Use of a Processed Hematopoietic Stem Cell Product (FCRx) in Unmatched Related and Unrelated Donor — Recipient Pairs Is Associated with High Levels of Donor Chimerism and Donor-Specific Tolerance to Kidney Allografts

Conference Paper

Abstract The prospect of eliminating the long term costs and side effects of drug-based immunosuppression (IS) is a compelling reason to pursue the establishment of transplant tolerance. Tolerance in kidney transplant (KTx) recipients has been achieved through the infusion of donor HSC under some form of conditioning. The increased upfront cost and intensive treatment required by tolerance induction protocols demands that the long term outcomes be superior to that achieved with SOC IS regimens. Since 2009 we have conducted a Phase 2 trial of combined stem cell/living donor kidney transplantation in mismatched and unrelated subjects where the stated goal has been the establishment of durable donor macrochimerism. Our protocol is based upon tolerogenic CD8+/TCR-facilitating cells (FCRx) and 200 cGy TBI-based nonmyeloablative conditioning. Recipients were conditioned with fludarabine (30mg/m2/dose, days -5,-4,-3), cyclophosphamide (50mg/kg/dose, day-3 and+3), 200 cGy TBI (day-1) followed by a living donor KTx (day0). A G-CSF mobilized peripheral blood mononuclear cell product was apheresed from the donor >2 weeks pre-KTx, processed to remove graft-versus-host disease (GVHD)-producing cells yet retain CD34 + cells and FC, and cryopreserved until administration day+1 post-KTx. MMF and tacrolimus-based immunosuppression (IS) was weaned and discontinued at 1 year if chimerism, normal renal function and normal KTx biopsy were noted. 37 subjects were transplanted between 2009 and 2016. 17 of 37 subjects were transplanted from 0-2 of 6 HLA matched unrelated donors. 26 of 37 subjects achieved high levels of durable donor chimerism and have been removed from all immunosuppression (7-95 months). Durably chimeric subjects show normal yearly protocol biopsies at 6 months, 12 months, and yearly thereafter, while standard of care patients begin to show abnormal biopsies and deterioration of renal function as early as 24 months post-transplant. Among the 26 subjects who were removed from immunosuppression, none have experienced biopsy proven acute rejection, none have lost chimerism, and none have had to have immunosuppression resumed. Patient and graft survival at 5 years post-transplant are similar to standard of care (SOC) subjects. Two cases of graft-versus-host disease (GVHD) have occurred (6% incidence). One subject experienced grade 2 GVHD that responded to therapy and was successfully removed from all immunosuppression. One subject experienced steroid unresponsive grade 3-4 GVHD resulting in death. Among 7 durably chimeric subjects who had an underlying autoimmune disease that caused their renal failure, none have experienced recurrence of the autoimmune disease (expected rate of recurrence 40-60%). In summary, patient and graft survival at five years was comparable between FCRx and SOC pts. Tolerant FCRx subjects had significantly better renal function than SOC. Medical therapy for hypertension and hyperlipidemia was more common in SOC than tolerant FCRx pts. We conclude there are significant long-term medical benefits to establishing tolerance in KTx recipients using the FCRx approach that become apparent within < 5 years. Disclosures Horwitz: Gamida Cell: Research Funding. Ildstad:Regenerex, LLC: Equity Ownership, Other: CEO.

Full Text

Duke Authors

Cited Authors

  • Leventhal, JR; Galvin, JP; Mathew, J; Gallon, L; Ravindra, K; Horwitz, ME; Abecassis, M; Ildstad, ST

Published Date

  • November 29, 2018

Published In

Volume / Issue

  • 132 / Supplement 1

Start / End Page

  • 202 - 202

Published By

Electronic International Standard Serial Number (EISSN)

  • 1528-0020

International Standard Serial Number (ISSN)

  • 0006-4971

Digital Object Identifier (DOI)

  • 10.1182/blood-2018-99-118832