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SIENA, Italy

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2013.2.4.1-2 | Award Amount: 7.78M | Year: 2013

T-cell engineering strategies for Cancer therapy, either Chimeric Antigen Receptors (CARs) or TCR transfer holds promise to revolutionize cancer treatment. There are, however, considerable barriers to be overcome to take this form of therapy to a format that can benefit all EU citizens with a wide range of common cancers. The aim of this consortium is to exploit advances in T-cell engineering to allow the full potential of CAR therapy to be unleashed. At present, CAR therapy requires a bespoke autologous therapeutic product for each patient. This greatly limits practicality, scalability and commercialisation. The development of a strategy for creation of universal engineered T-cells is the first key aim of this consortium. There is an increased appreciation of the immunological hostilities (CAR) T-cells face in the tumour microenvironment, and prevention of this local immune suppressive effect will likely be critical in permitting effective tumour control. The second main aim of this proposal is therefore to engineer CAR T-cells to be resistant to the hostile microenvironment. CAR T-cells can only be effective if they can access the tumour site. Exploiting the fact that neo-angiogenesis is a hallmark of neoplastic progression, the third aim of the consortium is to utilise endothelial cues of neo-angiogenesis to direct CAR T-cell migration and activity. The central technological theme of this consortium is the application of TALEN-mediated gene editing strategies alongside genetic modification with integrating vectors. Using this approach, we will implement a clinical study of universal CAR T-cells in refractory lymphoma. Further, this work will be complemented with highly focused development of T-cells which are resistant to hostile microenvironments and which can home to sites of neovascularization. The legacy this consortium wishes is commercialization of universal CAR therapy for a broad swathe of human cancers.

Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: HEALTH.2012.2.1.1-1-B | Award Amount: 15.82M | Year: 2012

EURenOmics will integrate several established consortia devoted to rare kidney diseases with eminent need and potential for diagnostic and therapeutic progress (i.e. steroid resistant nephrotic syndrome, membranous nephropathy, tubulopathies, complement disorders such a haemolytic uraemic syndrome, and congenital kidney malformations). The Consortium has access to the largest clinical cohorts assembled to date (collectively >10,000 patients) with detailed phenotypic information and comprehensive biorepositories containing DNA, blood, urine, amniotic fluid and kidney tissue. The project aims to (1) identify the genetic and epigenetic causes and modifiers of disease and their molecular pathways; (2) define a novel mechanistic disease ontology beyond phenotypical or morphological description; (3) develop innovative technologies allowing rapid diagnostic testing; (4) discover and validate biomarkers of disease activity, prognosis and treatment responses; and (5) develop in vitro and in vivo disease models and apply high-throughput compound library screening. For these purposes we will integrate comprehensive data sets from next generation exome and whole-genome sequencing, ChiP-sequencing, tissue transcriptome and antigen/epitope profiling, and miRNome, proteome/peptidome, and metabolome screening in different body fluids within and across conventional diagnostic categories. These data will be combined in a systems biology approach with high-resolution clinical phenotyping and findings obtained with a large array of established and novel in vitro, ex vivo and in vivo disease models (functiomics) to identify disease-associated genetic variants involved in monogenic or complex genetic transmission, disease-defining molecular signatures, and potential targets for therapeutic intervention. These efforts will converge in the development of innovative diagnostic tools and biomarkers and efficient screening strategies for novel therapeutic agents.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2012.2.1.2-1 | Award Amount: 3.88M | Year: 2012

Therapeutic antibodies are the largest and fastest growing class of pharmaceutical biotechnology products, with annual sales above 30 billion US$. In some cases, antibody products have revolutionized the management of patients, e.g. TNF-blocking antibodies in Arthritis or Rituxan in lymphoma. However, for most antibody therapies, only a subset of patients benefit from treatment. Thus, there is an urgent need to develop more potent therapeutic antibodies and to understand the molecular basis for the differential responses of patients to treatment. This consortium consists of European centres of excellence being pioneers in the field of therapeutic antibody development and (pre-) clinical studies and will tackle both of these challenges: Innovative immunocytokines L19-IL2 and F8-IL10 are developed by Philogen for the treatment of metastatic melanoma and rheumatoid arthritis respectively at multiple clinical centres including Graz and Tbingen. Building on the strong background in proteomics biomarker discovery of ETH Zurich and Philochem, an innovative methodology (HLA-peptidome analysis) will be utilized for gaining information on the immune response in animal models and patients which receive antibody treatments. This method is based on the observation that HLA molecules in complex with peptides can be detected in the patient blood and that hundreds of HLA-associated peptides can be sequenced by mass spectrometry. The technology will be used for the profiling of responses following antibody treatment for patients with cancer and rheumatoid arthritis, as well as animal models of transplant rejection. This systems biology approach has the potential to revolutionize patient stratification in very short time. Finally, patient selection strategies will be investigated using the clinical-grade immunocytokine (F8-IL10) as an example, monitoring antibody uptake at the site of disease by immuno-PET imaging methodologies at VUMC Amsterdam in collaboration with Philogen.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2011.2.4.1-1 | Award Amount: 7.43M | Year: 2012

Merkel cell carcinoma (MCC) is a highly aggressive, often lethal neuroendocrine cancer of the skin associated with the recently discovered, common Merkel cell polyomavirus (MCV). With an incidence of 0.44 per 100,000 MCC is a very rare cancer. Notably, however, although MCC is 40 times less common than malignant melanoma, MCC has a dramatically higher mortality rate than melanoma rendering MCC to the most lethal skin cancer (37 versus 15 percent). This high mortality rate is largely due to the fact that to date none of the currently available therapeutic interventions is able to improve overall survival of patients suffering from metastatic disease. Consequently, new therapeutic strategies are needed for metastatic MCC. Since several lines of evidence indicate the outstanding immunogenicity of MCC, immune modulating treatment strategies are particularly attractive. IMMOMEC is a 5-year project to establish and investigate an innovative and effective immunotherapy for MCC, thus directly responding to the aims of the topic HEALTH-2011.2.4.1-1 Investigator-driven treatment trials for rare cancers. IMMOMEC will develop a rational immune therapeutic approach for treatment of patients with MCC that is based on the targeted delivery of interleukin-2 to the tumor microenvironment. However, IMMOMEC will not only provide a new therapeutic option for MCC patients, but will also establish the relevance of immune modulating strategies to treat solid cancers in general, establish and validate new tools to monitor patients receiving such therapies as well as compile prognostic and predictive biomarkers to individualize immune modulating therapies. Moreover, IMMOMEC will introduce a new immune modulating therapeutic produced by a European SME, which also holds the intellectual property rights. Objectives of IMMOMEC: I. Establish an effective therapy for Merkel cell carcinoma evaluated in a multicentre randomized clinical phase II trial II. Establish the feasibility of effective immunotherapy for solid cancers III. Identification and characterization of HLA-restricted immunodominant T cell epitopes specific for MCC to monitor the immune modulating effect and to develop specific therapeutics IV. Identification of prognostic and predictive biomarkers, i.e. search for markers foretelling the course of disease or treatment response in MCC, respectively V. Establish a European network for research and therapy of MCC

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