Liver cancer in the paediatric population is rare with an incidence approximately 1-1.5 per million population. The commonest tumour seen in the childhood population is hepatoblastoma (HB), usually seen in young children and infants. Much rarer (about 10% of paediatric liver cancers) is hepatocellular carcinoma (HCC), usually seen in the teenage population and sometimes associated with underlying cirrhotic liver diseases. The ChiLTERN project relates to topic PHC 18 ‘establishing effectiveness of health care interventions in the paediatric population’. The ChiLTERN project builds on a unique opportunity to undertake a comprehensive research programme linked to an ambitious global partnership which will see the single largest clinical trial (the Paediatric Hepatic International Tumour Trial - PHITT) ever undertaken in this population of patients, with several randomised questions in six subgroups of patients. ChiLTERN will allow us to move towards an era of personalised therapy in which each patient will receive the correct amount of chemotherapy and will undergo has the best surgical operation (surgical resection or liver transplant). By using both clinical and biological information, we can assign patients more accurately to risk groups based on their survival. Using genetic tests and biomarkers, we will determine those children who may be at risk of developing long term side effects (deafness, heart failure, kidney damage). In addition, biomarkers will allow us to monitor during therapy and detect toxicities early before serious damage is done so that we can adapt treatment and prevent these problems. Finally, we will be using imaging technology tools which will help our surgeons plan liver operations more safely and effectively. Ultimately ChiLTERN will allow us to cure more children with liver cancer, expose fewer children to toxic chemotherapy and ensure their surgery is both effective and safe.

TIGER delivers proof of principle (PoP) in humans for a novel best-in-class therapeutic mRNA cancer vaccine platform optimized for intravenous (IV) administration, with the aim to show clinical benefit. The antigens used for the PoP consists of mRNAs encoding the proteins E6 and E7 of Human Papilloma Virus strain 16 (HPV16), and TriMix mRNAs that act as adjuvant to stimulate dendritic cells to start strong T cell responses. The mRNAs will be formulated in a novel patented lipid nanoparticle shielding the mRNA, and delivering it to immunoactive antigen presenting cells, vastly enhancing T-cell response. Safety and potent efficacy of our IV mRNA product have been demonstrated in rodent experiments. Furthermore, preclinical to clinical translation has been shown for our TriMix based vaccines using different delivery strategies. Based on the preclinical and prior clinical data, our platform has the potential to cure cancer patients. The PoP study will be in patients with recurrent HPV16 positive cancer, which is categorised as a non-communicable disease by the WHO, without and with a PD-1 checkpoint inhibitor. Safety, immunogenicity and clinical benefit will be key endpoints of the study. Biomarker and PROM research will allow future informed therapeutic and care decisions by both patient and care team. Recruitment and stratification plans will be in place. Interactions with regulatory, reimbursement and ethical authorities together with patients and carers will help laying out the route to the patient not only for our product but also for all other mRNA cancer vaccines. The project encompasses essential elements for preparing therapy validation in later stage clinical studies, while addressing patient needs, values and choices. Upscaling of GMP-production for IV mRNA vaccines will enable further clinical studies. Once validated, our platform will be easily translatable to a wide range of cancers using other tumour antigens, be they TSA, TAA or neoantigens.

