1. IRB Strategy

1.1Scientific and medical strategy

Biotherapies, in particular regenerative medicine, a major stake of medicine and an economic stake.

Regenerative medicine consists in repairing tissues or organs with cells that have been modified ex vivo. This discipline applies to most medical domains (cancers, cartilage and bone diseases, cardiac insufficiency, diabetes, hepatitis, muscular dystrophies, neurodegenerative diseases) and constitutes one of the most promising developments of the medicine and of the biotechnology industry (a 10 billion $ market in 2010). Given the medical and economic importance of this discipline, the state of California is investing 3 billions $ (300 millions $ per year) for 10 years for stem cell research. Biotherapies begin to revolutionize the treatments of some pathologies: anti-CD20 in B cell lymphoma and rheumatoid arthritis, anti-TNF and anti-IL-6 in inflammatory pathologies, targeted treatments of cancers, manipulation of the immune system in cancers.

The aim of the IRB is to develop novel therapeutics in the field of cancer and regenerative medicine, in particular cellular and biological drugs.

Therefore, three thematics are developed within the IRB covering topics that fulfill the following criteria: clinical importance for the CHU Montpellier and preexisting experimental and clinical expertise in the Montpellier campus.

1.1.1 Biotherapy in Cancer

IRB teams are looking to identify and target the cancer stem cells (CSC) - able of self renewal and generation of tumor diversity - in multiple myeloma or acute myeloid leukemia. These CSC have been identified in various cancers and their frequency – 1/100000 to 25% - is a matter of debate, depending of the accuracy of the detection assay. We are characterizing the CSC niche, which provides the CSC the communication signals necessary to be homed, to survive, proliferate and differentiate. To identify the myeloma CSC, we are developing in vitro and in vivo assays (xenotransplantation in fully immunodeficient mice), in order to detect markers making it possible to enrich CSC. Using large scale gene and protein expression assays, we pick up the major mechanisms controlling the homing, survival and differentiation of the CSC in close contact to the CSC niche. The biological function of the most promising proteins is studied in detail. In particular, we focus on the genes or proteins whose expression is linked with treatment response and survival of patients, with the aim to develop targeted therapies.

An important focus is the development of immunotherapy strategies in patients with multiple myeloma or B cell lymphoma.
Patients with MM or AML resistant to conventional therapies can be treated with allografts, after deletion of patient’s T cells. The donor’s grafted lymphocytes will destroy the patient’s hematopoietic stem cells, residual patient’s lymphocytes and also the tumor cells. The toxicity of allografts has considerably decreased with the development of non myeloablative treatment. The possibility to use grafts from unrelated adult donors or from umbilical cord blood has made it possible to get a graft for a majority of eligible patients. The CHU Montpellier Hematology center is one of the main allograft center in France. IRB teams are looking to understand how the donor’s lymphocytes, in particular NK cells, can kill efficiently patient’s tumor cells, while reducing the toxicity towards healthy tissues. IRB teams are looking how to optimize the use of monoclonal antibodies, in particular anti-CD20 antibody, in patients with B cell lymphoma. This involves to optimize the antibody dependent cell cytoxicity, by characterizing and recruiting a maximum of effectors.
At IRB, several teams are looking to characterize the stem cell involved in B cell neoplasias, the cell communication signals with the tumor niche.

1.1.2 Pre-embryonic development and embryonic stem cells

The human pre-embryo development is at the heart of two major medical stakes: in vitro fertilization (IVF) and regenerative medicine. Despite important progress in the field of in vitro fertilization (IVF) during the last forty years, it requires throughout the world the in vitro culture of millions of human embryos, 75% of which never reach the blastocyst stage (allowing implantation into the recipient mother) because of developmental defects. Today, a large part of these failures remain unexplained. Therefore, one of our goals is to identify the abnormalities in the oocyte ploidy and in the molecular maturation of the oocyte, its surrounding cumulus cells and/or the pre-embryos. Human embryonic stem cells (hESC) can differentiate into every type of tissue during embryonic development and into many if not all tissues during in vitro culture. Because hESC are pluripotent, they are regarded as an essential stem cell model for regenerative medicine strategies. We have obtained new, genetically stable, hESC under GMP conditions. We have also obtained stable pluripotent stem cell lines, reprogramming human adult cells. Our major aim is to obtain germ cells – oocytes and sperm cells, from the pluripotent stem cell lines, which is a major request from European people. We aim also to study the mechanisms underlying pluripotency using very high resolution transcriptome analysis. We have the unique situation in France covering early human development from the oocyte before fertilization up to the formation of human pluripotent stem cells, including embryonic stem cells (hESC). The combination of our expertise in the fields of fertility and stem cells together with state-of-the-art techniques for genomic analysis, will allow us to identify and prospectively validate reliable oocyte and embryo quality markers, to generate germ cells from pluripotent stem cells that will be readily applicable for future clinical trials.

