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Restoring tissue regeneration in patients with visceral Graft versus Host Disease.

Periodic Reporting for period 4 - RETHRIM (Restoring tissue regeneration in patients with visceral Graft versus Host Disease.)

Reporting period: 2019-07-01 to 2020-12-31

Allogeneic stem cell transplantation is a potentially curative treatment for a variety of haematological disorders. While offering the potential for cure, one of the major complications after transplantation is the occurrence of acute Graft-versus-Host Disease (aGvHD), which in its severe form (grade III-IV with organ involvement) caries a mortality risk of up to 75%. The consortium partners have been involved in a number of phase I/II trials that indicated that the use of third-party Mesenchymal Stromal Cells (MSC) might be an effective therapy for visceral (organ involvement) GvHD. However, no definitive proof of effectiveness through double-blind placebo controlled multicentre studies has been obtained. The current phase III clinical trial is aimed at setting a new standard for the treatment of visceral GvHD. MSC regenerative therapy will be employed to determine its potential to improve the rates of remission and overall survival and to improve quality of life.

The underlying hypothesis of the project is that outcome of MSC treatment is determined by the interplay between the MSC product and the inflammatory environment in the patient. To this end, patient samples obtained from the clinical trial and the MSC products produced to treat patients will be extensively studied to provide insight into the mechanisms of response to MSC therapy. Ideally this will provide insight for diagnostic and therapeutic development of MSC potency assays and biomarker assays to predict response to therapy.

In addition to the clinical trial, quality of life and health technology assessments will be performed as well as ethical studies regarding patient access to care. Output from these studies will allow the consortium to formulate a set of measures to convince health authorities, regulatory bodies and insurance companies on the usefulness of MSC therapy and provide suggestions and recommendations for changes in clinical practise, legislation and regulation of MSC regenerative therapy.

Within RETHRIM, clinical work is the central part of the project. The three main objectives are all closely linked to the clinical trial. In short the objective can be characterised as Treat, Design and Recommend:

- Objective 1, Treat patients to establish therapy effectiveness;
- Objective 2, Design potency signatures for MSC and biomarker assays to predict therapy outcome; -
- Objective 3, Provide recommendations to initiate changes in clinical practice and to allow the implementation of better regulatory requirements for regenerative therapies.
WP1, PROJECT MANAGEMENT: so far 10 TFT consortium meetings, 1 online consortium meeting and 20 teleconferences have been organised to discuss the progress of the project.

WP2, MSC PRODUCTION: All products for all patients that were included were manufactured. Reports on between centre comparability studies and between methods comparability studies were finalised and MSC products were analysed using transcriptional analysis for homo/heterogeneity.

WP3, CLINICAL TRIAL, a total of 42 patients have been included. The study was terminated due to slow accrual and a foreseen failure to include enough patients to achieve statistical significant results.

WP4, IMMUNOLOGICAL PROFILE DEVELOPMENT: Patient samples were analysed combining a powerful antibody and sequencing based pipeline with statistical analysis that enables identification of plasma protein and mRNA targets that allow distinction between groups of patients.

WP5, QUALITY OF LIFE, uses data obtained in the clinical trial. For this a number of assessment forms is used and the specific order in which these forms are handed to the patients has been established. Now that the study has been terminated and some personnel is deblinded, the data of the patients that have been included can be analysed.

WP6, HEALTH TECHNOLOGY ASSESSMENT, studies the cost effectiveness of using MSC therapy for the treatment of Graft versus Host Disease. A conceptual model was generated and published. Now that the study has been terminated and some personnel is deblinded, the data of the patients that have been included can be analysed.

WP7, ETHICAL ISSUES. In this reporting period an empirical study on ethical aspects of randomised placebo-controlled double blind trials in the setting of GvHD with the use of ATMP was supposed to be finalised but due to Covid this has been delayed.

WP8, COMMUNICATION, DISSEMINATION AND EXPLOITATION: A file and data sharing platform has been created, a website is up and running and 3 EU-MSC2 meetings assembling all consortia working on MSC therapy have been organised. Little dissemination at scientific meetings has taken place due to covid travel restrictions.
The overall ambition of the project was to set a new standard for the treatment of severe and steroid resistant acute GvHD following allogeneic stem cell transplantation, thereby improving the rates of remission and overall survival and improving quality of life. Within the consortium clinical centres collaborate with diagnostic and biomarker companies, to identify a signature of biomarkers that will help to predict response enabling the selection of only those patients that benefit from the treatment. These studies may be considered as part of a pre-commercial development and will allow our partners from biotech to further commercialise these diagnostic tools. Next to performing the clinical trial and providing signature profiles for commercialisation, the consortium will provide recommendation to competent authorities and demonstrate the cost effectiveness of MSC regenerative therapy for GvHD to be able to provide a convincing health management plan to policy makers and health insurance companies. Finally, we aim to facilitate future clinical trials involving cellular therapies by identifying the legal and ethical hurdles involved in obtaining Europe-wide ethical approval. We equally aim to contribute to the ongoing ethical debates by investigating the conditions that would justify withholding a potential successful treatment benefit in randomized placebo controlled trials, in particular in cases where the benefit of the potentially successful experimental treatment amounts to potentially life-saving therapy and where the efficacy of the existing "best proven" therapy is poor and by examining the criteria for (non)involvement of children in such trials.
RETHRIM work package integration