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Abstract: SA-OR59

A Phase 1/2a Trial of Autologous Regulatory T Cell Therapy Together with Donor Bone Marrow Infusion in Kidney Transplantation

Session Information

Category: Transplantation

  • 2102 Transplantation: Clinical

Authors

  • Oberbauer, Rainer, Medizinische Universitat Wien, Wien, Wien, Austria
  • Muckenhuber, Moritz, Medizinische Universitat Wien, Wien, Wien, Austria
  • Mucha, Jasmin, Medizinische Universitat Wien, Wien, Wien, Austria
  • Reindl-Schwaighofer, Roman, Medizinische Universitat Wien, Wien, Wien, Austria
  • Heinzel, Andreas, Medizinische Universitat Wien, Wien, Wien, Austria
  • Berlakovich, Gabriela, Medizinische Universitat Wien, Wien, Wien, Austria
  • Wolzt, Michael, Medizinische Universitat Wien, Wien, Wien, Austria
  • Lion, Thomas, Medizinische Universitat Wien, Wien, Wien, Austria
  • Worel, Nina, Medizinische Universitat Wien, Wien, Wien, Austria
  • Wekerle, Thomas, Medizinische Universitat Wien, Wien, Wien, Austria
Background

In preclinical models combining Treg therapy with donor bone marrow transplantation leads to mixed hematopoietic chimerism and tolerance without myelosuppressive recipient conditioning, avoiding the adverse effects of irradiation or cytotoxic drugs.

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, tocilizumab is injected s.c. for the first 3 weeks. No irradiation or cytotoxic drugs are given. Immunosuppression (IS) consists of thymoglobulin, belatacept, sirolimus and steroids. Starting at 6 months, sirolimus and steroids are gradually withdrawn in stable study group patients. A parallel control group receives the same IS, but no Tregs, bone marrow or tocilizumab. Total leukocyte donor chimerism and safety are co-primary endpoints. Immune monitoring accompanying the trial includes NGS of the TCR repertoire (of the recipient and Treg cell product), flow cytometric leukocyte subset analysis, scRNAseq and protocol biopsies (at 6, 12, 24, 36 and 60 months) including transcriptomic analysis.

Results

Ten patients have been enrolled and treated so far. One additional patient was enrolled but not treated as Treg manufacturing failed. Treg (1.1-1.5x10^7 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 (<1%) in the first weeks post-transplant, whereas no chimerism was detectable in the control group. The study group shows a favorable clinical course, with GFRs of 50-82 ml/min/1.72m2 at latest follow-up (median follow-up 23 months) and no safety signals were observed. IS reduction has been completed in three patients currently maintained on belatacept monotherapy q8 weeks and is in progress in all other patients. Protocol biopsies at 12 months were clear.

Conclusion

Combined Treg therapy and bone marrow transplantation is safe and feasible in living donor kidney transplantation and induces low-level chimerism.

Funding

  • Clinical Revenue Support