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Tolerance Via Mixed Chimerism A. Benedict Cosimi

Tolerance Via Mixed Chimerism A. Benedict Cosimi. Innovators in Transplantation ATC 2013. “INNOVATOR”. “ A person who first introduces into reality something better than before. “ Among those called innovators : Isaac Newton – Classical mechanics

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Tolerance Via Mixed Chimerism A. Benedict Cosimi

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  1. Tolerance ViaMixed ChimerismA. Benedict Cosimi

  2. Innovators in Transplantation ATC 2013

  3. “INNOVATOR” “ A person who first introduces into reality something better than before. “ Among those called innovators : Isaac Newton – Classical mechanics Albert Einstein – Theory of relativity Wright Brothers – Controlled flight Thomas Edison – Economically feasible light bulb Alfred Nobel – Annual Prize for “greatest benefit to mankind” Henry Ford - Mass produced automobiles Sir Peter Medawar – Immunologic studies Steve Jobs – Novel consumer electronics Jonas Salk – Defeated polio Joseph Murray – Successful kidney transplant

  4. Why Tolerance? Drug treatment-related complications Chronic rejection

  5. THERE ARE THREE GOLDEN RULES FOR ACHIEVING TOLERANCE INDUCTION IN HUMANS (adapted from:)R. Morris

  6. UNFORTUNATELY, WE DON’T KNOW ANY OF THEM (adapted from:)R. Morris

  7. Outcomes in Recipients of Solid Organ Transplants after BM Tx.Dey B, et. al. Medicine 1998;77: 355-369 • Recipients of renal or lung allografts from same donor after successful BM Tx • Transient I.S. in 5, none in 1 • Sustained tolerance in 6/6 patients

  8. Renal Allograft Tolerance via Mixed Chimerism: 13 years post I.S. withdrawal

  9. NHP Conditioning • TBI: 250-300cGy • TI : 700cGy • ATGAM • Anti- CD40L mAb • CNI x 1 month

  10. First Clinical Protocol (1998)ESRD + Mult. Myeloma (HLA-matched) • Cyclophosphamide: 120mg/kg • TI : 700cGy • ATGAM • DLIs • CNI x 6-8 mos.

  11. HLA-matched Kd/BMT for MM and ESRD (MGH) • Multilineagechimerism in 10/10 • Hematopoietic graft loss in 5/10 • 7/10 alive, 5 in CR of MM. Post-Tx. Remissions, 3+ to 14+ yrs. (Expected survival: 3-5 years) • 1 death from MM recurrence plus AML, 2 from recurrent MM • Acute and chronic GVHD (1), acute GVHD (1) , chronic GVHD (3) • Transient renal graft rejection (2)

  12. Kd/BMT for HLA-mismatched Recipients • Cyclophosphamide: 120mg/kg • TI : 700cGy • Anti-CD2 mAb • CNI x 8-10 mos. • Rituximab + steroids in last 7 pts.

  13. Results of HLA- mismatched tolerance induction (MGH) • Transient chimerism in 10/10 • D/C I.S. in 8/10; 1/8 failed • 70% 5-yr I.S. free graft survival • 100% 4-11 yr recipient survival • DSA problem largely controlled • “Engraftment” syndrome in 9/10

  14. Stanford Tolerance Trial (HLA-Id & Mismatched Kd. Recips.) Treatment: ATG TLI, 800-1200cGy CD34+ enriched cells (105-107/kg) Chimerism HLA-Id: Durable in 15/20 Mismatched: Transient Status HLA-Id: 15 off I.S. (2-5yrs); 4 on I.S. post rej. episodes; 1 late death Mismatched: None off to date

  15. Northwestern Tolerance Trial (HLA-mismatched) Treatment: Fludaribine / CTX / TBI / “Facilitating Cells” Chimerism: 18/20: 6-100% at 1 mo; 12 durable Status: 9 pts. Off I.S. (6-24 mos.) still chimeric 6 pre weaning, 3 still chimeric 2 recurr. disease, back on I.S. 2 reject, back on I.S. 1 Kd loss (Viral/ R.A. thromb.) Re-Tx.

  16. Tolerance via BM Tx Limitations(2014) 1. “Engraftment” Response (MGH) 2. Mainly applicable to living donor recipients 3. Need for durable chimerism (Stanford, N W ) 4. Ineffective for non-renal TX. 5. Lack of Tolerance “Assay” (Risk of rejection after I.S. withdrawal)

  17. MGH Protocol Addressing Engraftment Syndrome Kidney/ BM transplant steroids TI Tacrolimus TBI 1.5GyX2 Rituximab -7 -5 –4 -2 –1 0 1 5 12 day 8-10 months Anti-CD2 mAb

  18. MGH Tolerance Team

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