Day 1 :
University of Pisa, Italy
Keynote: Mesangiogenic progenitor cells (MPCs) in orthopedics, a new tool for cell-based medicinal products?
Time : 10:00-10:40
Simone Pacini has completed his PhD in 1997. Until 2003 he was active in oncohematology and responsible of flow cytometry and cell sorting facility. Later, his studies focused on clinical use of MSCs and participated actively on isolation of a novel progenitor of MSC in adult human bone marrow. He is currently working in collaboration reputed Universities and Medical Colleges. Actually, he is a Lab Director of the “Michele Cavaliere Laboratories for Cell Therapy” at University of Pisa. He has published more than 40 papers in reputed journals and he is Editorial Board Member of the Frontiers in Cell Developmental Biology journal.
Mesangiogenic progenitor cells (MPCs) have been firstly described in 2008 in human bone marrow (hBM) mononuclear cell cultures, intended to isolate mesenchymal stromal cells (MSCs) in animal-free conditions. Later, we developed a clinical-grade and selective culture method to isolate MPCs with high grade of purity with yields around 1% of plated cells. MPC are characterized by lack of MSC markers, specific integrin profile and phenotype that include CD31 and surprisingly CD45. From the first report on MPCs, these cells showed both mesengenic and angiogenic potential in vitro. Interestingly, pluripotency-associated gene, as OCT-4, NANOG and nestin expression were also detected. Mesengenic differentiation protocol has been set up in chemical defined conditions and more recently, the angiogenic potential was clearly demonstrated also in vivo, applying MPC constructs on chicken chorioallantoic membrane. Surprisingly, the ex vivo precursor of MPCs in hBM has been identified in CD45dimCD64brightCD31brightCD14neg population with a morphology resembling the monoblast. For their peculiar differentiation properties and clinical-grade isolating methods, MPCs could represent a new tool for the implementation of cell-based medicinal products (CBMPs) applicable for skeletal tissue regeneration, as these cells could also support the neo-vascularization. In fact, future studies on tissue reconstruction should take in consideration that the newly formed tissue growth and integration should be supported by concomitant neo-vessels formation. The co-existence of mesengenic and angiogenic potential in MPCs could significantly improve the regeneration potential of new therapeutic approaches that involve these interesting cells.
University of Liverpool School of Medicine, UK
Keynote: The impact of IR radiation on the induction of bystander killing by genetically engineered ovarian tumor cells: implications for clinical use of cancer vaccines
Time : 10:40-11:20
Jehad Zweiri, Lecturer in cancer studies at the University of Liverpool Medical School, received his Bachelor’s degree from the University of Jordan in 1990. He obtained his Master’s degree from London School of Hygiene and Tropical Medicine/University of London, and then obtained his PhD degree in 2000 from Kings College Medical School/University of London, in the field of Immune Gene Therapy of Cancer under the supervision of Professor Farzin Farzaneh. He then started his work as Postdoctoral Associate at the Department of Immunology and Medicine at the University of Liverpool in 2002. In 2010 he was appointed as a Lecturer in the University of Liverpool Medical School and he is currently Fellow of the British Higher Education Academy since 2012.
Cellular based therapeutic approaches for cancer rely on careful consideration of finding the optimal cell to execute the cellular goal of cancer treatment. Cell lines and primary cell cultures have been used in some studies to compare the in vitro and in vivo efficacy of autologous vs. allogeneic tumour cell vaccines. This study examines the effect of g-irradiation on a range of tumor cell lines in conjunction with suicide gene therapy of cancer. To determine the efficacy of this modality, a series of in vitro and in vivo experiments were conducted using genetically modified and unmodified tumor cell lines. Following co-culture of herpes simplex virus thymidine kinase (HSV-TK) modified tumor cells and unmodified tumor cells both in vitro and in vivo we observed that the PA-STK ovarian tumor cells were sensitive to g-irradiation, completely abolishing their ability to induce bystander killing of unmodified tumor cells. In contrast, TK-modified human and mouse mesothelioma cells were found to retain their in vitro and in vivo bystander killing effect after g-irradiation. Characterisation of tumor cell death showed that PA-STK cells underwent pyknosis (necrosis) after g-irradiation. These results suggest that PA-STK cells are not suitable for clinical application of suicide gene therapy of cancer, as lethal g-irradiation (100Gy) interferes with their bystander killing activity. However, the human mesothelioma cell line CRL-5830-TK retained its bystander killing potential after exposure to similarly lethal g-irradiation (100Gy). CRL-5830 may therefore be a suitable vehicle for HSV-TK suicide gene therapy. This study highlights the diversity among tumor cell lines and the careful considerations needed to find the optimal tumor cell line for this type of suicide gene therapy of cancer.
