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  • Periodic Report Summary 3 - BIO-DRIM (Personalized minimization of immunosuppression after solid organ transplantation by biomarker-driven stratification of patients to improve long-term outcome and health-economic data of transplantation)

Periodic Report Summary 3 - BIO-DRIM (Personalized minimization of immunosuppression after solid organ transplantation by biomarker-driven stratification of patients to improve long-term outcome and health-economic data of transplantation)

Project Context and Objectives:
The central focus of the BIO-DrIM project is the implementation of biomarker-driven strategies for personalizing immunosuppression (IS) in order to improve the long-term outcome and to decrease the adverse effects (graft toxicity, diabetes, cardiovascular events, opportunistic and community acquired infections, bone loss, and malignancies) and costs of chronic IS in solid organ transplant patients. The mission of the BIO-DrIM reflects the new strategy in the field of solid organ transplantation: leaving the path of one-size-fits-all weaning strategies and administration of new drugs in favour to a more personalized approach.

The biomarker-guided management of immunosuppressive therapy is an ambitious program that started time ago with other projects (IOT and RISET) in which a set of promising biomarkers was identified and developed, but the methodical validation was missing. Implementation of these biomarkers into the clinical routine requires multiple cross platform tests, high quality standardization, multicenter clinical validation and with this an international network. All these requirements meet up in the BIO-DrIM project, that includes 5 innovative clinical trials (~2.000 patients in screening phase and ~800 patients enrolled in trials).

More in detail, the BIO-DrIM project addresses several highly innovative issues:
- First IS withdrawal study in long-term liver transplant patients based on the presence of a molecular tolerance signature (personalized withdrawal –study 1);
- Two novel trials on systematic partial IS withdrawal in selected highly stable long-term kidney transplant patients for validation of decision making biomarkers to detect operationally tolerant patients (personalized withdrawal- studies 2+3);
- First controlled biomarker-driven perioperative stratification of kidney transplant patients into low/high responders to prevent high-dose standard IS in low responders (personalized minimizing IS –study 4)
- Novel approach to target selectively activated (allospecific) memory/effector T cells (to increase the proportion of low responders after kidney transplantation suitable for low-dose monotherapy – validation by biomarkers –study 5
Safety is a key issue of the clinical trials: all studies are performed according to the international rules and all drugs are used according to their applications.
In addition to the well-validated set-1 biomarkers used for decision-making, all trials are accompanied by a panel of standardized biomarkers (set-2a) and a panel of exploratory biomarkers (set-2b):
i) to further improve the predictive value of the biomarkers for patient stratification
ii) to learn more about the mechanisms behind success/failure of IS minimizing.
Gaining knowledge about the mechanisms behind successful weaning (regulation/effector balance) is also part of the project. Well-defined in vitro and experimental mouse/rat transplant studies will be used to address questions regarding the mechanisms of success/failure of IS minimizing. In particular, the scientists within BIO-DrIM will address the interaction between regulatory pathways and donor-reactive memory/effector T cells.
The research and trials planned in BIO-DrIM are strongly translational. The involvement of SME´s and pharmaceutical industry guarantees a fast commercialization of promising product candidates.
Furthermore, health-economic studies will push forward the translation into products used at the market as reimbursement strategies can be early developed and discussed with the health insurance companies and the government authorities.

Project Results:
Set-up and validation of all tests of the biomarker panel and establishment of the ELISpot technique as stratification tool in a prospective trial.
Technical advice and equipment were provided and installed by Beckman Coulter - Immunotech and GenID at the clinical sites of six European countries. More precisely, 8-color Navios cytometers were provided by Beckman Coulter - Immunotech to the clinical sites of Berlin, Nantes, London, Barcelona, Prague, Amsterdam, Regensburg and Hamburg, and 10 ELISpot Readers were installed by Gen-ID at each local laboratory in the clinical sites of Berlin, Barcelona, London, Amsterdam, Regensburg, Hamburg, Prague, Nantes, plus Santander and Oviedo. Establishment at the local sites took place by extensive technology transfer, combined with training sessions and technical support.

Preparation of five multicenter clinical studies.
LIFT Study (WP1a; biomarker-based weaning of liver transplant patients): 148 patients to be recruited at 11 European clinical sites. All regulatory approvals are in place in all 4 countries, all 11 sites are opened and most have started recruitment. An electronic Case Report Form was created and this has been functioning well. A minimisation algorithm is implemented for treatment group assignment.
At the moment, there are 109 consented patients, which are or have undergone screening, and 50 of them have been randomised. Recruitment rate is now within target, but due the delay in initiating the trial and opening some of the sites, there are plans for extending the enrolment period until 2018.

WEANING trial (WP1b; weaning of long-term stable kidney transplant patients):
The fully blinded WEANING trial, coordinated by ITUN (Nantes), had to be stopped after a very difficult restart when approved for further continuation. The results of the WEANING Study were published (Dugast et al. AJT 2016).

GAMBIT study (WP1c):
We selected 9 genes, showing no material difference in performance to the best-performing signature comprising 19 of the original 28 genes, previously identified by KCL. The results of our studies were published in December 2016 (PMID: 27328267). However, there is still an ongoing debate in the kidney transplant community on the safety of the clinical application of biomarkers of tolerance. Therefore, proceeding with the originally planned Study III design, as a safety and feasibility pilot Phase II trial for initiating IS minimization in patients who score ‘tolerant’, would have been unethical at this stage, without extensive further validation.

