99. First Case of Extended Immunosuppression-free Survival of a Face Allotransplant Via Immune Chimerism Induction the Non Human Primate Model

PURPOSE: Immunosuppression and rejection continue to pose significant challenges to vascularized composite allotransplantation (VCA). Achieving immune tolerance, particularly difficult due to the high immunogenicity of VCAs, would represent a major breakthrough. This study focuses on developing a novel tolerance induction protocol for VCAs. METHODS: Partial heterotopic face transplants were performed on cynomolgus macaques with full MHC mismatch. Two protocols were tested: a simultaneous VCA and bone marrow transplant protocol, and a second protocol where the bone marrow transplant was delayed by two months. The conditioning regimen included treatment with Thymoglobulin, irradiation, and a BCL-2 inhibitor, followed by a donor bone marrow transplant. Recipients were maintained on costimulation blockade and calcineurin inhibitors for 15 and 28 days, respectively. Post-operative monitoring involved daily clinical assessments, weekly blood draws for cell counts, and chimerism level assessment using flow cytometry. Donor-specific antibodies and histological rejection signs in skin biopsies were also evaluated. RESULTS: Transient myeloid and lymphoid mixed chimerism was established in two monkeys with the simultaneous protocol, whereas the delayed protocol was hindered by opportunistic infections before the bone marrow infusion could occur. Chimerism levels peaked between the second and third weeks. So far, the longest post-operative survival achieved is 6 months, including 3 months off immunosuppression, without any clinical, biological, or histological signs of rejection. The main adverse effects of the conditioning regimen were CMV opportunistic infection and isolated anemia, both of which resolved after appropriate treatment. CONCLUSIONS: For the first time, prolonged survival of a face transplant without immunosuppressive treatment has been achieved in this animal model using a mixed chimerism protocol with BCL-2 inhibition. This proof of concept represents a significant milestone in the quest for immune tolerance induction in VCA.