Kidney Week

Abstract: TH-PO1175

Phase I/IIa Trial of Autologous Regulatory T Cell Therapy Together with Donor Bone Marrow Infusion in Kidney Transplantation

Session Information

• Late-Breaking Science Posters
  October 24, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Transplantation

• 2102 Transplantation: Clinical

Authors

• Oberbauer, Rainer, Medizinische Universitat Wien, Vienna, Vienna, Austria

Rainer Oberbauer, MD, PhD, FASN

• Muckenhuber, Moritz, Medizinische Universitat Wien, Wien, Wien, Austria

Moritz Muckenhuber, MD

• Mucha, Jasmin, Medizinische Universitat Wien, Wien, Wien, Austria

Jasmin Mucha, PhD

• Reindl-Schwaighofer, Roman, Medizinische Universitat Wien, Vienna, Vienna, Austria

Roman Reindl-Schwaighofer, MD

• Heinzel, Andreas, Medizinische Universitat Wien, Vienna, Vienna, Austria

Andreas Heinzel

• Weijler, Anna Marianne, Medizinische Universitat Wien, Wien, Wien, Austria

Anna Marianne Weijler, PhD

• Berlakovich, Gabriela, Medizinische Universitat Wien, Wien, Wien, Austria

Gabriela Berlakovich, MD

• Worel, Nina, Medizinische Universitat Wien, Wien, Wien, Austria

Nina Worel, MD

• Wolzt, Michael, Medizinische Universitat Wien, Wien, Wien, Austria

Michael Wolzt

• Lion, Thomas, Medizinische Universitat Wien, Wien, Wien, Austria

Thomas Lion, MD, MSc, PhD

• Edinger, Matthias, Krankenhaus Barmherzige Bruder Regensburg, Regensburg, Bayern, Germany

Matthias Edinger, DrMed

• Wekerle, Thomas, Medizinische Universitat Wien, Wien, Wien, Austria

Thomas Wekerle

Background

In preclinical models combining Treg therapy with donor bone marrow transplantation leads to mixed hematopoietic chimerism and tolerance without myelosuppressive recipient conditioning.

Methods

A single center, controlled, first-in-human phase I/IIa trial is conducted in HLA-mismatched living donor kidney transplant recipients. In vitro expanded polyclonal recipient Tregs and MNC-separated donor bone marrow cells are administered within 3 days after transplant. No irradiation or cytotoxic drugs are given. IS consists of thymoglobulin, belatacept, sirolimus and steroids. Starting at 6 months, sirolimus and steroids are gradually withdrawn in study group patients. A parallel control group receives the same IS, but no Tregs & bone marrow. Total leukocyte donor chimerism and safety are co-primary endpoints. Immune monitoring accompanying the trial includes NGS of the TCR repertoire, flow cytometric leukocyte subset analysis, scRNAseq and protocol biopsies (at 6, 12, 24, 36 and 60 months) including transcriptomic analysis. ClinTrials.gov NCT03867617.

Results

Thirteen patients have been enrolled and twelve treated according to the predetermined sample size of six per group. One patient was enrolled but not treated as the Treg cell product was out-of-specification (77% viable cells at 80% cut-off). Treg (1.0-1.5x10^7 cells/kg) and bone marrow cell (0.7-1.9x10^8 nucleated cells/kg) infusions were well tolerated. The study group developed low levels of total leukocyte donor chimerism whereas no chimerism was detectable in the control group. Leukocyte subset analysis and transcriptomics analysis of biopsies (MMDx) are ongoing. TCR repertoire sequencing revealed clonal deletion of donor-specific T cells.
The study group shows a favorable clinical course, with GFRs of 33-99 ml/min/1.72m^2 at median follow-up 32 months and no infusion-related safety signals were observed. IS reduction has been completed in three patients currently maintained on belatacept monotherapy and is in progress in all other patients.

Conclusion

Combined Treg therapy and bone marrow transplantation is safe and feasible and induces low-level chimerism which is sufficient to cause clonal deletion of donor specific T cells.

Funding

• Government Support - Non-U.S.