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THE ONE STUDY Report Summary

Project ID: 260687
Funded under: FP7-HEALTH
Country: Germany

Periodic Report Summary 6 - THE ONE STUDY (A Unified Approach to Evaluating Cellular Immunotherapy in Solid Organ Transplantation)

Project Context and Objectives:
The success rates of transplant surgery have improved remarkably over the last half century, making this procedure a life-saving option for many patients with organ failure. Early outcomes in transplant recipients are outstanding and patients normally recover from surgery with a well-functioning replacement organ and typically return to an active lifestyle in a short period.

Unfortunately, transplant practice is complicated by the fact that the adult human immune system is strongly biased towards damaging reactions against allogeneic tissues, resulting in total donor organ destruction within a matter of weeks after transplantation, unless the immune system is profoundly inhibited. To impede the immunological response, researchers have developed an armamentarium of general immunosuppressive drugs necessary for sparing transplanted organs from early destruction. During the therapy with immunosuppressive drugs the whole immune system is impaired and a myriad of side-effects arise. Thus, patients maintained on conventional immunosuppressive treatment suffer the consequences of drug toxicity, the development of chronic rejection, reduced resistance to infections, and a high rate of cancer occurrence. Besides these important side effects, financial costs can be high for the families and for health care systems. Added to the reality of presently available treatment options is the fact that 10-year organ survival rates in renal transplantation have astonishingly not shown improvement over the last decades. Improvements in treatment for these patients is imperative.

The ONE Study Focus
Preventing immunological rejection of transplanted organs with less need for long-term use of pharmacological immunosuppression is a primary objective. New transplant research should concentrate on early strategies that support long-term immunological acceptance of transplants, allowing for at least a reduction in the use of general immunosuppression. It would dramatically improve the outcome for transplant recipients and reduce healthcare costs. A means to achieve this goal has not been realized with pharmacological or biological agents, so we must now look towards new, innovative approaches.

The ONE Study applies the novel concept of cell therapy to human clinical organ transplantation. This cooperative project aims at developing and trialling various immunoregulatory cell products in organ transplantation recipients, allowing a direct comparison of the safety, clinical practicality and therapeutic efficacy of each cell type.

The central focus of The ONE Study project is to:
▪ Produce and manufacture distinct population of haematopoietic immunoregulatory cells
▪ Comparatively study the tolerogenic characteristics of these regulatory cell types
▪ Test these cell therapy products side by side in a clinical trial of living donor renal transplant recipients
The health economics of cell therapy as a new medical technology is another essential aspect of The ONE Study work program that will be fully evaluated. True viability of the proposed new cellular treatments will depend not only on their clinical benefit, but also on an acceptable health-economics profile.

Project Results:
The principal objective of The ONE Study is to establish whether purified haematopoietic regulatory cells can be used therapeutically to modulate the immunological response of recipients of transplanted organs, thus reducing the level of pharmacological immunosuppression needed. To assess this, several regulatory cell products are to be licensed for manufacture under good manufacturing practice (GMP) conditions and will be tested in a coordinated clinical study. By directly evaluating the various immunoregulatory cell therapies against one another in this way, and also against a group of patients not receiving cell therapy, The ONE Study will lead to a clear conclusion as to whether further testing with each cell product is warranted. We have chosen to include in The ONE Study those cell preparations which, in our view, represent the most promising therapeutic agents and which are closest to clinical application: Regensburg (Tregs and Mregs), Charite-Berlin (Tregs), King's College-London (Tregs), Oxford (Tregs), UCSF (Tregs), MGH (Tregs), Milan (Tr1 cells), Nante (DCs). (WP1).
During the past six years of the project the main activities of the clinical centres involved in The ONE Study have been the preparation of the clinical protocols for the Reference Group Trial (RGT) and the Cell Therapy Group (CTG) trials, submission of IMPD (Investigational Medicinal Product Dossier) and IND (Investigational New Drug) to the regulatory agencies for the cell therapy trials, and the development of a centralized immune monitoring program. The RGT has been completed, the last follow-up visit occurred in December 2015. A tailored, very complex, eCRF system has been developed by a project beneficiary and collects data from the RGT and CTG trials. At the end of the sixth year of the project, after having obtained all the regulatory and ethical approvals for the trials, CTG trials have been initiated in the UK, Germany, USA and France and each trial centre has treated patients with cell therapy. Overall we have enrolled 57 patients and treated 35 with a cell infusion.
In Italy, full approval for the CTG is still pending.
Therefore, the group is moving towards the primary objective of the project.
Furthermore, an innovative cell tracking technology has been developed to assess where and for how long cells traffic when administered to humans. (WP2)
Another objective is to perform an in-depth comparative analysis of the different regulatory cell types to uncover both the common and unique mechanisms of their suppressive action. It will contribute to basic scientific knowledge and will allow the opportune evaluation of the true functional differences between alternative cell preparations. Based on present knowledge and the new knowledge we gain by our investigations, we will continue to design modified versions of cell products that have potential for use in organ transplantation. (WP 5, 6)

