Adoptive T cell therapies have revolutionised cancer treatment in some haematological tumours. Despite astounding advances, patients often relapse because the transferred T cells have low persistence and they lose their effector function against cancer cells. The prime challenge for improving T cell therapies is to decipher the mechanisms that define T cell effector function and memory formation. The MA6TCELL project aims to disentangle this problem by defining how m6A methylation on mRNA regulates human CD8 T cell differentiation and function. m6A is the most abundant mRNA methylation and determines gene expression by regulating mRNA metabolism, altering as such cell function. Using the miCLIP assay, I previously mapped genome-wide the m6A sites on the mRNAs of human CD8 T cells (unpublished data I will provide the host with). This map revealed that m6A occurs not only at the known DRACH sequences, but also at AU-rich sequences (AREs). Intriguingly, the host has uncovered that AREs are critical regulators of cytokine production in memory CD8 T cells (host expertise). My pilot experiments revealed that chemical inhibition of a m6A demethylase in CD8 T cells decreased cytokine production, further supporting my hypothesis that m6A methylation controls CD8 T cell differentiation and function. To test this hypothesis the M6ATCELL project will: 1) define the regulatory mechanisms of m6A methylation in human CD8 T cell differentiation and effector function and 2) test whether m6A enzyme inhibitors improve the potency of CD8 T cell therapies using chimeric antigen receptor (CAR) T cells. Our findings will yield fundamental insights in T cell biology, which can be relevant for multiple adoptive T cell therapies. My long-term aim is to transfer my scientific findings from bench-to-bedside. Thus, I also secured a placement at the European Medicines Agency and if this proposal is granted, I will be trained on the regulatory guidelines of medicinal T cell products.

Anaemia is the most common pathological condition affecting 1.6 billion individuals worldwide. It thus presents a serious health care problem and an economic burden. Reduction in red blood cell (RBC) number can be caused by blood loss, diet, stress conditions including endurance sport, and pathologies which are caused by primary genetic aberrations or are secondary to the malfunction of other cell types. Transfusion of RBC, which is often the only cure for severe cases of anaemia, is associated with risks such as thrombosis and transfusion reactions due to allo-immunisation. There is an unmet need to improve treatment of anaemia through early and accurate diagnosis, targeted treatment, and increased safety and effectiveness of RBC transfusion. The aim of RELEVANCE is to improve fast and cost-effective diagnosis of the underlying cause of primary anaemia, and to improve treatment options for both general and personalised medicine. We defined five key objectives: (1) to improve diagnostics of anaemia, particularly for hereditary rare forms of anaemia (RA); (2) to find novel treatments for anaemia that target RBC production, ageing and clearance; (3) to reduce premature loss of RBC following transfusion; (4) to produce cultured RBC for transfusion; (5) to monitor and optimise RBC function during sport and exercise. RELEVANCE will train 15 early stage researchers (ESR) at four SMEs and eight academic partners, two of whom are at blood supply centres and two are diagnostic centres for RA. The continuous interactions between the clinic, blood supply centers, basic research, and industry will select for the most relevant unmet medical needs, and will stimulate innovative procedures that are immediately probed for applicability and validity both in a research and a clinical setting. RELEVANCE will organize three open access summer schools, extending training beyond the ESR of the ITN sustaining the critical number of young talented professionals in the field.

