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Improving HSCT By Validation Of Biomarkers & Development Of Novel Cellular Therapies

Final Report Summary - CELLEUROPE (Improving HSCT By Validation Of Biomarkers & Development Of Novel Cellular Therapies)

The main curative therapy for leukaemia and other blood disorders is haematopoietic stem cell transplantation (HSCT). However, life threatening complications hamper the success of this therapy. Graft versus Host Disease (GvHD) is a life-threatening complication which occurs when the transplant donor's immune system reacts against the patient’s tissue causing damage to the gastrointestinal tract (GI tract), liver, skin, and lungs. GvHD can also be difficult to diagnose, with the early symptoms being similar to viral infection.
The CELLEUROPE Project aimed to improve the understanding of GvHD and allow training for both clinical and non-clinical scientists

CELLEUROPE delivered a four year training programme to nine Early Stage Researchers, of whom seven completed post-graduate degrees (PhD) and four Experienced Researchers, including scientific workshops, secondments to academic and industry and international conferences. The training focused on expertise in molecular biology, animal studies, cell biology, clinical application and immunology and generated 12 research projects covering the topics of Predictive Biomarkers, Assessment of Biomarkers, Graft versus Leukaemia, Animal Models, Novel Therapies and Cellular Therapies.

The CELLEUROPE team was a cohesive group of researchers and SMEs committed to advancing knowledge of GvHD. Led by Professor Anne Dickinson (Newcastle University), the team included specialists in their respective areas.
The project was supported by six Associate Partners from Industry who provided training and development opportunities specific to the work programme. The Associate Partners included the European for Blood and Marrow Transplantation (EBMT) Education Committee, who gave opportunities to disseminate project results to an international audience; the Centre for Process Innovation (CPI), who gave expertise in the exploitation and dissemination of project results and collaborated in the business development workshop; the Helmholz Zentrum Munich, who gave training and clinical expertise in haematopoietic stem cell transplantation (HSCT); AptaIT gave training and expertise in Bioinformatics and analysis and NewGene Ltd gave support and expertise in Next Generation Sequencing.
The overall aim of CELLEUROPE centred on providing more of an insight into the mechanisms of action of GvHD and its counterpart , the beneficial Graft versus Leukaemia effect of donor cells, in order to improve current therapies and develop and test novel diagnostics via clinical trials and/or animal model experiments.
The project aimed to:
•Investigate the immunopathology and genomics of graft versus host disease (GvHD) and Graft versus leukaemia (GvL) effect (where in coming transplanted donor cells help to eradicate residual leukaemia) in order to discover new drugs/diagnostics and novel targets for therapy.
•Validate novel targets on relevant target tissues and during clinical trials.
•Develop novel therapies in the context of legal and regulatory issues.
•Exploit the results via patentable technologies via industrial partners.
•Strengthen European collaborations and increase European competitiveness by bringing together collaborative research groups from industry, academia, clinical and scientific fields to develop a unique training network of value to partners and ESRs/ERs.
•Promote the implementation of cellular therapy under current Good Manufacturing Practice (cGMP) and under the EU Directive 2001/83/EC that regulates such activities.
•Understand the mode of action of cellular therapies in order to improve their efficacy in the future via partners and outreach.
All Work packages were carried out as planned, or with agreed modifications, and culminated in 7 PhD thesis, 49 publications and 52 presentations at conferences, as well as a special edition journal e-book in Frontiers of Immunology. CELLEUROPE delivered 13 training workshops and a final conference as well as 8 chapters in an e-journal in Frontiers of Immunology which is being completed. All ESR’s contributed to the e-journal and gained complementary as well as new scientific skills throughout the project. The main results from their work is summarised in the next section.
Main Achievements- The following summarises some of the published research:
•CELLEUROPE has validated and identified novel biomarkers, assessed their validity in large patient groups and has advanced the state of the art with regard to understanding the mechanisms of GvHD. Published work from the partner in Hannover (Borcher at al, 2014) describes the ability to monitor virus specific T cells in the peripheral blood of transplant patients, enabling the detection of early virus and monitoring the anti-viral response to T cell therapy. Similarly, our partners in Munich (Gehrmann et al, 2014) have published on an important biomarker (heat shock protein 70) for monitoring tumour and leukaemia cell detection after radio therapy.
•A risk score has been developed for survival using SNP analysis. Published papers Balavarca Y et al, 2015 and Pearce KF et al, 2016.
•B cell biomarkers were developed and validated for monitoring GvHD and response to therapy (extracorporeal photo therapy).Kralj Juric et al, 2016.
•Novel studies on MSC and exosomes as new biomarkers and potential for therapy have been developed. Paper in press Reis M et al, MSC derived extracellular vesicles modulate DC function and migratory potential.
•The safety of anti-viral T cell therapy using in vitro techniques, using a novel skin explant assay, has been demonstrated. Qesari et al, 2016.
•A critical mass of researchers have been trained in crucial transferable skills e.g. cGMP necessary to integrate with academia and industry for use in other clinical fields, including regenerative medicine and cellular therapy.
•The project delivered unique training in translational medicine such as cGMP for the development of advanced medicinal therapy products (AMTPs)

•The project strengthened European collaborations and increased European competitiveness by bringing together collaborative research groups from industry, academia, clinical and scientific fields to develop a unique training network of value to partners and ESRs/ERs.

The work of CELLEUROPE has enabled further understanding of “Acute GvHD”, which is difficult to diagnose and for which few biomarkers exist to monitor the disease, and its transition to the more complex disease state of “Chronic GvHD”. Diagnostic criteria to distinguish between acute and chronic GvHD has not yet been accomplished and the project results has enabled a new application for a Marie Curie Innovative Training Network to further the understanding and prevention of chronic GvHD. Prevention would allow clinicians to tailor therapy to an individual patient, encourage a curative graft versus leukaemia (GvL) response and improve outcomes, including transplant survival rates and long term complications. In addition, the consortium has applied for a COST project to aid in dissemination, exploitation and research development. The overall aim of delivering a strategy for improving clinical outcome in HSCT patients will give rise to reduced health care costs and patient quality of life. Improved biomarker analysis has enabled the clinical teams to use the results to aid in diagnosis, as well as monitoring response to therapy, which will be translated for patient benefit and improved health care.
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