Over two decades have elapsed since the beginnings of pilot clinical trials of combined hematopoietic cell and organ transplantation to induce tolerance in clinical living-donor kidney transplantation, at Massachusetts General Hospital in 1998 and at Stanford in 2000. Northwestern joined the effort in 2009. What is the status of tolerance induction trials today?
The protocols initiated at the three institutions, differing in the components, conditioning regimen, and timing of their respective hematopoietic cell transplants, were based on decades of preclinical work by the respective senior investigators. While chimerism is considered the pathway to tolerance in each, the protocols differ in their chimerism goals, from transient mixed chimerism in the MGH protocol to complete chimerism in the Northwestern. Tolerance, defined as successful complete immunosuppressive drug withdrawal, was achieved to a degree in both the HLA-mismatched protocols (MGH and Northwestern) and in the Stanford HLA-matched protocol. The primary risk in all these hematopoietic cell transplant-based protocols is graft versus host disease, which is prone to occur in the presence of complete chimerism. An uncommon risk is immune cytopenia – autoimmune hemolytic anemia, immune thrombocytopenia.
HLA-mismatched protocols remain works in progress at MGH and Stanford, continuously informed by preclinical investigation aimed to improve achievement and durability of tolerance. However, two of the protocols, the Northwestern HLA-mismatched protocol and the Stanford HLA-matched (HLA-identical) protocol, have advanced to industry-sponsored, multicenter phase 3 clinical trials. The Stanford protocol has also been used in centers in Zurich and Tel Aviv, with replication of the success seen at Stanford, demonstrating its reproducibility.
The industry sponsor of the Northwestern HLA-mismatched protocol is Talaris Therapeutics, its multicenter trial in the U.S. is titled FREEDOM-1. Goal enrollment is 120 living donor kidney transplant recipients, with 2:1 randomization to tolerance induction with their hematopoietic cell product (FRC001) versus standard of care. Three early participants in 2022 developed acute graft versus host disease, two grade II and one grade IV. The grade IV disease was complicated by infection and renal and respiratory failure, leading to death of the patient. The correlation of GvHD with high CD34+ cell and total nucleated cell counts in the hematopoietic cell product led to revision of the protocol, specifically the discontinuation of the use of plerixafor for donor hematopoietic cell mobilization and the addition of a second dose of cyclophosphamide after transplantation. The trial is open to enrollment.
The industry sponsor of the Stanford HLA-matched protocol is Medeor Therapeutics, its multicenter trial in the U.S. and Canada is titled MDR-101. The goal enrollment of 30 living donor kidney transplant recipients has been met, with 2:1 randomization to tolerance induction with their hematopoietic cell product (MDR-101) versus standard of care. An interim analysis in 2021 reported that 12 of the 20 participants enrolled in the treatment group had reached the 12-month time point. Eleven of the 12 had been successfully withdrawn from immunosuppressive drugs and been free of immunosuppression from 5 to 33 months. One patient presented with recurrence of kidney disease and mild acute rejection 5 months after being withdrawn from immunosuppression; the rejection was treated, and immunosuppression resumed. These results are akin to those seen in the Stanford trial, providing further demonstration that tolerance protocols can be successfully reproduced at transplant centers without previous experience. The Medeor study is expected to complete its post-transplant observation phase in 2024.
Within several years, it will be evident if these trials succeed. Thereafter, regulatory approval of the hematopoietic cell products is anticipated, followed by health insurance approval of the living donor transplantation tolerance induction protocols using these cell products. Success of these trials will propel the nascent efforts to expand these protocols to deceased donor transplantation despite the logistical challenges. And it is likely that refinement of hematopoietic cell therapy will advance current and developing HLA-mismatched protocols, expanding the potential of offering the prospect of tolerance to many solid organ transplant candidates.
Tolerance has been the Holy Grail of transplantation for over half a century. It is nearing reality. In the words of the late Sam Strober, our Stanford mentor and colleague, “If we were able to make organ transplantation a reality in the 20th century, the goal for the 21st should be to do it without drugs.”
By John D. Scandling, MD
Stephan Busque, MD, FRCSC
Stanford School of Medicine