Allogeneic Stem Cell Transplantation: The Journey

1. Allogeneic Stem Cell Transplantation:The Journey H.A. Messner

2. Objectives • Hemopoietic stem cells • Concepts of blood and marrow transplants • Clinical results • Long term outcomes • New developments • Increase the number of transplants Matched unrelated donors Cord blood transplants Haplo-identical donors Non-myeloablative preparations • New platforms to reduce malignant cells in the recipient • The new paradigm in stem cell biology • Blood and marrow transplants as a form of cell therapy in regenerative medicine

6. 1949 Jacobson et al: Radioprotection by lead shielding of the spleen of a lethally irradiated animal

7. 1951 Lorenz et al: Radiation protection of lethally irradiated animals by marrow and spleen cells from non-irradiated animals of the same strain

8. 1956 Barnes et al: Successful treatment of leukemia in mice after lethal irradiation followed by injection of normal marrow cells

9. Donnell E. Thomas

10. The first wave of transplants

11. The first wave of transplants Engraftment Failure Graft versus Host Disease Relapse

12. The first wave of transplants Where to go from here?

13. Establishment of principles : The pillars of modern transplantation • HLA typing • Stem cell biology • Transplant immunology • Supportive care

14. 45,000 40,000 35,000 30,000 25,000 20,000 15,000 10,000 5,000 0 The second and sustained wave of transplants Autologous NUMBER OF TRANSPLANTS Allogeneic 1970 1975 1980 1985 1990 1995 2000 YEAR 1

15. Emerging complexity of the HLA-system HLA-A alleles N=6 HLA-B alleles N=6 1968

16. Emerging complexity of the HLA-system HLA-A alleles N=6 HLA-B alleles N=6 1968

17. Jean Dausset

18. Hemopoietic Stem Cells

19. Stem Cells: A PMH Tradition

21. HSC Self renewal Proliferation Differentiation

22. Stem Cell Subpopulations Weissman et al

23. Stem Cell Subpopulations Weissman et al

24. Gene expression patterns in hemopoietic progenitor cells Manfredini R et al Stem Cells 2005; 23: 496 – 506

25. Gene expression profiles in different hemopoietic progenitor subpopulations Manfredini R et al Stem Cells 2005; 23: 496 – 506

26. Stem cell migration and homing via SDF-1 and CXCR4 interaction Lapidot T et al 2004

27. The hemopoietic niche LIF SCF SDF-1 G-GSF TGF-β GM-CSF IL1α FLT 3 IL6 OSM IL7 BMP-4 IL8 PTH IL11 IL12 IL15 IL14 Modified: Dazzi F et al Blood Reviews 2006; 20: 161-171

28. Sources of Stem Cells • Marrow • Peripheral blood • Cord blood

29. Transplant Immunology

30. Alloimmune responses by T cells • Induction phase Priming • Expansion phase Proliferation • Effector phase Interaction with cognate AG on host target cells (Perforin, Granzyme, CK) TH1 cells Type 1 Cytokines IL2, IFN-gamma, TNF-beta Pro-inflammatory IL12 (reciprocal suppression) IL4 Donor T cells Type 2 Cytokines IL4,IL10,IL13 Host APC Anti-inflammatory TH2 cells

31. The problems after allotransplant Prophylaxis Calcineurin inhibitors MTX ATG Alemtuzumab aGvHD aGvHD Secondary Therapy Primary Therapy Steroids plus Monoclonal antibodies Photopheresis Mesechymal stem cells Steroids

32. MSC MSC MSC Alloimmune responses by T cells • Induction phase Priming • Expansion phase Proliferation • Effector phase Interaction with cognate AG on host target cells (Perforin, Granzyme, CK) TH1 cells IL12 IL4 Donor T cells Type 2 Cytokines IL4,IL10,IL13 Anti- inflammatory Host APC TH2 cells

33. Supportive Care

34. Aspect of supportive care • Improved GvHD prophylaxis and management • Better infectious disease prophylaxis and therapy • Improved transfusion support • Improved graft preparation

35. Survival of AML Patients Since 1986 Survival Before 1986 YearsafterBMT

36. Indications for stem cell transplants • Cell deficits Aplastic Anemia Immune deficiencies • Hemopoietic Malignancies Leukemias Lymphomas Multiple Myeloma • Genetic disorders Hemoglobinopathies Inborn errors of metabolism • Autoimmune disorders • Selected solid tumors that may benefit from Marrow ablative therapy Cell therapy • Repair of certain organs