Potential Impact:
End-stage renal disease (ESRD) is a life-threatening condition for which kidney transplantation is the only curative treatment. Long-term treatment with immunosuppressive drugs, which is currently necessary after transplantation, results in severe toxic side effects, including chronic kidney graft failure, infections and cancer. The ONE Study aims to use cell-based therapies to reduce the need for these costly and toxic drugs. The novelty of this proposal is taking a haematopoietic cell therapy approach in humans to reduce the long-term need for pharmacological immunosuppression after organ transplantation. A direct comparison (feasibility, safety, cost and promise of effect) of different haematopoietic cell products will be made in a centralised clinical study in renal transplant recipients. Two critical components of The ONE Study are the focus on translating basic haematopoietic cell therapy research into clinical utility and extending our knowledge of the mechanisms by which different immunoregulatory cells work, so that cell therapy treatment can be adapted optimally for obtaining a clinical benefit. As a consequence, The ONE Study will also lead to the development of important, novel ancillary technologies for cell tracking and for immune monitoring.
The expected outcome of this comprehensive program is that the most promising haematopoietic cell therapy products will be tested in clinical trials on humans, with the expectation that cell therapy can ultimately reduce the need for immunosuppressive drugs in organ transplant recipients.
The age of patients with ESRD undergoing transplantation is steadily increasing. Particularly, in an ageing population, it is desirable to reduce the number of drugs prescribed. The ONE Study aims to do precisely this and, as a consequence is predicted to decrease healthcare costs. The annual cost of immunosuppressive drug therapy exceeds 10,000€/year; this sum does not include the costs of managing side-effects. Our health economics assessment team will carefully evaluate this important aspect of using cell therapy in organ transplant recipients.
As stated in the EU document on “Life sciences and biotechnology-A Strategy for Europe” there is a huge need in global health care for novel and innovative therapeutic approaches to human diseases. Therefore, there is a genuine need for networking within the European Scientific Community to facilitate open access to knowledge, skills and best practices, and to create a close community involved in life sciences and biotechnology. In response, the participants of this project have decided to join their efforts in conditioning the immune response of transplant recipients towards allograft acceptance using cell-based therapies. Reducing immunological rejection of transplanted organs with less need for long-term use of pharmacological immunosuppression would dramatically improve the outcome for transplant recipients and reduce healthcare costs. The European dimension of the project is an added value of the proposal, in terms of achieving the necessary critical mass and financial support. Expert research partners from the USA are involved into this consortium to add to this genuine global effort.
Due to the primary EU integrative nature of this proposal, The ONE Study is also expected to have a great impact in reinforcing competitiveness of European science. Furthermore, The ONE Study is intended to contribute to the strategic goal set in the EU's growth strategy for the coming decade, Europe 2020: in a changing world, EU must become a smart, sustainable and inclusive economy. The triangle of knowledge -education, research and innovation - is essential for achieving this goal.

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