4HISTORY OF STEM CELL TRANSPLANTATION Turn of the 20th century, scientists began to formulate the idea that a small number of cells in the marrow, referred to as “stem cells”, might be responsible for the development of all blood cells.Marrow injury was an important and potentially lethal side effect of exposure to the atomic bomb or to industrial accidents in the atomic weapons industry.Spurred by the Atomic Energy Commission's and the military’s concern about the spread of nuclear technology and weapons, studies of bone marrow transplantation were initiated.
6Effects of Spleen Shielding on Mice After Total Body Irradiation TBI Dose(cGy)SpleenShieldingSurvival70010501200YesNo96.3%0.0%30.4%
7Treatment Necessary for Cure Rationale for High Dose Therapy and Hematopoietic Stem Cell TransplantationDeath due toother organtoxicityIncreasing DoseDeath due toMarrow toxicityTreatment Necessary for Cure
8CONDITIONING (PREPARATIVE) REGIMEN To suppress the patient’s immune system from rejecting the stem cells.To eliminate the cancer
10TYPES OF STEM CELL TRANSPLANTS AUTOLOGOUS TRANSPLANTS - Patients receive their own stem cells.SYNGENEIC TRANSPLANTS - Patients receive stem cells from their identical twin.ALLOGENEIC TRANSPLANTS - Patients receive stem cells from someone other than the patient or an identical twin.
11Potential Stem Cell Sources Autologous stem cellsHLA-matched related donorsHLA-matched unrelated donorsHaploidentical related donorsUmbilical cord blood
12Autologous Bone Marrow Transplantation CriteriaTumor with dose response curveTumor sensitive to myelosuppressive agentsPurging techniques if marrow is contaminatedwith tumor- Preserve stem cells- Eradicate tumorTechnique for peripheral stem cell collectionsMinimal tumor burdenMarrow ablation
13Allogeneic Engraftment HostImmunosuppressionPreparative regimenPost-transplant RxDisease effectsSensitizationGraftStem cell doseT-cell dose (CD8)Graft facilitating cellsStromal stem cells?With reduced immunosuppression in current NST regimen, we rely on graft cells (stem, T-and accessories cells) to overcome rejection.
14Allogeneic Engraftment HostImmunosuppressionPreparative regimenPost-transplant RxDisease effectsSensitizationGraftStem cell doseT-cell dose (CD8)Graft facilitating cellsStromal stem cells?With reduced immunosuppression in current NST regimen, we rely on graft cells (stem, T-and accessories cells) to overcome rejection.
15Engraftment Host Graft Immunosuppression Preparative regimen Post-transplant RxDisease effectsSensitizationGraftStem cell doseT-cell dose (CD8)Graft facilitating cellsStromal stem cells?With reduced immunosuppression in current NST regimen, we rely on graft cells (stem, T-and accessories cells) to overcome rejection.
17HUMAN LEUKOCYTE-ASSOCIATED (HLA) ANTIGENS A set of proteins on the surface of their cells.A set of HLA proteins are inherited equally from patients.Chances of having a full match are ~ 1 in 3.The higher the number of matching HLA antigens, the greater the chance that the patient’s body will accept the donor’s stem cells.
21Alternatives to HLA-matched Related Donors HLA-matched unrelated donorsCord Blood Transplantation-Related-UnrelatedHLA-mismatched related Donors(Haplo-identical)(Autologous stem cell transplantation)
30Cord Blood Transplantation AdvantagesDisadvantagesWaste product of normal deliveriesReadily availableIncreased availability for minoritiesDecreased transmission of viruses (e.g. CMV)One unit rescues one patient/no DLITheoretical risk of genetic disease transmissionTheoretical risk of maternal cell contamination (GVHD)Efficacy in adults unknown
31Haplo-identical HSCT Advantages Disadvantages Nearly all patients have a donorShare major (e.g. HLA-C) and minor hitocompatibility antigensImmediate donor availabilityHLA Barriers:-Graft rejection-GVHD-Immunedysregulation
32Strategy for Donor Selection BMTNoUrgentReferralSimultaneous Search URD, BM and UCBNon-urgent orNon-malignantDiagnosisYesUCBT6/6 HLA-matched BMDonor Available?4-6 HLA-matched UCB(s)Identified with Cell Dose>1.5 x 107 NC/kg?
33Choice of Stem Cell Source DiagnosisUrgency of transplantHLA typingCell dose available in UC units(s)AgeChemo-sensitivity
35Indications for Blood and Marrow Transplantation in North America (2000)4,5004,000Allogeneic (Total N=67,000)Autologous (Total N=11,000)3,5003,0002,500Transplants2,0001,5001,000500Non-HodgkinLymphomaAMLHodgkinDiseaseCMLMDS/OtherLeukemiaCLLMultipleMyelomaBreastCancerOtherCancerALLNon-MalignantDiseaseOvarianCancer
36Annual Numbers of Blood and Marrow Transplants Worldwide ( )4030AutologousNumber of Transplants(Thousands)2010Allogeneic1970197519801985199019952000Year
37Advancements in Allogeneic Stem Cell Transplantation Alternative donorsUnrelated bone marrow donorsStored cord bloodGanciclovirHematopoietic growth factorsBlood as a stem cell productDonor lymphocyte infusions
38Donor Lymphocyte Infusions Efficacy varies:High incidence of GVHD (40-60%)High correlation of GVHD and responseOptimal dose, frequency and timing remain undeterminedCML = 50-90%AML = 25-50%
39Allogeneic Hematopoietic Stem Cell Transplantation Old ParadigmNew ParadigmThe allograft is a rescue product to replace the defective stem cells following ablation with cytotoxic therapy.Main therapeutic component of an allogeneic stem cell transplant is the “graft vs. leukemia” effect mediated by T-cells in the allograft.
40Non-myeloablative Regimens in Allo SCT Advantages:-Decreased acute toxicity-Application to older and/or morbid patients-Application to broader spectrum of diseasesDisadvantages:-Toxicity of the procedure (GVHD)-Loss/decrease in anti-tumor activity fromcytotoxic chemotherapy/radiation