Phase I/IIA Trial Of Autologous Regulatory T Cell Therapy Together With Donor Bone Marrow Infusion In Kidney Transplantation

▪         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.

By - Eeshan Aggarwal

Reference: American Society of Nephrology. Presented at Kidney Week 2024.