1.1.3 Stem cell biology and regenerative medicine.

In the year 2020, up to 40 percent of the European population will be older than 65 years. This ageing society is prone to various diseases causing an enormous socio-economic burden. Many of these disorders will be related to acute or chronic organ dysfunction. Thus, the central aim for a causative treatment of organ dysfunction will be functional tissue repair and is covered by the emerging field of regenerative medicine. This discipline applies to most medical disciplines (cardiovascular diseases, diabetes, liver failure, neurodegenerative diseases, cartilage and bone diseases, muscular dystrophies) and, therefore, constitutes one of the most promising developments in medicine and biotechnology industry. A plethora of concepts have been developed to restore tissue function, including drug- and gene-based strategies as well as transplantation of cells, bioengineered tissues, and organs. A growing number of studies have reported the isolation of stem and progenitor cells from the bone marrow and also from a variety of non-bone marrow tissue sources. Most approaches are based on the utilization of stem and progenitor cells that may or may not be modified ex vivo prior to their use in the patients. Since stem cells have yet to acquire the identity of any specific cell type, are still not committed to any dedicated function, and are defined by their self-renewal capacity, they might not only be used as tools to study tissue formation but might also be employed for tissue repair and regeneration. Despite our recent advances in stem cell biology, regenerative medicine is still in its infancies and currently far from being routinely used in the clinical setting. Indeed, still very little is known about the mechanisms, by which progenitor cells improve organ specific and vascular function. There is currently considerable controversial discussion about the relative contributions of differentiation, cellular fusion and/or paracrine effects. With regard to tissue resident stem and progenitors isolated from kidney, liver, and pancreas, there is very limited data regarding their lineage relationships, self-renewal properties, clonality and repopulation from bone marrow derived precursors. Given the concerns about the ability of adult stem cells to rebuild diseased organs tissue cell-autonomously, it seems overdue to identify and dissect those signals that direct the migration, renewal and differentiation of distinct adult stem/progenitor cell populations. The functional benefits of the autologous transplantation of bone marrow derived progenitor cells for treatment of injured and failing organs should be exploited, improved, and mechanistically underpinned, and its impact on organ vascular and parenchymal remodeling be analyzed. Finally, identification of the optimal cell transplants, their optimization prior to application with respect to treatment efficacy, transplant function, and survival as well as improvements in the administration of the treatment modality are key factors for the success of this promising research area. An enhanced knowledge of the molecules and processes that govern the differentiation and renewal of stem/progenitor cells during development and disease will result in a further refinement of already explored therapies and provide a rationale for new clinical trials in regenerative medicine.

1.2 Organization strategy

Our best asset to establish the IRB in this very tight competition is a complete chain of expertise from the fundamental research to therapeutic applications. The region of Montpellier is the third French region (excluding Paris) for biomedical research with large CNRS or INSERM institutes with high technology platforms which are connected through Federative Structure of Research (SFR), and a high level Biology-health doctoral school. IRB has for objective to offer to the teams of the various institutes of the region the possibilities to develop their research in biotherapy, in close interface with the clinical departments.

The criteria of success of the projects developed in IRB are:

An hospital implantation that permits the use of human cells and tissues, with all criteria of ethics, the high technology facilities for characterization, sorting, culture and modifications of these cells.

Fundamental research to understand the mechanisms of growth, of differentiation of these cells in the laboratories of the IRB, in close link with their institute / unit of origin.

Translational research to adapt these basic research to therapeutic use done in the CHU R& D laboratories of IRB.

A high-level insurance quality to secure the works of research, to facilitate the valorization and the transfer towards therapeutic applications. Valorization by the partners.

Industrial partnership permitting to develop the therapeutic applications, notably in the companies that are hosted in IRB.

Clinical expertise, notably with the Clinical Investigating Center approved by INSERM and CHU.

Mastering of production costs. A scientific and medical project will lead within 5-10 years to a therapeutic application and possibly to a marketable cellular product. The conception of the research must integrate this parameter cost from the beginning. Indeed some choices in fundamental research could be critical for the final cost of the cellular product.

Efficient communication between clinicians and basis scientist. Low hierarchical structures and encouragement for the development and establishment will lead to an effective scientific exchange. All scientists should be fluent in English to enhance the exchange of ideas. Rapidly advancing modern science demands flexibility, provision for novelty and charge and a laboratory design that also promotes synergy, cooperation and community.

Specific platforms will drive scientists to come together, to create the critical mass necessary for new discoveries.

Regular meetings (Journal Clubs, Method seminars, Research Seminars, Institute Seminars, and Group Meetings).

Secretary and ressource management available for all group at the IRB.

International office providing information and assistance to the incoming and expatriate IRB members. It helps new staff members to feel at home in Montpellier and to handle the wheels of bureaucracy, allowing them to concentrate on research issues.

These are the criteria of success that the organization and the direction of the IRB must guarantee through the selection of the topics and the teams, if we wish IRB to establish the IRB as an international center of excellence despite the very intense international competition.

To achieve this objective, IRB gathers in a same building of 2874 m2 INSERM fundamental research laboratories (6 laboratories, 870 m2), CHU research and development laboratories (4 laboratories, 876 m2), as well as private companies (5 laboratories, 470 m2). These different entities are gathered around common technical platforms with an area of 658 m2.

IRB is implanted on the hospital Saint-Eloi site of Montpellier CHU. It is localized close to the department for Clinical Hematology and Oncology, the unit for Cell and Gene Therapy, and the INSERM "Institute of Neurosciences" (120 people). IRB can host about 130 people.

Figure 1: Location of the Institute for Research in Biotherapy in the Saint Eloi site of Montpellier CHU.