David H. Sachs, MD | Harvard Medical School

Massachusetts General Hospital

Basis/Rationale: Evidence that tolerance can occur in humans is illustrated by the fact that recipients of successful allogenic bone marrow transplants with end-stage renal disease have undergone kidney transplantation from the same donor without the need for immunosuppressive therapy. However, full allogenic bone marrow transplantation for routine use, specifically for the induction of functional tolerance to a solid organ allograft, is neither necessary or desirable. Nonmyeloablative conditioning regimens have been shown to result in mixed chimerism and donor-specific immunologic tolerance in a number of rodent model systems, in miniature swine and in fully mismatched cynomolgus monkeys. Our group has reported the successful induction of tolerance in patients with advanced multiple myeloma and renal failure through simultaneous bone marrow and renal transplantation (ITN study NKD01). More recently, we have reported tolerance induction in patients with end-stage renal disease (ESRD) without myeloma who received one-haplotype mismatched kidney and bone marrow transplants from parents or siblings (ITN study NKD03).

This study will extend the initial pilot trial using a slightly modified conditioning regimen for the induction of donor/recipient lymphohematopoietic chimerism and functional tolerance to a renal allograft in a multi-institution investigation that will enroll completely mismatched, as well as one-haplotype mismatched, recipients.

Significance: Induction of transplantation tolerance has the potential to free renal transplant recipients from long-term, chronic immunosuppressive medications and their complications and from the effects of chronic rejection. Extension of this protocol to non-HLA-matched and unrelated donors has the potential benefit of providing this therapeutic option to a much larger segment ofthe ESRD population.

Clinical Protocol Summary: This is a multicenter, open-label study of 15 adults with end stage renal disease and no evidence of prior sensitization, and their donors. Recipients will receive a conditioning regimen comprising Rituximab, cyclophosphamide, MEDI-507 and thymic irradiation prior to combined renal and bone marrow transplant. A short postoperative course of steroids will be administered. Tacrolimus will be given for a defined period and then tapered if specific criteria are met.

Participants will be followed for all endpoints for 104 weeks (24 months) after immunosuppression has been withdrawn. An additional assessment at 156 weeks (36 months)  after immosuppression withdrawal will be performed for participant and graft survival, and for any long-term adverse events. Participants who fail to complete immunosuppression withdrawal will be followed for 104 weeks (24 months) from the time they cease further reduction in immunosuppression.

The proportion of participants successfully withdrawn from immunosuppression will be assessed. Clinical outcomes will be compared with measurements of donor-specific tolerance and other immune parameters.