Medical University of South Carolina, USA
Keynote: Mesenchymal stem cells from chronic pancreatitis patients prolongs mice and human islet survival
Time : 11:35-12:15
Hongjun Wang has completed her PhD from China Agricultural University and Postdoctoral studies at the University of Rome, “La Sapienza” and St. Jude Children’s Hospital. She was an Instructor and Assistant Professor at the Harvard Medical School/Beth Israel Deaconess Medical Center from 2001-2011. She is now a full Professor and the Scientific Director of the Center for Cellular Therapy, at the Medical University of South Carolina, USA. She has published more than 50 papers in reputed journals and has been serving as an editorial board member of repute.
Mesenchymal stem/stromal cells (MSCs) have tissue repair abilities and immunoregulatory effect. We investigated whether MSCs derived from chronic pancreatitis (CP) patients are suitable for use in cell therapy. We first compared MSCs from CP patients with those from healthy donors. We found that cell surface markers, ability of colony formation and multi lineage differentiation abilities were similar between healthy MSCs (H-MSCs) and CP-MSCs. Gene profile study indicated 4 out of 84 human MSC-related genes were differentially expressed in CP-MSCs in comparison with healthy MSCs, among which growth differentiation factor 6 (GDF6), hepatocyte growth factor (HGF) were down-regulated, whereas transforming growth factor (TGF) β3 and matrix metalloproteinase-2 (MMP2) were upregulated. CP-MSCs displayed great potential of inhibition of T cells proliferation to the same extent as healthy MSCs, with even higher indoleamine 2, 3-dioxygenase (IDO) expression upon IFN-γ stimulation. The protective effects of MSCs on hypoxia-induced β cell death are also comparable between CP-MSCs and H-MSCs. We further tested the protective effects of MSC in a marginal mass mouse islet transplantation model, and found that co-transplantation of islets with CP-MSCs improved islet survival and function after transplantation. The effects are in part mediated by paracrine secretion of insulin-like growth factor-1 (IGF-1), suppression of inflammation, and promotion of angiogenesis. In addition, in a pilot clinical trial, co-transplantation of patient islets with autologous MSCs showed safety and primary efficacy. Therefore our rodent and clinical trial data demonstrated that CP-MSCs have the potential to be used as a synergistic therapy to enhance the efficacy of islet transplantation.
King’s College London, UK
Time : 14:45-15:25
Farzin Farzaneh holds the Chair of Molecular Medicine at King’s College London. He has published over 250 research articles with an average citation of over 30, and an impact factor of 47. He has run a licensed GMP facility at King’s College London, since 2001, for the production of cell and gene therapy based investigational medicinal products. He has extensive industrial and academic collaborations, including research council, charitable and pharmaceutical sponsorships of £25 M. He has initiated a number of clinical trials in novel applications of gene therapy and holds MHRA licences (IMPs and “Specials"). He is a Qualified Person (QP) for release of cell and gene therapy products in UK and EU and an Individual Designate under a Human Tissue Authority licence that allows procurement, testing, processing, distribution and/or import/export of tissues and/or cells intended for human applications. He is also appointed by the Commission on Human Medicines, as a member of the Clinical Trials, Biologicals & Vaccines Expert Advisory Group since 2016.
Autologous chimeric antigen receptor (CAR) T cells, one of the most effective of the new immune therapy strategies, are extremely expensive, as they are made for each patient individually. Deletion of the endogenous T cell receptor allows the use of allogeneic CAR T cells, which if proven to be safe and effective, will be substantially cheaper and suitable for large populations of patients. We have helped with the development of allogeneic CAR T cells, now in a number of phase-I clinical trials, providing preliminary evidence of safety and efficacy. In an entirely different form of immune gene therapy, we have shown that myeloid leukaemia cells expressing immune co-stimulatory molecules and appropriate cytokines can induce the rejection of previously established cancers in several mouse models. In two phase-I clinical trials, in poor prognosis acute myeloid leukaemia (AML) patients, we are now assessing the safety and potential efficacy of autologous CD80/IL-2 expressing AML cells. Preliminary data shows evidence of vaccination induced antigen specific cellular immunity and clinical efficacy. In order to develop therapeutic cancer vaccinations, we have identified combinations of adjuvants for synergistic activation of cytotoxicity (CASAC) that can induce antigen-specific cellular immunity, even in immune senescent aged mice. Using a simpler version of CASAC in combination with a selected library of hTERT peptides, we are completing a phase-I trial in patients with therapy resistant, progressive, metastatic disease. Early results indicate safety and stimulation of immunological responses, as well as objective clinical responses and disease stasis in up to 40% of patients.