Periodic Reporting for period 5 - 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)
Okres sprawozdawczy: 2020-07-01 do 2021-12-31
TREGeneration is a clinical research consortium funded by the European Commission's Horizon 2020 Framework Programme for Research and Innovation. Our shared goal is to treat organ damage associated with Graft versus Host Disease (GVHD).
Hematopoietic Stem Cell Transplantation (HSCT) in the main curative treatment for many hematological malignancies. However, despite many advances in the field, GVHD remains a major hurdle to the success of such therapeutic approach. GVHD is a life-threatening condition occurring in about 30-50% of patients undergoing HSCT. GVHD occurs when the donor’s immune system reacts against the tissues of the patient, in an autoimmune-like phenomenon. Mortality is high in patients with intermediate to severe forms of the disease and there is clearly an unmet need for novel treatment strategies that reduce disease burden, with fewer side effects than current therapeutic approaches.
The TREGeneration project tested a cell-based therapeutic approach to treat GVHD in seven parallel Phase I/II clinical trials, where patients were treated with regulatory T cells (Treg), isolated from the blood of the original bone marrow donor. Treg are known to control autoimmunity and have the capacity to suppress immune responses. With these trials the consortium had the following aims:
i) identify the safe dose to be administered and
ii) generate preliminary efficacy data.
Overall, the study encompassed the following overall objectives:
1. Development of different Treg products for infusion into patients with steroid-refractory 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 lymphocytes in Treg-treated patients through 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, and Hans Lehrach’s team from the SME Alacris Theranostics GmbH, both from Berlin, Germany. The integrated statistical analysis of the data generated by the clinical trials will be performed by Marta García-Fiñana’s team at 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.
Hematopoietic Stem Cell Transplantation (HSCT) in the main curative treatment for many hematological malignancies. However, despite many advances in the field, GVHD remains a major hurdle to the success of such therapeutic approach. GVHD is a life-threatening condition occurring in about 30-50% of patients undergoing HSCT. GVHD occurs when the donor’s immune system reacts against the tissues of the patient, in an autoimmune-like phenomenon. Mortality is high in patients with intermediate to severe forms of the disease and there is clearly an unmet need for novel treatment strategies that reduce disease burden, with fewer side effects than current therapeutic approaches.
The TREGeneration project tested a cell-based therapeutic approach to treat GVHD in seven parallel Phase I/II clinical trials, where patients were treated with regulatory T cells (Treg), isolated from the blood of the original bone marrow donor. Treg are known to control autoimmunity and have the capacity to suppress immune responses. With these trials the consortium had the following aims:
i) identify the safe dose to be administered and
ii) generate preliminary efficacy data.
Overall, the study encompassed the following overall objectives:
1. Development of different Treg products for infusion into patients with steroid-refractory 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 lymphocytes in Treg-treated patients through 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, and Hans Lehrach’s team from the SME Alacris Theranostics GmbH, both from Berlin, Germany. The integrated statistical analysis of the data generated by the clinical trials will be performed by Marta García-Fiñana’s team at 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.
The TREGeneration project has met planned deliverables and milestones to achieve the following main results:
Clinical Trials - We established and validated production of different donor Treg cell products at each manufacturing site. The number of chronic GVHD patients treated with Treg in the Phase I/II trials has increased, as follows: Lisbon – 20 patients; Regensburg - 19 patients; Bologna – 9 patients; Liège – 1 patient; Seville –14 patients. Our project was severely impacted by the Sars-Cov2 pandemic which delayed inclusion of new patients and has led to the loss of some time-points in clinical and immune monitoring. The teams have worked to compensate such delays and setbacks.
Safety data has demonstrated that Treg infusions are not associated with any obvious toxicities and preliminary efficacy is being evaluated.
Immunological Monitoring - Our consortium has established workflows for centralized quantification of tissue damage biomarkers and immunological signatures in patient serum. Patient serum samples from all clinical trials have been tested iMM and the data sent to the team in Liverpool for analysis. We standardized protocols and strategies for flow cytometry analysis between the centres to ensure consistency and transferability of our results. Some patients remain under monitoring but preliminary data has been generated by the team in Liverpool. Patient samples from all trials were sent to the team at the Max-Plank for tracking analysis which is now close to completion.
Communication, Dissemination and Exploitation - We have project management and internal communication frameworks in place and have held annual General Assemblies, in addition to frequent smaller meetings. Despite the cancelation of in person meetings due to the Sars-Cov2 pandemic the consortium has met very frequently online. 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/). Throughout the project, all partners were involved in dissemination activities at scientific meetings, educational lectures in house and in external events.
Clinical Trials - We established and validated production of different donor Treg cell products at each manufacturing site. The number of chronic GVHD patients treated with Treg in the Phase I/II trials has increased, as follows: Lisbon – 20 patients; Regensburg - 19 patients; Bologna – 9 patients; Liège – 1 patient; Seville –14 patients. Our project was severely impacted by the Sars-Cov2 pandemic which delayed inclusion of new patients and has led to the loss of some time-points in clinical and immune monitoring. The teams have worked to compensate such delays and setbacks.
Safety data has demonstrated that Treg infusions are not associated with any obvious toxicities and preliminary efficacy is being evaluated.
Immunological Monitoring - Our consortium has established workflows for centralized quantification of tissue damage biomarkers and immunological signatures in patient serum. Patient serum samples from all clinical trials have been tested iMM and the data sent to the team in Liverpool for analysis. We standardized protocols and strategies for flow cytometry analysis between the centres to ensure consistency and transferability of our results. Some patients remain under monitoring but preliminary data has been generated by the team in Liverpool. Patient samples from all trials were sent to the team at the Max-Plank for tracking analysis which is now close to completion.
Communication, Dissemination and Exploitation - We have project management and internal communication frameworks in place and have held annual General Assemblies, in addition to frequent smaller meetings. Despite the cancelation of in person meetings due to the Sars-Cov2 pandemic the consortium has met very frequently online. 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/). Throughout the project, all partners were involved in dissemination activities at scientific meetings, educational lectures in house and in external events.
The use donor-derived Treg cells has not been tested for treatment of chronic GVHD. The success of this approach has the potential to impact on future alternative strategies to address this currently untreatable disease. By directly comparing results of the different clinical trials, which apply slightly different Treg infusion strategies, 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 successfully 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 developed. Patient samples, originating from all the clinical trials have been shipped and will be centrally analyzed at iMM-Lisboa. 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 patient samples in a platform that already filed a patent application.
As a consortium of European partners conducting groundbreaking 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
Aside from the novel clinical application of Treg cells, we have also successfully 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 developed. Patient samples, originating from all the clinical trials have been shipped and will be centrally analyzed at iMM-Lisboa. 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 patient samples in a platform that already filed a patent application.
As a consortium of European partners conducting groundbreaking 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