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.

Allergic rhinitis (AR) is one the more prevalent respiratory allergic disease affecting 20-30% of the global population. The inflammatory process is mediated by eosinophil infiltration and IgE secreted by plasma cells. IgE is a key component in allergies so understanding IgE production and its inhibition is important for treating these diseases. Allergen immunotherapy (AIT) is the only treatment that targets the etiology of allergic diseases. However, the efficacy of the treatment reaches 70-80% in the best scenarios (lower for food allergy), it has a high cost, and most important, prediction of the effectiveness of the treatment is not possible with actual biomarkers. In this proposal the candidate seeks to better understand the phenotypes of B cells, key cells implicated in allergy that are modified with AIT. The knowledge generated by this study will provide biomarkers of AIT prognosis and even predict the outcome of the therapy by analyzing the B cell compartment in patients candidate for AIT. Using very innovative approaches, we will analyze the B cell repertoire involved in the resolution of AR through AIT. B cell repertoire will be analyzed in bulk before and after AIT. In addition, antigen specific B cells will be immortalized so the antibody sequence as well as reactivity can be studied. Moreover, we will perform an ex vivo class switch assay that could potentially predict the outcome of AIT using cytokine microenvironments like those produced by the therapy and or the pathogenic situations. B cell switching from IgD/M or IgG1 to IgG2/4 appears to be a critical step in the effectiveness in AIT because IgE memory resides in the IgG compartment. We will use AR to house dust mite patients as a model as it is one of the most prevalent allergic diseases.

Betalactams (BL) are the most widely used antibiotics and the first-choice drugs to control several bacterial infections, however, they can lead to serious allergic reactions in up to 10% of the general population. The current diagnosis of allergy to BL includes skin test and/or drug provocation tests, which are invasive and carry a risk of anaphylaxis requiring hospitalisation. Basophil activation test (BAT) is one of the best options for diagnosis of allergy because it is free of risk and at a reduced cost for health care. The ASSERT project will bring a nanotechnology-based BAT assay specific for allergy to BL with higher sensitivity and specificity, which are the main weakness of the current assays. Of importance, the number and conformation of displayed antigens at the nanoparticle surface will be controlled to assure standardisation and increase precision and reproducibility of the assay. In addition, a complete validation plan is envisaged to fit the standards for clinical diagnostics. The two factors for the success of the project are, one one hand, the solid experience of the host lab in immunology, specially allergy and nanoparticle technology and, on the other hand, the expertise of the candidate in immunology, molecular biology and test validation design for clinical diagnostics. Moreover, the the two way of transfer of knowledge is assured, which will help the candidate to restart her research career in the European Union. Finally, the expected results of the project will contribute to enlarge the basic knowledge about allergen-specific activation of basophils, and will give rise to an optimised BL-BAT assay with the required clinical and analytical validation to be used in diagnostics.

HR+/HER2- breast cancer (BC) patients often show limited response to current neoadjuvant chemotherapy, highlighting the critical need for alternative therapeutics strategies. The combination of CDK4/6 inhibitors (CDK4/6i) with endocrine therapy (ET) is the standard of care in adjuvant treatment for HR+/HER2- BC, with the potential for significantly improved outcomes in the neoadjuvant setting. However, drug resistance remains a significant challenge, with a critical need for early-stage biomarkers to predict resistance. The CARABELA phase 2 clinical trial, led by Dr. Emilio Alba (the supervisor of this proposal), provides valuable data on the efficacy and resistance patterns of prolonged CDK4/6i plus ET in neoadjuvant settings. Previous research by Dr. Chica-Parrado (the candidate) identified NF1 loss-of-function (LOF) mutations as key drivers of resistance to both ET and CDK4/6i. The CARABELA-NF1 study aims to leverage this expertise to integrate preclinical data with clinical insights from the CARABELA trial. The objectives of CARABELA-NF1 project are: (1) To perform targeted sequencing of circulating tumor DNA (ctDNA) to identify genomic alterations associated with resistance to CDK4/6i or ET and correlate these with clinical responses. (2) To develop an NF1-loss signature (NF1sig) from cell line data and validate this predictive signature using RNA from pre-treatment samples in the CARABELA trial. (3) To conduct drug screening in HR+/HER2- BC organoids derived from patients resistant to ET and CDK4/6i with NF1 mutations, focusing on the activation of pathways induced by the treatment. This project combines advanced genomic profiling with clinical trial data and drug screening to address the pressing need for effective biomarkers and novel therapeutic strategies in the neoadjuvant setting for HR+/HER2- BC.