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs)—are multilineage as well as immunomodulatory. There is strong consensus that human MSCs possess strong capacity to modulate CD4 lymphocytes from an effector T and T helper type 1 (Th1) response to an immunoregulatory phenotype with significant regulatory T cell (Treg) expansion. Our lab has also demonstrated that paracrine non-immune cytokines secreted by MSCs including hepatocyte growth factor (HGF) and interleukin-25 (IL-25) also impart strong immodulatory effects towards diverse types of innate and adaptive leukocytes, including myeloid-derived suppressor cells (MDSCs), CD14+ monocytes, and Th17 lymphocytes. Based on these and numerous other reports, the use of MSCs towards immune- and inflammatory diseases appears increasingly viable, in addition to the more classical application of these versatile progenitors in regenerative medicine.
16:40 – 17:00
Benefits of hypoxic culture on human mesenchymal stem cells
Shih-Chieh Hung, MD, PhD
♢ Distinguished Professor & Director
♢ Department of New Drug Development, China Medical University
♢ Integrative Stem Cell Center, China Medical University Hospital
Human bone marrow-derived mesenchymal stem cells (MSCs) have emerged as a promising tool for clinical application. Cultivation of MSCs under hypoxic conditions, the normal physiological status of bone marrow, represents a new platform of MSCs expansion for clinical applications. In a long term culture, hypoxia can inhibit senescence, increase the proliferation rate and enhance differentiation potential along the different mesenchymal lineages. Hypoxia also modulates the paracrine effects of MSCs, causing upregulation of various secretable factors, including the vascular endothelial growth factor and IL-6, and thereby enhances wound healing and fracture repair. Hypoxia also plays an important role in mobilization and homing of MSCs, primarily by its ability to induce stromal cell-derived factor-1 expression along with its receptor, CXCR4. After transplantation into ischemic limb, an environment combined of hypoxia and serum deprivation, can lead to apoptosis or cell death, which can be overcome by the hypoxic preconditioning of MSCs. Recently, we have demonstrated the application of MSCs expanded under hypoxic conditions for treatment of a variety of diseases, including bony defect, tendon healing, osteoarthritis, hindlimb ischemia, graft versus host disease, and acute hepatic failure. We have filed a clinical trial and was approved by Taiwan Food & Drug Admiration (TFDA). In the current project, bone marrow MSCs were isolated from allogenic healthy donors, expanded under hypoxic conditions, and applied for Phase Ⅰ/Ⅱa study in treating 18 recipients with critical limb ischemia, including placebo, low dose and high dose groups. We currently enrolled and treated 18 patients with the longest follow-up for more than 12 months. All of these patients tolerated the treatment very well. No treatment-related adverse events were reported. Some patients reported the improvement of skin color, hair and snail in the affected limbs.