CELLIMIN trial (WP2; Prospective donor-specific cellular alloresponse assessment for Immunosuppression minimization in de novo renal transplantationtrial using a biomarker as stratificator for IS). The CELLIMIN trial has been approved by the Voluntary-Harmonization Process (VHP). CELLIMIN is a non-inferiority trial with enrichment design aiming to demonstrate the utility of the IFN-γ ELISpot marker for the stratification of kidney transplant recipients into “low” and “standard-of-care” IS regimen. All clinical sites participated in extensive lab and interlab comparision to validate the robustness and correctness of the IFN-γ ELISpot assay, the biomarker used as stratification tool.
115 patients have been screened with pre-transplant donor-specific IFN-γ ELISpot. 76 (66%) have been negative and randomized.

RIMINI trial (WP3, Tacrolimus after rATG and infliximab induction immunosuppression).
RIMINI is an international multicenter open-label single-arm Simon’s two-stage Phase II clinical trial aiming to estimate confidence interval for the observed efficacy of the induction regimen with rATG and infliximab and a go/no go rule for further clinical development. A total of 75 patients will receive the proposed induction regimen, accounting for a drop-out rate of 10%.
Using tolerance/rejection biomarker monitoring we aim to prove shift from high responders to low responders while using infliximab as co-induction agent to target recently activated memory/effector T cells.
The initiation meeting was held in Berlin, on November 15th 2016. Enrolment into the RIMINI trial started in January 2017 and the termination of the recruitment is expected by December 2017. Up to date, 12 patients have been enrolled.

Set up of human skin graft in humanized mice based on the protocol developed by the team of K. Wood.
In this model, we compared the administration of fresh versus frozen human PBMCs. We also continued to develop and use our model of accelerated heart rejection in rats. Preliminary experiments have been performed to establish the efficacy of new therapeutics in this model.

The last major achievement of BIO-DrIM is the involvement of big pharma company TEVA in the consortium. In October 2014 an agreement with TEVA was signed for supporting the BIO-DrIM consortium. It is the 1st time that a big pharma contributes to personalized IS studies.

Dissemination activities were also implemented, even if the major focus for the moment was the setup of the clinical studies and enrolment of patients.

Potential Impact:
The focus of BIO-DrIM is to contribute to an improved and cost-effective long-term outcome of solid organ transplantation by implementing decision-making biomarkers into the clinical management of transplant patients (personalized IS) but the results will be more broadly relevant also to other ancillary disciplines and have very important exploitable potential. At this aim, three research performing SMEs and two big companies are involved in the project with very deep commitment.
Despite the progress in short-term organ transplant survival, long-term graft and patient survival remain almost unchanged and unsatisfactory. Our data suggest that about 10-15 % of stable long-term kidney transplant patients express the full or partial tolerance signature suggesting opportunities for (partial) weaning. Additionally, even in any stable drug-free transplant patient, rejection can be suddenly triggered by immune activation, such as infection, even after years. Thus, there is a high unmet need for well validated biomarkers helping to identify operationally tolerant transplant patients and to monitor the stability of this situation. Low responders, requiring low-dose IS from beginning, exist already early after transplantation. To identify low responder patients to avoid unnecessary high-dose IS would have major advantage for this subset of patients. Based on our preliminary work we will address this topic by switching from “one-size-fits-all” IS to a stratified IS peri-transplant. Moreover, donor-specific memory/effector T cells were identified as the “bad guys” making transplant recipients to high-responders and preventing safe early IS minimization. To target selectively these cells resulting in a switch from high to low responder state would allow early IS minimization in a much higher population. This would have a major impact on costs and adverse effects in the majority of transplant recipients. IS in transplant patients has an EU/US market of about 3 Bill. €/a – personalized IS protocols have a big chance to dominate the IS market; and to expand to the huge autoimmunity market.
The most important impact of this proposal is the personalization of immunosuppressive therapy in organ transplant recipients, thereby significantly improving their survival and quality of life, while at the same time decreasing health care costs. Secondarily, the results of BIO-DrIM will broadly impact the treatment of other diseases related to undesired immune reactions, such as autoimmune diseases and graft-versus-host disease after hematopoetic stem cell transplantation. In addition, it might have also impact on the new field of cell transplantation (e.g. adult differentiated cells, like hepatocytes; but also allogeneic stem-cell derived cell products); in other words diseases with chronic or repetitive IS treatment.
The novelty of this proposal is the stratification of transplanted patients regarding their individual immunological responsiveness to the allograft and their respective individual need of IS. A second area of novelty is the integrative design of this program, whereby a direct comparison (feasibility, safety, cost and promise of effect) of biomarker driven strategies for personalized therapies is foreseen in 5 innovative investigator-driven biomarker clinical trials designed by the consortium with >2147/805 patients screened/enrolled, respectively (liver and kidney transplant patients) These outputs have a strong potential for further commercial exploitation, with the expectation that personalized therapy can ultimately optimize the need for immunosuppressive drugs in organ transplant recipients.

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