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Agency: GTR | Branch: MRC | Program: | Phase: Fellowship | Award Amount: 881.20K | Year: 2007

Cancers are not just a mass of malignant cells, but instead can be viewed as ‘rogue‘ tissues made up of many normal cells as well. Malignant cells use these normal cells to help them grow and spread. One normal cell type that is particularly common and abundant in tumours is the macrophage. Although macrophages, as part of the immune system, are capable of recognising and destroying tumour cells, in advanced cancer the malignant cells ‘corrupt‘ the macrophages, turning them into cells that actually promote instead of inhibiting the growth of the cancer. The aim of this project is to understand exactly how tumour cells corrupt macrophages and to find ways to switch these tumour macrophages from ‘bad‘ cells to ‘good‘. This work involves experiments of cells in dishes in the lab, in mouse models of cancer and in samples obtained from cancer patients. An intervention that switches ‘bad‘ macrophages in tumours into ‘good‘ cells may be a powerful way of helping a cancer patient‘s immune system attack their disease.

Agency: Cordis | Branch: H2020 | Program: RIA | Phase: NMP-06-2015 | Award Amount: 4.99M | Year: 2016

FOLSMART will bring to phase I clinical trials novel folate-based nanodevices (FBN) for the treatment of rheumatoid arthritis (RA). These nanodevices for folic acid (FA)-mediated targeting of activated macrophages showed improved clinical scores in a mouse model of RA when compared to methotrexate (MTX), a first-line drug therapy for the treatment of RA. In this way, FBN will be benchmarked against this drug. MTX has significant associated toxicity and second line biological therapies poses a great economic burden to hospital/public health systems. In parallel, nanodevices encapsulating Sulfasalazine (SSZ), will be tested. SSZ is a second line indication for the treatment of RA, unresponsive to MTX or MTXintolerant patients. Furthermore, FOLSMART propose the optimization of mechanisms for the release of the drugs, through pH and temperature sensitive nanodevices. An exploitation and business plans will be elaborated. In parallel, initial economic evaluation of all proposed treatments will be performed to validate these claims. Specific technological objectives of FOLSMART will be: Good Manufacturing Practice (GMP) production of the FBN based therapies which have been positively bench-marked in the previous FP7 European project NANOFOL in comparison with the use of MTX in a RA mouse model: -Liposomal MTX and SSZ with FA-neck domain peptide as targeting agent -Nanoparticles from HSA-FA/MTX conjugates and SSZ -Optimization of mechanisms of drug release and application to other fields Pre-clinical development on RA models -Toxicology and pharmacokinetics, to determine tolerability and efficacy benefit in two animal models rat and dog, under Good Laboratory Practice (GLP) standards -Genotoxicity and Carcinogenicity Phase I clinical trials of the best therapies bench marketed against MTX -Nanodevices with MTX and SSZ will offer improved tolerance and greater efficacy meaning that patients who do not do well on MTX will have cost-effective alternatives.

Agency: Cordis | Branch: FP7 | Program: BSG-SME | Phase: SME-1 | Award Amount: 1.48M | Year: 2008

The consortium has a lead series of p38 inhibitors with unusual anti-inflammatory properties. The drug leads were originally elaborated as a potential therapy for inflammatory bowel disease, however, the potency of the compounds and their general anti-inflammatory mode of action has raised the possibility of studying their utility in other diseases including rheumatoid arthritis. In addition, feedback from licensing partners has indicated that clear activity in a range of other disease models would dramatically increase interest. A key issue in bringing substances of this class to the clinic is variable patient response to p38 inhibitors in previous trials. Data to date have indicated that there is a potential groups of responders for whom therapy with this class is highly beneficial. The effect of non-responders has, however, made trial outcomes to variable to warrant further development. To solve this problem, we intend to further extend proof-of-concept in patient stratification to allow us to select responder populations for initial patient trials. The objectives of the project are, therefore: To prepare analogs of the existing compounds Conduct pre-clinical models for rheumatoid arthritis, IBD, sepsis, liver fibrosis and motilin dependent gut stimulation Examine the activity of the compounds in human tissue explant models Select a pre-clinical candidate class Develop a scaled-up process for GMP synthesis of the lead Conduct a survey of p38 expression in IBD and RA sub-types at various stages of disease and correlate this plasma markers. Based on results of tissue explant studies and p38 expression, select a patient stratification protocol for phase 2A studies in man.

Agency: Cordis | Branch: FP7 | Program: MC-ITN | Phase: FP7-PEOPLE-2012-ITN | Award Amount: 3.76M | Year: 2012

The ITN TIMCC brings together eight expert teams from different disciplines within Immunology, Genetics and Oncology, to provide substantive and methodological training in the analysis of the role of the Tumor Infiltrating Myeloid Cell Compartment (TIMCC) of the innate immune system. Leukocytes recruited to (pre)malignant tissues are mainly myeloid cells. They can either prevent or functionally contribute to cancer development. However, the mechanisms underlying pro- versus anti-tumor programming of neoplastic tissues by these immune cells remain obscure. The ITN TIMCC aims to improve anti-tumor therapy by defining general and tumor type specific molecular and cellular immunological pathways (e.g signal transduction and downstream effector pathways) in tumor development and during therapeutic intervention based on an extensive analysis of the infiltrating myeloid cell compartment in human tumor biopsies using a large variety of techniques and functional analysis of the corresponding models of a variety of human tumors, affecting different organs, in a unique cohort of genetically modified mice treated with different types of anti-tumor therapy. The program will train the appointed researchers in a variety of methodology and technology from genomic technologies and bioinformatics via genetically modified mice to the design and application of therapeutic strategies to understand and manipulate the many interactions of the myeloid cell compartment with developing tumors. By defining underlying molecular and cellular pathways new targets will be identified to be explored by the participating SMEs. The program will deliver young researchers equipped with a broad knowledge in immunology, genetics and oncology and insight in the complexity of translational medicine therefore better prepared to meet new challenges in the field.

Agency: Cordis | Branch: FP7 | Program: CP-IP | Phase: NMP-2008-4.0-1 | Award Amount: 6.64M | Year: 2009

NANOFOL proposes to develop a new diagnostic/therapy approach using folate based nanobiodevices (FBN) able to provide a new type of cost efficient treatment for chronic inflammatory diseases such as Atherosclerosis and Rheumatoid Arthritis with low side effects that will constitute a more advantageous solution than current therapies. NANOFOL will achieve all that by fulfilling the following objectives: Design , development and production of nanobiodevices (FBN) targeting directly effector cells Proof of concept in vitro and in vivo of a folate based nanodevice targeting activated macrophages in chronic inflammation not affecting bystander cells Proof of concept in vitro and in vivo of a nanodevice containing a bispecific antibody (against folate receptor and another macrophage marker) targeting activated macrophages in chronic inflammation not affecting bystander cells Proof of concept of FBN delivery therapeutic agents (by small interfering ribonucleic acid molecules (siRNA) or lipophylic molecules) targeting inflammatory signaling pathways In vitro and in vivo testing of cellular toxicity caused by the novel nanobiodevices in cells other than activated macrophages Design of models that will enable to minimize animal experimentation. Development of a strategy to assess potential risks in order to ensure nanobiodevice safe delivery. NANOFOL has adopted a specific risk strategy to attain objectives in a step by step approach allowing improving gradually the concept (specificity, stability, side effects efficacy) from the lower to the higher risky solutions ensuring reduced experimental animal testing and high human safety. The NANOFOL project will combine expertise in nanotechnologies, biology, chemistry, materials science, biotechnology, engineering, risk analysis, medical and pharmaceutical sciences.

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