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Allogeneic transplantation for Adults with Severe Sickle Cell Disease

Allogeneic transplantation for Adults with Severe Sickle Cell Disease. John F. Tisdale, MD Senior Investigator Molecular and Clinical Hematology Branch. Hematopoietic stem cells as vehicles for therapeutic gene delivery. Allogeneic stem cell transplantation.

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Allogeneic transplantation for Adults with Severe Sickle Cell Disease

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  1. Allogeneic transplantation for Adults with Severe Sickle Cell Disease John F. Tisdale, MD Senior Investigator Molecular and Clinical Hematology Branch

  2. Hematopoietic stem cells as vehicles for therapeutic gene delivery Allogeneic stem cell transplantation • Transplantation using allogeneic stem cells from a normal donor • HLA-matched sibling Autologous stem cell gene transfer • Transplantation using autologous stem cells which have been corrected by transfer of a normal or therapeutic gene • Retroviral vectors

  3. Hematopoietic stem cells as vehicles for therapeutic gene delivery Allogeneic stem cell transplantation • Myeloablative transplantation curative in children with sickle cell disease • Stable mixed chimerism sufficient • 13/50 surviving patients 11-99% donor chimerism • (Walters et al., BBMT, 7, 665, 2001) • None experienced recurrent painful crises or other related events • Toxic conditioning and GVHD limit application to children • Engraftment without ablation

  4. Nonmyeloablative conditioning sufficient for reliable allogeneic PBSC engraftment • Cytoxan/fludarabine based immune ablative conditioning piloted in patients with metastatic cancer • Childs, R.W., et al., JCO, 17, 2044, 1999. • Childs, R., et al., NEJM, 343: 750-758, 2000. • Extended to high-risk patients ineligible for conventional myeloablative conditioning • Kang, E.M., et al., Blood, 99, 698-701, 2002. • Kang, E.M., et al., J Hematother and Stem Cell Res, 11, 809-816, 2002.

  5. Application to sickle cell disease? • NIH experience overall (n>100) • Engraftment through donor alloimmune response • GVHD common • T cell alloreactivity not necessary in nonmalignant disorders • Treatment related mortality 21% • GVHD principal cause • Prohibitive in nonmalignant disorders

  6. Cumulative non-ablative BMT experience in sickle cell disease Chakrabarti S et al, BBMT 2004 A non-ablative protocol for adults with severe sickle cell disease is needed

  7. F1-Hybrid C57Bl6 (Kb) X BalbC(Kd) Harvest mobilized stem cells 6 Days G-CSF (200 ug/kg) 100x106 cells Recipient C57Bl6 (Kb) Day -1 Week Day 0 (300 cGy) RAPA (3mg/kg) or CSA (20mg/kg) A Murine Model of Nonmyeloablative Stem Cell Transplantation for the Treatment of Sickle Cell Disease • Develop regimen that: • Promotes tolerance without need for long term immunosuppression • Allow for stable mixed chimerism • F1-Hybrid donor mice • Myeloid-flow cytometry • Erythroid-Hb electrophoresis • Donors mobilized with G-CSF • Mobilized cells collected day 6 • Recipient mice conditioned with 300 cGy and a 30d course of either • Cyclosporine (CSA) • Rapamycin (RAPA)

  8. Why Rapamycin?? IL-2 RAPA CSA TcR-CD3 CD28 Effector Function Proliferation Anergy Induction of tolerance

  9. Rapamycin but not Cyclosporine Maintains Chimerism in the Absence of Long-term Immunosuppression

  10. Recipient 1 Recipient 2 Recipient 3 SS Control Donor ASC Sickle Hemoglobin is Replaced by Donor Hemoglobin in Chimeric Homozygote Mice Powell, J, Fitzhugh, C. et al., Transplantation, 80(11):1541-5, 2005

