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

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

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

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

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

Donnell E. Thomas

The first wave of transplants

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

The first wave of transplants Where to go from here?

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

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

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

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

Jean Dausset

Hemopoietic Stem Cells

Stem Cells: A PMH Tradition

HSC Self renewal Differentiation Proliferation

Stem Cell Subpopulations Weissman et al

Stem Cell Subpopulations Weissman et al

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

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

Stem cell migration and homing via SDF-1 and CXCR4 interaction SDF-1 binds exclusively to its receptor CXCR4 Secretion of SDF-1 by bone marrow is critical for the colonization of marrow by fetal liver derived hemopoietic stem cells SDF-1/CXCR4 knock out mice have developmental defects in the heart, brain, and large vessels SDF-1 is highly expressed in bone marrow, lymph nodes, lung, liver, kidney and skeletal muscle. SDF-1 secretion increases with tissue damage eg hypoxia, radiation, chemotherapy. HIF-1 and NFΚB upregulate both SDF-1 and CXCR4 VEGF, IFN alpha, IL 2,4,& Transcription factors of the PAX-family may regulate CXCR4 expression in a tissue specific manner (eg PAX1 for osteoblastic SC, PAX5 for B lymphocytic progenitors) Lapidot T et al 2004

The hemopoietic niche LIF SCF SDF-1 G-GSF TGF-β GM-CSF IL1α FLT 3 IL6 Bony niche lined with osteoblasts positioned proximal to the endosteal surface. Frequency of HSC increases with increasing numbers of osteoblasts. Their number can be influenced by BMP and PTH/PTHR. In vitro osteoblasts suppress proliferation of HSC and maintain their immature phenotype. Stromal niche composed of reticular cells, fibroblasts, adipocytes, endothelial cells and macrophages. Reticuler stroma has the opposite effect, Adipocytes IL6 OSM IL7 BMP-4 IL8 PTH IL11 IL12 IL15 IL14 Modified: Dazzi F et al Blood Reviews 2006; 20: 161-171 Cell contact Notch and Wnt/beta catheninsignalling BMP4 Tie2/Ang1 pathways Soluble factors Transcription factors Cell cycle regulators Chromosome modifiers such as telomerase Adhesion molecules

Sources of Stem Cells Marrow Peripheral blood Cord blood

Transplant Immunology

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

The problems after allotransplant Prophylaxis Calcineurin inhibitors MTX ATG Alemtuzumab aGvHD aGvHD Secondary Therapy Primary Therapy Hemopoietic stem cell transplants are associated with a number of problems that influence survival. These complications are usually assessed independent of each other and strategies are usually employed to address specific complications. This approach does not take into account linkeages where alteration of one complication may influence incidence and/or severity of others. Steroids plus Monoclonal antibodies Photopheresis Mesechymal stem cells Steroids

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 MSC MSC IL12 MSC IL4 Donor T cells Type 2 Cytokines IL4,IL10,IL13 Anti- inflammatory Host APC TH2 cells

Supportive Care

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

Survival of AML Patients Since 1986 Survival Before 1986 Years after BMT

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