4 HISTORY 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.
6 Effects of Spleen Shielding on Mice After Total Body Irradiation TBI Dose(cGy)SpleenShieldingSurvival70010501200YesNo96.3%0.0%30.4%
7 Treatment Necessary for Cure Rationale for High Dose Therapy and Hematopoietic Stem Cell TransplantationDeath due toother organtoxicityIncreasing DoseDeath due toMarrow toxicityTreatment Necessary for Cure
8 CONDITIONING (PREPARATIVE) REGIMEN To suppress the patient’s immune system from rejecting the stem cells.To eliminate the cancer
10 TYPES 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.
11 Potential Stem Cell Sources Autologous stem cellsHLA-matched related donorsHLA-matched unrelated donorsHaploidentical related donorsUmbilical cord blood
12 Autologous 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
13 Allogeneic 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.
14 Allogeneic 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.
15 Engraftment 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.
17 HUMAN 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.
25 Alternatives to HLA-matched Related DonorsHLA-matched unrelated donorsCord blood transplantation- Related- UnrelatedHLA-mismatched related donors(Haplo-identical)Autologous stem cell transplantation
26 The NMDP Network 98 Donor Center (8 foreign) Coordinating Center Minneapolis, MN114CollectionCenters(15 foreign)112TransplantCenters(23 foreign)ASCO 1998
27 Volunteer Marrow Donors 40Total Donors3,134,60130Volunteers in Registry(Millions)20Fully TypedDonors108990919293948895969798YearASCO 1998
28 Probability of Finding a Six-antigen HLA Matched Donor North America CaucasianPool SizeJapanese100100010,000100,000500,0001,000,0000.0%11.9%54.2%90.6%99.9%0.0%3.3%20.7%60.0%85.7%93.7%
29 DR Typing Confirmatory Typing Work-Up Transplant Formal Search Preliminary Search1.6%15.8%20.2%43.5%54.7%7.2%2.1%25.6%Beatty et al., 1995
30 Cord 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
31 Haplo-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
32 Strategy 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?
33 Choice of Stem Cell Source DiagnosisUrgency of transplantHLA typingCell dose available in UC units(s)AgeChemo-sensitivity
35 Indications 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
36 Annual Numbers of Blood and Marrow Transplants Worldwide ( )4030AutologousNumber of Transplants(Thousands)2010Allogeneic1970197519801985199019952000Year
37 Advancements in Allogeneic Stem Cell Transplantation Alternative donorsUnrelated bone marrow donorsStored cord bloodGanciclovirHematopoietic growth factorsBlood as a stem cell productDonor lymphocyte infusions
38 Donor 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%
39 Allogeneic 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.
40 Non-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