  11. Nonmyeloablative Allogeneic PBSC Transplantation for Adults with Severe Congenital Anemias Eligibility: Adults with Hb SS, SC, or Sb0-thal Severe end-organ damage • stroke or abnormal CNS vessel • TRV ≥2.5 m/s • renal damage • Or modifiable complication(s), not ameliorated by hydroxyurea • > 2 hospital admissions per year for pain crises (VOC) • previous acute chest syndromes (ACS) • red cell alloimmunization • osteonecrosis of multiple joints

  12. Screening and Accrual of Patients

  13. Characteristics of 10 Patients Undergoing Nonmyeloablative Hematopoietic Stem-Cell Transplantation (HSCT)

  14. Conditioning regimen Sirolimus taper if full donor chimerism achieved in the absence of GVHD

  15. Transplant course • All patients tolerated conditioning without serious adverse events • No need for nutritional support • No acute or chronic GVHD • No sickle cell anemia related events • Nine of 10 with stable engraftment

  16. Donor chimerism after transplantation

  17. Improvement in hemolysis parameters after transplantation

  18. Normalization of hemoglobin levels after transplantation

  19. Replacement by donor derived red cells allows tapering of narcotic analgesics

  20. Interim conclusions • Allogeneic PBSC transplantation after low dose TBI, campath, rapamycin conditioning and resulting mixed hematopoietic chimerism sufficient to revert the sickle phenotype • Accrual currently at 23 patients, 20 without SCD • Low toxicity allows application in adults with severe disease • ‘Split’ or mixed chimerism and absence of acute or chronic GvHD suggests operational tolerance • Protocol amended for weaning of rapamycin at CD3 >50% • 5 patients off immunosuppression with stable mixed chimerism • Longer follow-up and further accrual necessary • Barriers remain for widespread application

  21. Barriers to therapeutic gene delivery using HSCs:HSC source “The regimen use by Hsieh et al. is clearly an important development, but its applicability is still limited by the small number of available HLA-matched siblings.”

  22. Barriers to therapeutic gene delivery using HSCs:HSC source/MUD bone marrow Seven of 10 with potential 6/6 donor Using Haplogic, only 1/7 with >1% chance of having a 6/6 donor

  23. Barriers to therapeutic gene delivery using HSCs:HSC source/Cord blood Nine of 10 have at least one 4/6 cord blood match identified Higher degree of matching, higher cell dose, and ABO compatibility limits applicability

  24. Barriers to therapeutic gene delivery using HSCs:Haploidentical grafts? • Haploidentical donors • Most accessible • Large cell doses feasible • Repeat collections feasible • Immunologic barrier greater • Higher degree of immunosuppression • Post-graft cyclophosphamide • Reduce graft rejection/GvHD • Targets proliferating lymphocytes • Early success in ongoing clinical trials Luznik L et al. Blood, 2001. 98(12): 3456-3464.

  25. Post-Transplant Cy and Sirolimus are Synergistic Sirolimus (Sir, 3mg/kg IP) days -1 or +4 for 30 days 200cGy TBI, bone marrow cells infused on day 0 Cyclophosphamide (Cy, 200mg/kg IP) day +2 Will Sirolimus Prevent Post Transplant Cy effect on Engraftment?

  26. Conditioning regimen Escalating dose post transplant Cy TBI 200 cGy +1 +2 +3

  27. Validate results with continued accrual (Trial plan for 25 subjects) Allogeneic stem cell transplantation Expand to multicenter trial design (Facilitate recruitment) Determine engraftment level sufficient to revert phenotype (Compare marrow progenitor chimerism with peripheral blood) Characterize immunologic recovery (Mechanistic studies of tolerance induction) Tolerance for alternative donor transplantation (Haploidentical donors) Hematopoietic stem cells as vehicles for therapeutic gene delivery: Future efforts for human application

  28. Tisdale lab Pat Weitzel Naoya Uchida Courtney Fitzhugh O.J. Phang Kareem Washington Matt Hsieh Department of Transfusion Medicine Charley Carter Susan Leitman Dave Stoncek Roger Kurlander Elizabeth Kang Jonathan Powell Terri Wakefield Beth Link Karen Kendrick Griffin Rodgers Crew

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