Cell and gene therapies offer a massive paradigm shift from current treatment options and hold the potential to cure previously untreatable diseases. Naturally-occurring and genetically modified T cells with chimeric antigen (CAR) or T cell receptors (TCR) have demonstrated remarkable curative capacities against advanced hematologic malignancies but have shown limited efficacy in treating solid tumors. Major barriers hindering the full antitumor potential of T cells are the immunosuppressive signals and persisting antigenic stimuli within the tumor microenvironment that inexorably push T cells into a highly dysfunctional state called “exhaustion”. Herein, we propose a groundbreaking technology, T-FITNESS, which will enable antitumor T cells to become refractory to exhaustion. At the core of the platform are microRNA (miRNA)-based synthetic logic circuits capable of rewiring the transcriptional networks orchestrating T cell exhaustion. By harnessing the power of CRISPR/Cas genome editing, we will integrate sensors of miRNAs upregulated in exhausted cells into untranslated regions of one or more transcription factors driving T cell exhaustion, to enable their fine-tuned downregulation. We will validate the reprogramming efficacy of T-FITNESS by performing extensive functional analyses in vitro and in vivo and advance the best circuits towards the clinic by developing an automated cGMP-compliant manufacturing process for point-of-care production of T-FITNESS-edited CAR-T cells. To develop this innovative platform, we will bring together a multidisciplinary consortium of academic and industry partners that combine their unique expertise in T cell therapy and immunology, synthetic biology, genome editing, cGMP manufacturing, bioinformatics, and communication. Easily integrable within CAR-T, TCR-T, and tumor-infiltrating lymphocyte (TIL) platforms, T-FITNESS will unleash the curative potential of T cell therapy for the benefit of an ever-growing number of cancer patients.

To strengthen EU's ability to fight DENV and WNV epidemic and pandemic threats and elaborate effective emergency plans. The project is based on three pillars: 1) clinical investigation of host factors related to severe disease, 2) therapeutic development (i.e. host-viral protein binding inhibitors) and 3) One-Health-based surveillance of the infections. Open science practices will guarantee quality, efficiency of the research and maximise the impact of the project. The declaration of interest in the InFlaMe project of a company, world leader in the field, supports the thrustable of the network and the impact of the project’s expected outcomes. The project’s tasks will proactively be addressed in 7 sounding work packages and will go beyond the state-of-the-art. The partners have outstanding experience in all the aspects of the project, collaborated previously and working together on emerging flaviviral infections. The team includes Fondazione IRCCS Policlinico San Matteo as coordinator (IT; Fausto Baldanti), the National Institute of Molecular Genetics (IT; Renata Grifantini, Antonio Lanzavecchia and Raffaele De Francesco), Pasteur Institute (FR; Jouvenet Nolween), CIC Biogune Institute (ES; Jesus Jimenos-Barberez and Nicola Abrescia), University of Florence (IT; Cristina Nativi), Centro Nazionale per le Ricerche (IT; Giovanni Maga and Paolo Mazzetti ), Istituto Zooprofilattico Sperimentale della Lombardia e dell’Emilia Romagna (IT; Ana Maria Moreno Martin), IMAGINE Institute (FR; Jean Laurent Casanova and Shen-Ying Zhang,), University of Vienna (AT; Judith Aberle and Karin Stiasny) and University of Masaryk (Daniel Ruzek). This truly complementary and collaborating network has a robust know-how in diagnosis of flaviviruses in humans and animals, on host-pathogen interaction and drug discovery.

Despite novel treatment options and development of diagnostic tools invasive fungal infections (IFI) are still associated with an unacceptably high mortality and morbidity. Experts believe that a host directed approach is needed to overcome this problem. HDM-FUN proposes a transdisciplinary approach to identify host-pathogen factors (HPFs) needed for host directed medical interventions in IFI and will be the first of its kind. The overall concept is to identify host-pathogen factors in the setting of immunotherapy and prophylaxis that will allow the design for tailored novel therapeutic and preventive host-directed medicine approaches for patients with lethal invasive fungal infection in the intensive care. Specific objectives: 1. To identify host-pathogen factors that correlate with disease, and correlate them with preventive or immunotherapy- based strategies to stratify patients for personalized host-directed treatment options. 2. Two clinical trials of host-directed medicine approaches; an immunotherapy trial in patients with candidemia and a prospective observational trial for prophylaxis in patients with influenza at risk for aspergillosis. 3. To set-up a centrally managed biobank with samples of the patients enrolled in both clinical trials, and to standardize experimental procedures, protocols and centralize analysis. 4. To establish a unique infrastructure aimed to: explore host-directed medicine approaches in IFI, evaluate their impact on patients and health care, translate research efforts to clinical practice by designing point of care tests and teaching medical professionals. HDM-FUN brings together top scientists and clinical researchers to unravel host factors (genetics and transcription), immune modulators (metabolome, microbiome), and host pathogen interactions (genetics, metabolomics, immunology, signalling pathways, phagosome biogenesis, and inflammasome regulation) that determine the susceptibility and outcome of patients with fungal infection.

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.

There is an increasing prevalence of chronic diseases caused by undesired immune reactions (>10%) with high burden for the both patients (chronicity, organ failure, early death, decreased QoL) and society (EU:>100 bn €/a direct health costs) as current therapies are limited in efficacy and do not reshape sustainably the disturbed immune balance. Our ultimative goal is to develop a safe and efficient cell therapy based on genome-edited T cells with redirected specificity to sustainably combat IgA nephropathy (IgAN) - the most common glomerulonephritis and one of the most common causes of end-stage renal disease with unmet medical need. Our specific cell therapy approach is also suitable for other diseases with selective B-cell pathogenesis, such as IgA myeloma, IgA related celiac disease and rheumatoid arthritis, but as a blueprint also for diseases of other Ig classes (e.g. IgG4). Our novel concept offers a specific form of immunosuppression via Ig-(sub)class targeting & glycosylation targeting with redirected T cells in autoimmune diseases. Methodically, we benchmark three promising genome editing technologies, develop new standards for safety assessment and preclinical performance evaluation. At the end we will have a lead candidate of a new "living drug" product envisioned as a one-time treatment for IgAN and other IgA-associated that will be ready to enter clinical FIH trials (entry into TRL6). In addition, geneTIGA delivers enabling technology toolboxes with exploitation options beyond of the core project. They might de-risk and accelerate the development of next-generation gene and cell products in general. The project has thus, besides its scientific value, a high impact not only on the affected patients with IgAN and related immune diseases, but also for the European society by reducing the health economic burden caused by progressive chronic kidney disease, as well as by triggering innovation and business options in Europe's biotech and pharma field.