Sepsis is defined as a systemic inflammatory response to infection, while severe sepsis (SS) is a sepsis complicated by acute organ dysfunction. Lung infections, in particular community-acquire pneumonia (CAP), are the leading cause of SS. The pathophysiologic mechanism of CAP-mediated SS is the complete dysregulation of the patient´s immune system. In an initial phase, the systemic hyperactivation of the host immune response against infection leads to high levels of inflammatory mediators, systemic vasodilatation, micro-vascular thrombosis and organ failure. In a second phase, the exaggerated activation of the immune response leads to a state of ‘immunoparalysis’, which is characterized by the occurrence of secondary, opportunistic infections. This makes CAP-mediated SS a life-threatening condition with mortality rates as high as 28-50%. The current standard of care (infection removal and control, functional support) does not improve the high mortality and, thus, CAP-mediated SS represents a major unmet medical need with a huge social burden. Therefore, treatments with the potential to modulate both the initial exacerbated immunoactivation and the subsequent immunosuppression are needed. Mesenchymal stem cells (MSCs), including adipose mesenchymal stem cells (ASCs), are known for their broad range of immunomodulatory properties, targeting multiple pro- and anti-inflammatory pathways, and possess antimicrobial capacities (releasing bactericidal peptides and promoting the phagocytosis by immune cells). Indeed, therapeutic benefit of MSC treatment in in vivo experimental models of sepsis has been extensively reported. The SEPCELL consortium believes that cell therapy with allogeneic ASCs may be an innovative therapeutic approach in order to re-establish the normal immune homeostasis of CAP-mediated SS patients, reducing organ injury and restoring organ functionality. A phase Ia/IIb clinical trial will be performed to test this possibility.

The ARTEMIs project aims to consolidate existing computational mechanistic and machine-learning models at different scales to deliver ‘virtual twins’ embedded in a clinical decision support system (CDSS). The CDSS will provide clinically meaningful information to clinicians, for a more personalised management of the whole spectrum of Metabolic Associated Fatty Liver Disease (MAFLD). MAFLD, with an estimated prevalence of about 25%, goes from an undetected sleeping disease, to inflammation (hepatitis), to fibrosis development (cirrhosis) and/or hepatocellular carcinoma (HCC), decompensated cirrhosis and HCC being the final stages of the disease. However, many MAFLD patients do not die from the liver disease itself, but from cardiovascular comorbidities or complications. The ARTEMIs will contribute to the earlier management of MAFLD patients, by prognosing the development of more advanced forms of the disease and cardiovascular comorbidities, promoting active surveillance of patients at risk. The system will predict the impact of novel drug treatments or procedures, or simply better life habits. The system will therefore not only serve as a clinical decision aid tool, but also as an educational tool for patients, to promote better nutritional and lifestyle behaviors. In more advanced forms of the disease, therapeutic interventions include TIPPS to manage portal hypertension, partial hepatectomy, partial or complete liver transplant. ARTEMIs will contribute to predict per- or post-intervention heart failure, building on existing microcirculation hemodynamics models. The model developers will benefit from a large distributed patient cohort and data exploration environment to identify patterns in data, draw new theories on the liver-heart metabolic axis and validate the performance of their models. The project includes a proof-of-concept feasibility study assessing the utility of the integrated virtual twins and CDSS in the clinical context.

The objective of the SPCCT project is to develop and validate a widely accessible, new quantitative and analytical in vivo imaging technology combining Spectral Photon Counting CT and contrast agents, to accurately and early detect, characterize and monitor neurovascular and cardiovascular disease. Spectral Photon Counting Computed Tomography (SPCCT) is a new imaging modality, currently in development, with a totally new type of detection chain designed to provide high count-rate capabilities while offering energy discrimination with high spatial resolution of 200µm. Based on this discrimination, SPCCT can detect and quantify accurately a large variety of atoms (including Gadolinium, Gold, Bismuth…) by using the K-edge technique. SPCCT, by a more accurate, less invasive (in comparison with IVUS and coronary angiography) and reliable evaluation of vascular inflammation will allow earlier disease diagnosis such as plaque inflammation before rupture, leading to improved clinical decisions and outcomes. This will be achievable with a high spatial resolution combined to the newly developed vascular inflammation specific contrast agent detected with high quality K-edge technique that can only be provided by a multi-spectral X-ray system. The project will therefore provide a complete tool (acquisition system and specific probes) dedicated to CV imaging. It will finally contribute to: Improved early diagnosis of atherosclerosis, prevention of acute event (MI, stroke) and personalized preventive treatment; Improved management of patient presenting with an acute CV event and clinical validation of treatment efficiency; Sustainability and harmonization of healthcare systems, as costly disorders of heart failure and stroke-related disability would be better prevented and efficiently treated; Economic growth in the EU diagnostics sector, through the development of new targeted contrast materials for SPCCT by SMEs.