*Purpose: Despite the development of highly effective immunosuppressive medications, organ rejection and the toxicity of the drugs themselves remain significant obstacles to long-term graft and patient survival. It has been known for over 5 decades that peripheral blood chimerism was associated with immunological tolerance to a transplanted organ, beginning with the observations by Owen followed by the seminal investigations by Billingham, Brent and Medawar that ultimately earned them a Nobel Prize. A major limitation to tolerance induction approaches has been the lack of a robust and reliable biomarker that would allow the safe withdrawal of immunosuppression without a high risk of organ rejection.

*Methods: Work by Ildstad and colleagues led to the discovery of the Facilitating Cell (FC), a novel CD8⁺TCR^– bone marrow-derived cell, and the development of FCR001, an investigational allogeneic cell therapy product that could achieve chimerism and tolerance in highly HLA mismatched donor-recipient pairs, allowing for complete withdrawal of all immunosuppression without rejection.

*Results: A Phase 2 living donor kidney tolerance protocol at Northwestern and Duke Universities has achieved a 70% success rate in the ability to remove all immunosuppression therapy 12 months post-transplant in living donor transplant recipients receiving FCR001 and non-myeloablative conditioning. The therapy is successful in highly HLA mismatched related and unrelated donor-recipient pairs. Durable donor chimerism, as defined by T-cell or whole blood chimerism greater than 20% donor at 6 months post-transplant, was established in 27 subjects, 26 of whom were successfully weaned off of all immunosuppression at 1 year post-transplant.

*Conclusions: None of the 26 subjects have had kidney allograft rejection episodes or development of DSA, and all have maintained normal renal function with normal protocol biopsies over a follow-up period of 3 to 11 years post-transplant. Importantly, 1, 3, 6, and 12-month chimerism levels are highly correlated with each other and increasingly predictive over time of ability to withdraw IS at 1 year, suggesting that peripheral blood chimerism could be a valuable surrogate marker of efficacy. The present analysis explores factors influencing the time course and durability of hematopoietic chimerism in the setting of tolerance induction in living donor kidney transplantation.

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