There is a high medical need for more individualized immunosuppression (IS), in particular for personalised IS minimization strategies, in order to improve the long-term outcome and consequently the health economy of transplantation.
Biomarkers are very useful and important tools to achieve this objective.
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 had been identified. Implementation of these biomarkers into the clinical routine requires multiple and cross platform tests, high quality standardization, multicenter clinical validation and an international network.
BIO-DrIM is a collaborative research project with academic and industrial partners from all over Europe fulfilling all these requirements.
The project results will increase efficiency of solid organ transplantation by the implementation of biomarker-driven strategies that will improve the long-term outcome and decrease the adverse effects and costs of chronic immunosuppression (IS) in solid organ transplant patients.
BIO-DriM aims at implementing biomarker-guided strategies for personalizing immunosuppression (IS). The concept includes 4 innovative investigator-driven biomarker clinical trials designed by the consortium with more than thousand patients.
The expected results of the of BIO-DrIM project are:
Targeted complete/partial weaning of standard IS in long-term stable liver and kidney transplanted patients identified as "operationally tolerant" by recently developed biomarker panels
Stratification into tolerant/non-tolerant patients for safe weaning
From clinical observations we learned that few patients (liver > kidney transplantation) can be completely weaned off immunosuppression by keeping stable graft function. This phenomenon is known as operationally tolerance. Until recently, however, it had been impossible to discriminate between recipients who could safely wean their drugs and those who could not (non operationally tolerant patients). The BIO-DrIM consortium will use recently established tolerance signature biomarker tests to identify operationally tolerant patients and to discriminate these patients from those with a negative tolerance signature (non operationally tolerant).
|Tolerance signature for guiding immunosuppression withdrawal|
Prevention of the high-dose standard IS in low-responder kidney transplant recipients identified by perioperative patient stratification
Stratification into low/high-responder patients for guided IS
The BIO-DrIM consortium will use the IFNg-ELISPOT to assess the anti-donor memory/effector T-cell arlloresponse in order to perioperatively stratify transplant patients into low and high responders.
Patients identified as high-responders will receive stand-of-care immunosuppression and patients identified as low-responders will be randomised 1:1 into two groups. They will be treated either by a standard of care immunosuppression regimen or by a “low” immunosuppression regimen.
|Biomarker-driven identification of patients for personalized IS|
Shifting high-responder into low-responder kidney transplant patients who might be suitable for early minimization by the recently explored selective targeting of alloreactive effector/memory T cells
Using tolerance/rejection biomarker monitoring as surrogate markers
The scientific community is pursuing the concept of minimizing long term immunosuppression “as much as feasible” and “as early as possible”. The presence of donor-specific memory/effector T cells limits safe long-term drug minimization. With a novel approach (induction regimen with rATG and infliximab), targeting these cells, the BIO-DrIM consortium aims at expanding the proportion of patients (low responders) that can be maintained on minimized immunosuppression.
Several biomarker analyses using different BIO-DrIM immune monitoring platforms are being planned to underline the expected results.
|Expansion of patient number suitable for early minimization of immunosuppression|
Implementing new biomarker candidates supporting personalized IS within the clinical trials
New biomarker candidates
In addition to the decision-making biomarkers for patient stratification, the BIO-DrIM consortium will analyze several parameters either in central core laboratories or in on-site laboratories in order to explore the values of further biomarkers for stratification, safety, monitoring of therapy response etc.
|Biomarker discovery and PoC analyses|
Analyzing the health-economic impact of biomarker-guided personalized IS
The BIO-DrIM consortium will perform health-economic analyzes to demonstrate the enhanced benefit/cost ratio of implementing biomarker-driven personalized IS into clinical routine.
|Interesting exploitable potential|
Studying the mechanisms behind successful weaning (regulation/effector balance)
Mechanisms behind weaning
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 the BIO-DrIM consortium will address the interaction between regulatory pathways (“good guys”) and donor-reactive memory/effector T cells (“bad guys”).
|Mechanisms of success versus failure of IS minimization|
Disseminating the results to scientific, patient and public community and developing commercialization strategies by partnering with SME/industry
Dissemination and commercialization
The BIO-DrIM consortium aims at contributing 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 broadly relevant also to other ancillary disciplines with important exploitable potential.
The early partnering of SME´s and diagnostic industry with experiences in the development and commercialization of In-Vitro Diagnostics (IVD) helps to implement standardized test procedures and will allow a fast translation of the results into biomarker product development. The embedding of professional health-economic studies into all the biomarker trials will deliver cost/benefit data that are useful for the discussions following with health insurances regarding reimbursement options.
The big pharma partner within the BIO-DrIM consortium supports the performance of challenging clinical trials.
|Translation from clinical research to the broad implementation into clinical practice|
The research and trials planned in BIO-DrIM are strongly translational. Starting from basic research (in vitro, preclinical models) and preliminary data from clinical pilot and PoC studies (RISET/IOT studies), our program is straight forward on the added values chain of product development. 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.