PHASE I/IIA TRIAL OF AUTOLOGOUS REGULATORY T CELL THERAPY TOGETHER WITH DONOR BONE MARROW INFUSION

A groundbreaking phase I/IIa trial has demonstrated the safety and feasibility of combining autologous regulatory T cell (Treg) therapy with donor bone marrow infusion in HLA- mismatched living donor kidney transplant recipients. The approach, which eliminates the need for myelosuppressive conditioning, could pave the way for tolerance-based immunosuppressive strategies in transplantation.

Trial Design and Approach

The single-center, first-in-human trial enrolled 13 kidney transplant recipients with 12 treated according to the protocol. Patients in the study group received in vitro expanded polyclonal recipient Tregs and donor bone marrow cells within three days post-transplant, while a control group received standard immunosuppression (IS) without Tregs or bone marrow. Importantly, no irradiation or cytotoxic conditioning was used.

The IS regimen included thymoglobulin, belatacept, sirolimus and steroids, with sirolimus and steroids tapered off starting at six months in the study group. The primary endpoints were total leukocyte donor chimerism and safety. Immune monitoring, including next- generation sequencing (NGS) of T cell receptor (TCR) repertoires, flow cytometry and single-cell RNA sequencing, was conducted alongside protocol biopsies and transcriptomic analysis.

Early Results Show Encouraging Outcomes

The study group demonstrated low levels of total leukocyte donor chimerism, while no chimerism was detected in the control group. TCR repertoire analysis revealed clonal deletion of donor-specific T cells, indicating immune tolerance. Importantly, the therapy was well tolerated with no infusion-related adverse events reported.

Clinical outcomes in the study group were favorable, with glomerular filtration rates (GFRs) ranging from 33 to 99 ml/min/1.72m² at a median follow-up of 32 months. Immunosuppression reduction has been completed in three patients now maintained on belatacept monotherapy and is underway in others.

A New Horizon for Kidney Transplantation

This trial suggests that combining Treg therapy with donor bone marrow infusion is both safe and effective in inducing immune tolerance without the need for cytotoxic conditioning. The low-level chimerism achieved was sufficient to delete donor-specific T cells, potentially reducing the need for long-term immunosuppressive medications.

Further research, including ongoing transcriptomic analysis and immune monitoring is expected to refine and confirm these findings. If validated, this strategy could represent a major shift toward tolerance-driven approaches in kidney transplantation, offering patients improved outcomes and reduced dependency on lifelong immunosuppression.