CD8+ Tregs immune landscape in kidney transplantation and First-in-human cell therapy – Eight-Treg

Kidney failure affects between 1.7 and 2.5 million people in France. After transplantation, pharmacological immunosuppression (IS) is mandatory for the prevention of acute rejection, but induces serious adverse effects and is not effective in preventing chronic rejection. The minimization of IS and the induction of active immune tolerance are therefore priority objectives.
Regulatory cell therapy has the potential to establish active donor-specific tolerance and wean off IS. We and others have reported extensive preclinical evidence for the role of CD8+ Tregs in graft tolerance and self-tolerance, safety and efficacy of autologous CD8+ Tregs cell therapy in rat as well as humanized mouse models. However, studies exploring their contribution in the context of transplantation in patients are limited and there have been no clinical trials using them as cell therapy to modulate immune responses. By refining at the single cell level, the phenotype, regulation/evolution post graft and localization of CD8+ Tregs as well as evaluating the potential of CD8+ Treg therapy in a clinical trial in renal transplant patients, we aim to respectively improve monitoring immune responses and to induce long-term active tolerance to the transplant as well as to reduce IS burden. Our program proposes the following tasks:
1) To explore the diversity of CD8+ Tregs in blood sample kinetics and in graft biopsies from kidney transplant patients on standard IS treatment using the latest single-cell resolution multiomics technologies, to better understand the identity and partners of CD8+ Tregs, identify new temporal biomarkers of transplant outcome for graft monitoring and possibly new targets for therapies.
2) To evaluate, in a first phase I/IIa clinical trial in humans, on clinical criteria, the safety and the indices of efficacy of an IV infusion of autologous expanded CD8+ Treg cells the day before the transplant, by replacement of standard induction IS, in living donor kidney transplant recipients, supported by standard maintenance IS with possible withdrawal at clinician's discretion. With already successfully implemented GMP manufacturing of CD8+ Tregs, we will submit the dossiers to the regulatory agencies to initiate the Eight-Treg clinical trial (DGOS funding requested).
3) To explore the efficacy endpoints of CD8+ Treg cell therapy associated with a standard maintenance IS by evaluating the modulation of allogeneic cellular and humoral immune responses in the blood and in the graft and the spread of tolerance through education of new cells. Besides, this task will deepen knowledge on the persistence of infused CD8+ Tregs, their migration to the graft and their mechanisms of action through in-depth immunomonitoring from before to 1 year after the transplant.
4) To assess the specific biological immune benefits of CD8+ Treg cell therapy versus standard treatment by comparing the transcriptomic profiles of donor reactive T cells and Tregs in patients treated with CD8+ Tregs or standard induction IS.
Defining the safe dose needed to benefit from Eight Treg therapy will advance research in both organ or cell transplantation and autoimmunity that have unmet medical needs. This project will make it possible to rule, for the first time, on the potential of CD8+ Tregs to control unwanted immunities/inflammations and wean off IS in the long term when used in preventive treatment. The results, along with patents we have already generated on CD8+ Treg, could be of interest to industries for the development of future CD8+ Treg therapies.
Patients could benefit from minimization of IS, which could reduce long-term AEs and therefore improve the longevity of their graft and their quality of life, avoiding rejection and costly and tedious dialysis period, as well as the cost of a new transplantation, and increase the number of available organs.