Adoptive transfer of regulatory T cells (Treg) is a promising new therapeutic option to reshape undesired intra-tissue immune imbalance in immune-related disease entities. It supports long-term function of allografts and use of Advanced Therapy Medicinal Products (ATMP) by overcoming the challenge of unwanted immune reaction by the recipient of the ATMP. Therefore, adoptive Treg therapy is a potential game changer in health care, particularly in immune diseases, organ & hematopoietic stem cell (HSC) transplantation, and regenerative medicine, including gene therapy. Based on the Triple-T concept - Transdisciplinarity, Technology, Translation - the major goal of RESHAPE is to transform the treatment of patients suffering from undesired immunity/inflammation, who presently have limited curative treatment options, by applying novel Treg approaches that overcome the limitations of 1st generation Treg product developments. Members of the consortium, with academic & biotech backgrounds, are pioneers in the development of Treg therapy from basic science to very recent encouraging First-In-Human (FIH) clinical trials of the 1st generation Treg products. They have a longtrack record of collaboration, including in EC-funded projects. The first clinical trials were performed to combat organ transplant rejection and Graft-versus-Host-Disease. However, promising preclinical studies offer a broad application field of Treg therapy beyond allotransplantation. Based on our preclinical & clinical data, we have identified several opportunities for improving Treg therapy, such as enhanced antigen specificity & functional stability, and recipient conditioning, that will be addressed by RESHAPE. The next-generation Treg products, developed by advanced technologies including CRISPR/Cas9, will be tested on platforms applying new methods for cell characteristics in both in vivo /in vitro models, and finally proven in FIH-clinical trials accompanied by biomarker and health economic studies

Recently, a new class of “living drugs” has been developed – Advanced Therapies which aim to transform the current focus of “treatment of disease” into one that concentrates on “restoration of health” with promising results in a broad field of Regenerative Medicine, including targeted immune reconstitution for cancer treatment. Advanced Therapies are game changing in Health Care and have a rapidly expanding market size of approximately 12 and 50 bn € expected by 2020 and 2030, respectively. There is great value in European science and technology on Advanced Therapies but Europe has been losing ground because of scattered and underpowered efforts. If Europe wants a leading role in this emerging field in the future, a mission-driven approach is required to make the transforming promise of Advanced Therapies a reality. The development of new Advanced Therapy products and their implementation in clinical practice will enhance the value-based outcome of patients. Measurable by having dozens of premier-league Advanced Therapy Products “discovered & made in Europa” by 2030 and beyond. Bringing affordable, standard-of-care for currently incurable diseases which are accessible for every European citizen who need it to RESTORE Health. We propose a mission-driven programme led by the candidate LSRI RESTORE, aiming to build a coordinated, financially strong European partnership between different areas of interest and cross-sectors involving academia, industry, regulatory authorities, health care, patient organisations, and public society. In order to guarantee a smart start of the LSRI from 2021 onwards, the preparation phase aims to involve the growing RESTORE community even more closely in working groups on identified tasks and to jointly complete the RESTORE agenda for Research & Innovation Actions as well as Coordination & Support Actions. The deliverables of RESTORE will allow Europe to gain a world leading health position within this emerging field.

The European Consortium for Communicating Gene and Cell Therapy Information (EuroGCT) unites 49 partner organisations and institutions across Europe, including the major European advanced therapies learned societies, with the common goal of providing reliable and accessible information related to cell and gene therapy development to European stakeholders. EuroGCT has two major objectives: • To provide patients, people affected by conditions, healthcare professionals and citizens with accurate scientific, legal, ethical and societal information and with engagement opportunities, and thus to support better informed decision-making related to cell and gene-based therapies. • To facilitate better decision-making at key points in development of new therapies and thus enable improved product development, by providing the research community and regulatory and healthcare authorities with an information source on the practical steps needed for cell and gene therapy development. To achieve our aims, EuroGCT will adopt a highly structured system for coordinated management of information related to cell and gene therapy development and, from this, will implement an ambitious programme of online and direct stakeholder information provision and engagement. All outputs will be delivered in 7 European languages, to ensure broad accessibility, and will be rigorously evaluated against measurable objectives throughout the project duration. The proposed consortium comprises leading cell and gene therapy-related organisations and basic and clinical research labs across Europe, including new member states; together with experts in product development, ethical, legal and societal issues, and in evaluating clinical outcomes; patient representatives; and science communicators. It thus is uniquely placed to develop a world-leading cell and gene therapy information resource and to meet the challenge outlined in Topic SC1-HCO-19-2020.

CLINICAL PROBLEM AND UNMET NEED There are 11,827 patients with severe structural airway disease in Europe. Even with the current standard of care, when hospitalised this group of patients has a 22% risk of dying. Patients are currently subjected to repeated surgical interventions (stent insertion) which have a high failure rate. Other therapeutic strategies under development include synthetic tracheal scaffolds seeded with patients own stem cells. Preliminary data show that these scaffolds are poorly integrated and are susceptible to infection. TETRA PROJECT Our SME-led project will address the limitations of standard clinical care and competitor products under development and will: - Build on our successful compassionate use experience using autologous stem cell seeded scaffold-tracheal transplants in 48 patients - Follow on from our Phase I 4 patient INSPIRE clinical trial which will improve on the clinical prototype used in compassionate use cases - Conduct a 48 patient Phase II pivotal clinical trial to provide robust, quality data with validated GMP manufacturing processes to support an accelerated route to market for commercial exploitation in this orphan indication - Prepare a dossier for MAA submission BENEFITS Our product, an ATMP, aims to eliminate the need for repeated surgical interventions of high risk and limited efficacy, reduce deaths and improve the quality of life for surviving patients. If treating 20% of the patients with severe structural airway disease, we estimate that in Europe our technology will improve the quality and length of patient lives and result in savings of €517 million per year. We plan to further develop our platform technology to generate other complex tissues/organs such as bowel and liver replacements for clinical applications which will impact the lives of tens of thousands of patient in the EU with bowel and liver diseases.

AUTOSTEM will develop closed, scaleable and automated systems for therapeutic cell manufacture. The project vision is a donor-to-patient system where all aspects of processing, from tissue harvest to patient delivery are fully closed and aseptic. The process will involve new methods of biological cell selection from marrow, fat or other tissues, bioreactors to achieve scale and media formulations that are fully xeno-free. Process monitoring will utilise remote sensing and the automated retrieval of cells for microscopy, flow cytometry, karyotyping, differentiation or other tests. The final product will be a cryobag containing a specified cell dose, ready for thawing and clinical delivery. AUTOSTEM will be the factory of the future for therapeutic cell manufacturing. This system could ultimately be scaled for hospital-based use to produce autologous cells or at industrial scale for allogeneic therapy. It will achieve consistent cell production, minimise contamination, maximise scale and reduce cost of goods, thus enabling routine clinical use of cell therapies. The consortium will be a partnership of academic centres and industry with expertise across the disciplines relevant to the research and development goals. It will also include expertise in GMP and regulatory compliance and in healthcare economic analysis.