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  • Periodic Reporting for period 2 - TREGeneration (Repair of tissue and organ damage in refractory chronic graft versus host disease after hematopoietic stem cell transplantation by the infusion of purified allogeneic donor regulatory T lymphocytes)

TREGeneration Report Summary

Project ID: 643776
Funded under: H2020-EU.3.1.

Periodic Reporting for period 2 - TREGeneration (Repair of tissue and organ damage in refractory chronic graft versus host disease after hematopoietic stem cell transplantation by the infusion of purified allogeneic donor regulatory T lymphocytes)

Reporting period: 2016-07-01 to 2017-12-31

Summary of the context and overall objectives of the project

"TREGeneration is a 5-year clinical research project funded by the European Commission's Horizon 2020 Framework Programme for Research and Innovation. The shared goal of our consortium is to treat tissue and organ damage associated with Graft versus Host Disease (GVHD), a serious complication following bone marrow transplantation.

GVHD is a life-threatening condition occurring when the donor’s immune cells ""attack"" the tissues of the patient (skin, internal organs and mucosa). This disease occurs in about 30 to 50% of patients undergoing bone marrow transplantation. Mortality is high in patients with intermediate to severe chronic forms of the disease and there is clearly an unmet need for novel treatment strategies.

TREGeneration aims to test a cell-based therapeutic approach, expected to result in fewer side effects than the pharmacological strategies currently available. In each of six parallel clinical trials, patients will be treated with a particular blood cell population obtained from the original bone marrow donor. These cells (regulatory T cells, Tregs) have the capacity to suppress immune responses mediating GVHD. The clinical trials are Phase I/II, aiming to i) identify the safe dose to be administered and ii) generate preliminary efficacy data.

The study encompasses the following overall objectives and goals:

1. Development of different Treg cell products from donors for infusion into patients with steroid-resistant acute and chronic GVHD.
2. Evaluation of the safety, toxicity and efficacy of infusing different populations of donor Tregs into patients.
3. Evaluation of the effect (and underlying biological mechanisms) of donor Treg infusion on tissue regeneration.
4. Evaluation of the effect of donor Treg infusion on the immune function of patients.
5. Tracking and profiling of specific blood cell subtypes in GVHD patients through development of advanced sequencing technology.

The TREGeneration consortium, coordinated by João Lacerda’s team at Instituto de Medicina Molecular in Lisbon, Portugal, brings together expertise from four further EU countries: Germany, Belgium, Italy and the UK, plus a third party based in Boston, USA. The clinical trials are independently run by each centre: João Lacerda leads the clinical trial at Hospital de Santa Maria in Lisbon; Matthias Edinger leads the trials at Universitaetsklinik in Regensburg, Germany; Frédéric Baron leads the trial at Laboratory of Cell and Gene Therapy, Sart-Tilman in Liège, Belgium; and Mario Arpinati leads the trial at the Department of Hematology “Seràgnoli”, University Hospital S. Orsola-Malpighi, Bologna, Italy. The consortium further includes Marie-Laure Yaspo’s team at the Max Planck Institute for Molecular Genetics, guided by Hans-Jörg Warnatz, and Hans Lehrach’s team from the SME Alacris Theranostics GmbH, both from Berlin, Germany. The data generated by the different clinical trials will be integrated by the statistical analysis performed by Marta García-Fiñana’s team from the Department of Biostatistics, Faculty of Health & Life Sciences, University of Liverpool, UK.

The results of the clinical interventions and laboratory studies being performed by the TREGeneration consortium have the potential to become a landmark in the field of Hematology and Stem Cell Transplantation, translating to improved patient care, quality of life and survival rate.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Within the first 36 months of the project we have met planned deliverables and milestones to achieve the following main results:

Clinical Trials - We have established and validated production of different donor Treg cell products at each manufacturing site. Following some necessary amendments, all Phase I/II trials on the treatment of chronic GVHD are fully approved and treating patients (Lisbon - 13 patients; Regensburg - 5 patients; Bologna - 3 patients; Liège - 1 patient). So far Treg infusions show no obvious toxicities and preliminary efficacy is now beginning to be evaluated. For consistent evaluation and subsequent statistical analysis, we have implemented harmonized case report forms and data records to capture patient data from all of our trials.

Immunological Monitoring - Our consortium has established workflows for centralized quantification of tissue damage biomarkers and immunological signatures in patient serum. We have also standardized our protocols and strategies for flow cytometry analysis between the centres to ensure consistency and transferability of our results. As all laboratory analyses are conducted on patient samples from the clinical trials we have also implemented a cross-trial sample collection monitoring system. Our novel high-throughput advanced sequencing and analysis pipeline is established and optimized, and we have begun profiling samples of infused products as well as recipients’ blood, over time. We have developed a complementary strategy to examine T cell receptor gene repertoires in depth.

Communication, Dissemination and Exploitation - We have project management and internal communication frameworks in place and have held three annual General Assemblies to facilitate internal communication, in addition to frequent smaller meetings. We have developed and implemented a Data Management Plan to keep track of consortium data generated at all levels. Our updated Dissemination Plan is in action and so far has resulted in press releases for every partner, development and use of the project logo, a LinkedIn social media presence, project poster and flyer and website (, all maintained by a dedicated team. During this period, partners have attended and presented the project and its progress so far at several scientific and medical society meetings and exhibitions, ensuring our consortium and its results reach the widest possible relevant audience.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Application of original donor-derived regulatory T-cells with an immune modulatory function has not been tested for treatment of chronic GVHD, and so has a clear potential impact on future alternative strategies to address this currently untreatable disease. By directly comparing results of the different trials our study aims to identify the most promising regenerative treatments to progress to Phase II/III clinical trials.

Aside from the novel clinical application of Tregs, we have also developed novel processes to manufacture these cells for infusion, which will be applicable beyond the scope of this project and may lead to new processes and methods being launched to the market. The multiplex analysis under development for evaluating markers of tissue damage is currently not commercially available and novel in depth sequencing studies will produce a level of output that we have not yet seen applied to clinical trials. Our scientific SME partner, Alacris, is currently developing new techniques with the first patient samples provided by the TREGeneration consortium to analyse in a platform that already filed a patent application.

As a consortium of European partners conducting ground-breaking regenerative medicine clinical trials with detailed laboratory follow-up studies, all the conditions are present to generate scientific outputs of the highest level. This will increase the visibility of European institutions and thus the attractiveness of Europe as a location to develop new therapies.

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