Background Health systems face a time of unprecedented change, with spiraling costs, increasing cultural disparity in access to healthcare and research, and an infrastructure that is decades old. Today, telehealth is a realistic alternative making care and research more accessible and personalised with less burden to better support the most vulnerable and under-served in our society. The ability to test and monitor for illnesses using Patient Centric micro-Sampling (PCmS) is at the centre of this reform. Aim and main objectives This project is designed to build upon existing pilots and knowledge, then collaborate cross-sectorially to co-create and test the logistics, infrastructure and tools required to make PCmS a core healthcare tool and an acceptable alternative to venous blood-draw across Europe. This project aligns with many IHI’s objectives focusing on cross-sectorial collaboration, emphasizing patient and end-user- centric co-design of outputs, harmonised regulatory and data generation approaches enhancing the potential of digital innovations in healthcare, while aiming to reduce the environmental footprint during the project and in final outputs to ensure that the expected long-term impact is a reachable reality that will deliver significant benefit to the community and address unmet public health needs at scale. To achieve our objectives, we bring together a broad group of required expertise, know-how and end-users (i.e., public and patients) to form a public-private-partnership specifically equipped to tackle this challenge. This collaborative approach where the relevant stakeholders such as healthcare professionals, regulatory agencies and patients are involved and integrated to deliver solutions and innovation across healthcare systems and ensure the best chances for success and long-term positive impact from this project. Key deliverables include: 1) An optimized, tested and validated ‘Gold Standard’ infrastructure and workflow for PCmS across Europe as a proven and reliable alternative to venipuncture 2) Harmonised and clear regulatory and HTA pathways, standards and acceptability, measures and cost-benefit models across Europe 3) Documented evidence to draw a citable ‘line in the sand’ for future research to support decisions to integrate PCmS into decentralised trials and care pathways 4) Stakeholder engagement and patient involvement models and research on preferences and acceptability for PCmS 5) Foundation for future: Enable access to the developed PCmS scientific findings, tools and assessment measures for rapid uptake and integration of PCmS approaches into decentralised clinical studies and healthcare Expected impact: - Patient-centric microsampling becomes an accepted alternative to the current standard of care venipuncture and the data gathered can be leveraged in healthcare planning. - Lowered patient burden and lowered barrier to access in situations where blood samples need to be collected, whether as part of diagnosis, care plan, health monitoring etc. - A solution to leverage high amounts of data gathered from increased testing can be explored already in this project so that it can pave the way for future research that can improve health outcomes.

Coronavirus disease 19 (COVID-19) is provoking the greatest global health crisis of this generation. With no vaccine or specific antiviral treatment available to date, the use of convalescent plasma (CP) from recovered COVID-19 patients has been considered a potential curative strategy. To demonstrate its efficacy and safety, clinical studies are ongoing or planned in various EU Member States. Unfortunately, there lacks a coordinated approach involving a large number of blood establishments (BEs) and clinical centres to harmonise protocols and guidelines, to standardise assays for characterising the potency of the plasma and to validate clinical outcome which will be of great importance to ensure that significant conclusions can be drawn. SUPPORT-E brings together major European BEs with world leading research capabilities with the aim to support high quality clinical and scientific evaluation of COVID-19 CP (CCP) and thereby achieve a consensus on the appropriate use of CCP in the treatment of COVID-19 across EU Member States. Hence, SUPPORT-E will advance the current state-of-the-art by delivering the much needed harmonised evidence-based recommendations with respect to the use of CPP in clinical trials and monitored access programmes for COVID-19 patients in Europe. Further, standardised informative in vitro assays providing scientific insights that could support such recommendations will also be developed. SUPPORT-E offers an EU-wide collaboration between Member States, BEs and clinical centres in order to close the knowledge gap and to ensure applicability of the recommendations for all EU Members States. SUPPORT-E represents the first European Union coordinated research effort on passive immunotherapy, sharing data and protocols in real-time and pooling efforts to decrease the time as much as possible for validating CCP as a valid therapeutic treatment and also providing a basis for further optimisation by combined approaches with other anti-viral treatments.

The PROFILE Innovative European Industrial Doctoral programme will develop improved tools for stratification of patients with the autoimmune disorder acquired thrombotic thrombocytopenic purpura (TTP). Patient stratification is needed in order to further develop personalized medicine approaches for human disorders. Therefore, a detailed understanding of the disease at the molecular level is needed. Furthermore, implementation of a robust set of novel biomarkers is essential for stratification of patients. Also, highly flexible platforms to rapidly develop novel therapeutics are crucial to further boost the field of personalized medicine. The research program is embedded in a unique translational training program, which emphasizes clinical needs as a driving force for development of novel, innovative diagnostics and therapeutics (for personalized medicine). There is intersectoral knowledge transfer between academia and companies at the European level as 6 different EU Member states are involved in the network either as beneficiary or partner organization. The PROFILE network will allow 6 early stage researchers to follow this unique translational training. They will be trained in the clinic to identify clinical needs, in academia where they will contribute to a scientifically ambitious project and in the non-academic sector where they will be trained in a novel technologies and commercializing bioassays endowing them with an unique PROFILE for further advancing personalized medicine in Europe.