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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - TRACE (Transfer of multivirus-specific T-cells following transplantation)

Teaser

Summary

\"The objective of the TRACE-Project (\"\"TRansfer of Adenovirus, Cytomegalovirus and Epstein-Barr-virus-specific T cells\"\") is to bring adoptive transfer of virus-specific T cells into clinical routine.

Allogeneic stem cell transplantation (HSCT) is a curative treatment for a variety of diseases. Refractory viral infections, such as Cytomegalovirus (CMV), Epstein-Barr-virus (EBV) and Adenovirus (AdV) post-HSCT are rare, life-threatening conditions due to the deficient T-cell response and lacking effective treatment options. Using T-cell immunotherapy will enable the host to protect himself instead of receiving toxic antiviral chemotherapy.

Although cellular immunotherapy is considered a major recent breakthrough in medicine, none of the cellular treatment approaches has yet become a standard treatment. The reason for this limited translation into daily clinical practice is the lack of controlled, prospective clinical trials investigating efficacy of immunotherapy.

TRACE is the first multi-national clinical trial to prove efficacy and safety of adoptive T-cell transfer in immune-compromized individuals. For the first time, this trial will show that a unique individualized immunotherapy could be included into evidence based clinical routine in rare diseases. Regulatory and structural hurdles will be overcome by standardized GMP-procedures. It will be a major milestone in the development of medicine and health economics to bring such a unique personalized treatment approach into a clinical efficacy trial.

Furthermore the generated data could be used for a potential prophylactic intervention, so in the future patients may be protected in an individualized way, even before the onset of infections.\"

Work performed

Within the TRACE project regulatory and logistic hurdles of inclusion into clinical routine will be overcome by standardized GMP-procedures: In the first reporting period, donor testing as well as IMP manufacturing including quality control have already been harmonized in order to guarantee proper inclusion of patients and to ensure equal and high quality of the IMP across all countries (Work package 1 â€“ Harmonization and validation of GMP-production). Approvals from the German national ethical review board and ethical review boards of Munich, Duesseldorf, Hannover, Tuebingen and Wuerzburg as well as national regulatory authority ABR in the Netherlands and national ethics committee CCMO in the Netherlands have already been received. The infrastructure for the clinical trial has already been set-up in terms of eCRF finalization, trial logistics, contact office, trial committees, Data Management Plan and security structure. (Work package 2 â€“ Set up of the clinical trial and Work package 7 â€“ Ethics Requirements)

To overcome the limitation of restriction to very few specialized centres, 23 centres in 5 European countries have already been successfully assessed by the CRO to participate in the TRACE study until end of the first reporting period. (Work package 3 - Conduct of the clinical trial)

Further the TRACE project will contribute evidence-based data on this new treatment option: In order to determine the efficacy of the virus-specific T-cell products to restore anti-viral immunity in immunocompromised patients after HSCT, SOPs and experimental plans for the analyses of the quality of the T-cell products as well as immune monitoring of the patients have already been prepared. (Work package 4 - Immune monitoring and accompanying research). For dissemination of know-how and technology beyond the consortium a publication about adoptive T-cell transfer of virus-specific T cells applied in the TRACE study has been published in a scientific, peer-reviewed journal and a press-release as well as a website have been launched. (Work package 5 â€“ Communication, dissemination and exploitation of results)

The Project Office at LMU ensured a proper overall progress of the project by setting up communication infrastructures within the consortium, monitoring project progress on a daily basis, taking over contractual and financial management, reporting to the European Commission and serving as helpdesk. (Work package 6 - Project management and communication)

Final results

Virus-specific T cells are a new curative treatment option for patients suffering from life-threatening viral infections such as AdV, EBV and CMV after allogeneic stem cell transplantation. Due to the promising previous results, the avoidance of antiviral pharmacotherapy side effects and the manufacturing procedure doing without genetic engineering, public acceptance of adoptive transfer of multivirus-specific T cells is high and without any ethical concerns.

For the individual patient the prognosis of viral infection after allogeneic stem cell transplantation will be improved, since a successful adoptive transfer of multivirus-specific T cells will lead to reduced in-patient days, reduced intensive care, reduced toxic antiviral medication, improved quality of life and improved survival. European patient health will benefit through a safe, curative and innovative individualized treatment option, that has not been available for the majority of eligible patients in the past. The reason for this limitation was the restriction to very few specialized centres due to regulatory and financial hurdles. The TRACE project will cover all eligible patients in the participating countries as long as they can be transferred to one of the treating centres.

Further the project will contribute evidence-based data on this new treatment to current treatment recommendations. Apart from the recovery from the underlying viral infection, the trial will contribute novel evidence-based data on other expected benefits such as reduced rate of new CMV, EBV or AdV infections/reactivations, reduced frequency of hospitalizations, reduced medication intake and a GvHD rate which is not increased compared to an untreated population. Already during the TRACE project, the knowledge will yet be disseminated through an open source policy, so that also centres of non-participating countries will be able to adapt the approach of adoptive T-cell transfer and provide this technology to their patient population.

The major objective of TRACE is to provide data, ethical and regulatory approvals and logistic infrastructure to build the basis for market authorization of the product â€œmultivirus-specific T cellsâ€ and thus bring adoptive transfer of virus-specific T cells into clinical routine.