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Using Mtor-inhibiting Nanoimmunotherapy For Achieving Cardiac Allograft Tolerance In Non-human Primates
Parth M. Patel, MD1, Abraham Teunissen, PhD2, Cyntha Miller, MD3, Jane O, MD3, Tyler Costa3, Mubarak Momodu3, Abbas Dehnadi, DVM3, Isabel Hanekamp, PhD3, Venu Pothula2, Rodrigo Sanchez, PhD2, Geoffrey Prevot, PhD2, Willem Mulder, PhD2, Jordi Ochando, PhD2, Joren C. Madsen, MD, DPhil3.
1Emory University, Boston, MA, USA, 2Icahn School of Medicine at Mount Sinai, New York City, NY, USA, 3Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.

Objectives: Achieving cardiac allograft tolerance would transform pediatric heart transplantation. Graft infiltrating M2-macrophages provide a favorable local immunologic milieu and may promote tolerance. Nanobiologics loaded with a prodrug of rapamycin (mTORi-NBs) inhibit trained immunity and promote M2-macrophages; we investigate their use in inducing cardiac allograft tolerance. Methods: Nine non-human primates (NHPs) underwent simultaneous heterotopic heart and bone marrow transplantation using a mixed chimerism protocol. Group A (n=7) was given preoperative total body irradiation (TBI), thymic irradiation, ATGAM, and anti-CD154 monoclonal antibody until day 12 and a calcineurin inhibitor until day 28 post bone marrow transplant (pBMTx). In Group B (n=2), mTORi-NBs at a dose of 0.15 mg/kg were added from pBMTx 0-26 to this regimen. Results: In Group A, lymphocyte chimerism lasted on average until day 61 and all allografts rejected by day 168 pBMTx. Allografts in both Group B NHPs are contracting strongly and show no evidence of rejection at days 125 and 202 (p=0.043). The first recipient in Group B developed graft versus host disease (GVHD) which was treated with a short course of calcineurin inhibitor. TBI was reduced in the second Group B recipient which is showing no signs of GVHD or other toxicity. Conclusion: mTORi-NB nanoimmunotherapy extends lymphocyte chimerism and rejection free survival in a mixed chimerism cardiac allograft tolerance regimen. mTORi-NBs may facilitate achieving cardiac allograft tolerance in pediatric recipients.


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