IMMUNOSABR is geared towards opening up a new paradigm in treating metastatic cancer by obtaining clinical proof of concept for a novel bi-modal curative treatment strategy. High precision stereotactic ablative radiotherapy (SABR) is combined with immunotherapy to form a powerful synergistic anti-tumour strategy. The approach relies on the direct cytotoxic effect of SABR, the abscopal effect of radiation observed at distance from the irradiated metastatic site(s), and the effect of the tumour-specific immunocytokine L19-IL2 (watch our animation explaining the concept at https://youtu.be/6wDE6RkrikA). Palliative treatment is the current standard of care for patients with metastatic non small cell lung cancer (NSCLC), unless there is an actionable mutation. By using the concept of limited metastatic disease (≤10 sites, WHO 0-1: “oligo+”) we aim to develop a therapy with curative intent. IMMUNOSABR will gather evidence for the clinical efficacy of our bi-modal treatment strategy in a multicentre randomised phase II study (clinicaltrials.gov no. NCT02735850) in patients with limited metastatic NSCLC. IMMUNOSABR is complemented by two strong biomarker work packages which focus on developing an ambitious personalised biomarker strategy, to identify patients who can benefit from the novel treatment strategy. This includes promising non-invasive imaging techniques and state-of-the-art immunological monitoring approaches on tumour tissue and blood. IMMUNOSABR will spur further development of L19-IL2 as a commercial drug and translate the bi-modal treatment strategy towards clinical implementation.

In HT-ADVANCE we aim to revolutionise personalised management of arterial hypertension (HT) by using multi-omics (MOMICS) stratification biomarkers as companion diagnostics for the prescription of existing drugs. HT is the most important global risk factor for death and morbidity but is uncontrolled in more than 50% of patients. Causes of treatment failure include lack of identification of secondary forms such as endocrine hypertension (EHT) which can be curable by specific therapy. In addition, there is variable response to individual drugs and trial-and-error treatment leads to poor HT control and frustration for both patients and clinicians. The objective of HT-ADVANCE is to validate two multicomponent stratification biomarkers in patients with HT in order to i) identify patients with EHT, and ii) predict response to treatment in patients with primary hypertension. The hypothesis is that MOMICS biomarkers reflect specific forms of hypertension and susceptibility to specific drugs. To this end, we will run three clinical trials (HT-ENDO, HT-TREAT and HT-PREDICT) and apply machine learning techniques to integrate the genetic, genomic and metabolomic features that constitute the MOMICS biomarkers in order to generate accurate diagnostic and therapeutic response predictions for clinicians. We will also perform economic evaluation of the use of MOMICS for the treatment of HT, produce ethical and legal recommendations for clinical decision making, and develop a plan for their implementation as companion diagnostics. The study will be conducted by several HT Centres of Excellence and will build on the success of the ENSAT-HT project that has established methods and pipelines for integrating datasets derived from multiple platforms. We expect that HT-ADVANCE will provide a step change in the management of HT by enabling a personalised, more efficient and cost-effective treatment strategy, and importantly, will prevent the ensuing cardio-metabolic complications.

There is a very high need for improving the management of pain. Acute and persistent pain of different origins represent a common medical, social, and economic burden, and its pharmacotherapy is often inadequate. To advance management of pain patients and support decision making in clinical practice, more predictive assessments of treatment success are needed. The development of analgesics is onerous because promising preclinical data often do not translate into the clinic. Improved pharmacodynamic biomarkers could define whether nociceptive signalling is adequately modulated by a new drug, so increasing the chance of successful translation and greatly reducing the risk in initiating clinical development. Further, the pathophysiology of chronic pelvic pain indications is poorly understood and no adequate preclinical models are available, precluding focused preclinical research and leaving affected patients with little hope of relief. IMI-PainCare aims at making advances in these three pain areas in a complementary manner. Three subprojects will address specific scientific challenges. Subproject PROMPT will identify Patient Reported Outcome Measures as tools to standardise assessments of treatment success of acute and chronic pain in Real World conditions and controlled trials, and so improve its management; subproject BioPain will validate the translatability of pharmacodynamic biomarkers and PK-PD modelling in pain pathways of healthy subjects and preclinical species, thereby offering tools to improve drug development; subprojectTRiPP will identify biomarkers and novel therapeutic pathways of clinical phenotypes of patients with chronic pelvic pain, which after back-translation, can improve how preclinical models reflecting human diseases. The goal of IMI-PainCare is to improve the care of patients with acute or chronic pain by providing a toolbox to streamline the development process for novel analgesic drugs and to improve treatment quality in clinical practice.

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.

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.