Report

Teaser, summary, work performed and final results

Periodic Reporting for period 3 - 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)

Teaser

\"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...

Summary

\"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. 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 lead to fewer side effects than the pharmacological strategies currently available. In each of seven parallel clinical trials, patients are being treated with a particular blood cell population obtained from the original bone marrow donor. These cells (regulatory T cells, Treg) 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 products for infusion into patients with steroid-resistant GVHD.
2. Evaluation of the safety, toxicity and efficacy of donor Treg infusion.
3. Evaluation of the effect of donor Treg infusion on tissue regeneration and immune function of patients.
5. Tracking of specific blood cell subtypes in GVHD patients through development of advanced sequencing technology.

The TREGeneration consortium, coordinated by the team of João Lacerda at IMM, Lisbon, Portugal, brings together expertise from five other EU countries: Germany, Belgium, Italy, Spain and the UK, plus a third-party based in Boston, USA. The clinical trials are independently run by each centre, led by:
- João Lacerda at IMM-Lisbon
- Matthias Edinger at UHREG-Regensburg
- Frédéric Baron at CHUST-Liège
- Mario Arpinati at Seràgnoli-Bologna
- José Antonio Pérez Simón at SAS-Seville.
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 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

The TREGeneration project has 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 an amendment process, a new partner joined the consortium in order to increase patient accrual. Prof. Pérez Simón’s team joined the consortium during the current reporting period and, as the other partners, has been including patients within the Phase I/II trials on the treatment of chronic GVHD (Lisbon – 16 patients; Regensburg - 14 patients; Bologna – 8 patients; Liège – 1 patient; Seville – 8 patients). Thus 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 centers 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. Patients are being monitored at all centers and the overall data will be analyzed once all trials have been completed. The clonotypes of infused Treg and Tcon are currently being analyzed, and the consortium expects to be able to clarify the issue of cell tracking in the treated patients.

Communication, Dissemination and Exploitation - We have project management and internal communication frameworks in place and have held five 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 has resulted in press releases from every partner, a project logo, a LinkedIn account, project poster, flyer and website (http://www.tregeneration.eu/). During this period, partners have attended and presented the project and its progress at several scientific and medical society meetings and exhibitions, ensuring our consortium and its results reach the widest possible relevant audience.

Final results

Application of original donor-derived Treg cells 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, which apply slightly different strategies for the treatment with Treg cells, our study aims to identify the most promising regenerative treatments to progress to Phase II/III clinical trials. This is a very novel treatment that is, for the first time, being tested in the setting of controlled clinical trials.

Aside from the novel clinical application of Treg cells, 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. A detailed multiplex analysis kit for evaluating markers of tissue damage, which was not commercially available, has been successfully developed and will be used in the very near future to analyse patient samples collected during the trial. The novel in-depth sequencing studies being performed with patient samples from our consortium 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.

In order to fully complete the actions proposed at the outset, TREGeneration has applied for an extension of its activities for another 18 months after December 2019.

Website & more info

More info: http://www.tregeneration.eu.