The ONE Study

Introduction
The short-term success rates of transplant surgery have improved remarkably over the past few decades. Early outcomes in transplant recipients are quite good and patients typically return to an active lifestyle after transplantation. With this short-term success, however, the long-term survival of transplanted organs has been rather disappointing and has not progressively improved with the introduction of new immunosuppressive drugs.
To prevent organ rejection in transplant recipients, patients must take potent medication on a daily basis that suppresses the body’s immune system. While this medication reduces the immune response to the donor organ, thereby protecting it, it also suppresses normal immune reactions to challenges by bacteria, viruses and cancer cells, leading to a high risk of developing infections and cancer. In addition, these immunosuppressive drugs often cause undesirable side effects for the patient such as high blood pressure, diabetes, problems with metabolism, kidney damage, and so on. Moreover, immunosuppressive drugs incompletely protect the transplanted organ from rejection, resulting in a chronic loss of organ function. These combined factors have led to serious problems that jeopardize organ and patient survival after around 10 years.
Besides these important health issues for the transplant patient, financial costs are a significant burden for the families and health care systems. It is estimated that the annual cost of immunosuppressive drug therapy exceeds 10,000€/year, and this sum does not include the high costs of managing side-effects.
Taken together, current experiences in organ transplantation indicate a clear need for improving treatment options, especially with the aim of minimising chronic immunosuppressive drug use. The scientific community and national scientific funding agencies are searching for innovative approaches to address this problem.
Project focus
The ONE Study aims to use cell-based therapies to reduce the long-term need for costly and toxic immunosuppressive drugs in renal transplant recipients, by inducing a self-sustaining immune regulation that protects allografts from destruction.
Conditioning the immune response of solid organ transplant recipients towards allograft acceptance using cell-based therapies is now becoming technically feasible and clinically promising. The central focus of this proposed cooperative project is to manufacture distinct populations of regulatory cells, to study the tolerogenic characteristics of these regulatory cell types and to comparatively test their safety and efficacy in minimising pharmacological immunosuppression in solid organ transplantation 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.
Objectives and expected results
1) A first objective of The ONE Study cooperative project is to develop and manufacture distinct populations of immunoregulatory cells for the purpose of cell therapy in transplantation.
Internationally active research groups devoted to cell therapy applications have been assembled to participate in this critical part of the study. Their task is to develop a GMP compliant manufacturing procedure for the immunoregulatory cell population they believe will be useful in organ transplant recipients. At present, regulatory T cell populations, tolerogenic dendritic cells and regulatory macrophages are planned for development into cell products.
2) A second objective, which is the main objective, is to perform a side-by-side comparison of these different cell therapy product treatments in a clinical trial of living-donor renal transplant recipients. This trial will assess the safety of each cell product and provide a first assessment of their comparative potential for reducing long-term immunosuppressive drug therapy.
In addition, knowing the fate of immunoregulatory cells in the recipient after administration is important to understanding their mechanisms of action. As part of The ONE Study project, an innovative approach to tracking of regulatory cells will be pursued by labeling manufactured cell products with combinations of rare earth metals which can be tracked in blood and biopsy material using laser ablation-inductively coupled plasma mass spectrometry.
3) The third objective of The ONE Study is to learn more about the comparative characteristics of suppressive cell types and to assess their tolerogenic capacity and potential for clinical translation.
Groups producing cell therapy products will use the latest technology at experimental workshops to compare the suppressive characteristics of their cell populations. The questions to be answered include whether the cell products share mechanistic activities and whether these activities could potentially be synergistic in a combined cell therapy approach.
Impact
The most important impact of this research project is reducing the need for immunosuppressive drug therapy in organ transplant recipients, thereby significantly improving their survival and quality of life, while at the same time decreasing health care costs. Secondarily, if successful, the results of The ONE Study could be applied to recipients of other organ transplants (liver, heart, etc.) and could add more broadly towards treatment options for immunologically mediated diseases (e.g. multiple sclerosis, inflammatory bowel disorders).
Novelty
The novelty of this proposal is taking a cell therapy approach in humans to reduce the long-term need for pharmacological immunosuppression after organ transplantation. A second area of novelty is the integrative design of this programme, whereby a direct comparison (feasibility, safety, cost and promise of effect) of different cell products is made using a common (ONE) clinical trial protocol design in renal transplant recipients. Thirdly, The ONE Study will lead to the development of important, novel ancillary technologies (GMP-FACS sorting and cell tracking) needed for cell-based therapy in general.
The expected outcome of this comprehensive programme is that the most promising cell therapy products for further clinical trial testing and commercial exploitation will be identified, with the expectation that cell therapy can ultimately reduce the need for immunosuppressive drugs in organ transplant recipients.

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