Lode Swinnen, MD | Johns Hopkins Hospital | Baltimore, MD

Johns Hopkins Hospital | Baltimore, MD

Despite substantial progress in living donor transplantation, the problem of chronic rejection and the complications of long-term immunosuppression remain. Achievement of durable transplantation tolerance, maintenance of stable graft function off all immunosuppressive medications, remains the holy grail of organ transplantation.

Based upon early observations that natural or induced hematopoietic chimeras (temporary simultaneous presence of donor and recipient immune systems) are tolerant of solid organ allografts from the same donor, there has been substantial interest in combining solid organ and bone marrow or hematopoietic stem cell transplantation (HSCT) to achieve durable tolerance of the solid organ. This approach of transient mixed chimerism has demonstrated some success in a few small studies including the ITN’s Mixed Chimerism trial in which 5 of the original 10 patients remain off immunosuppression, some for over 10 years. However, the toxic-conditioning regimen and potential for graft-versus-host disease (GVHD) from allogeneic HSCT have prevented widespread adoption of  this approach for induction of chimerism.

Study investigators at Johns Hopkins have recently developed non-myeloablative conditioning regimens that permit the sustained engraftment of partially human leukocyte antigen (HLA)-mismatched (HLA-haploidentical) bone marrow from first-degree relatives with minimal toxicities. To mitigate the risks of GVHD, the regimen includes the IV administration of high dose cyclophosphamide on days 3 and 4 after transplantation to selectively deplete or inactivate proliferating alloreactive cells while permitting immune reconstitution from cyclophosphamide-resistant, non-alloreactive lymphocytes present in the donor graft. This regimen has been used extensively in patients with hematological malignancies and piloted using a similar regimen in sickle cell and thalassemia patients.

This trial is a phase II, single arm, open-label, single center study to assess the ability of a specialized pre-transplant conditioning regimen, bone marrow transplantation and high dose post-transplant cyclophosphamide to induce tolerance and enable long-term discontinuation of immunosuppression in six kidney transplant recipients. The accrual goal is six HLA-haploidentical living related recipient-donor pairs. Participants will remain in the study for up to five years.