1 / 44

Transplant: Past Present and Future

hesper
Download Presentation

Transplant: Past Present and Future

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

    2. Introduction History of stem cell transplantation Definition and biology of stem cells by source Practical aspects of the transplant process Future directions of BMT

    3. Highlights in Stem Cell Transplant Studies of atomic bomb victims showed marrow most sensitive to radiation Splenic shielding protected mice from radiation Bone marrow infusion rescued mice from radiation Murine and canine models developed for transplant Discovery that immune response controlled by genetic factors (histocompatibility factors) Marrow from histocompatible animals rescues from lethal radiation

    4. Highlights in Stem Cell Transplant 1957: marrow safely infused intravenously 1958: reports of successful identical twin transplants 1969: Cytoxan added to radiation 1970: bone marrow harvests perfected to obtain stem cells 1989: peripheral blood stem cells harvested 1990: first successful cord blood transplant 1996: first non-ablative transplant

    5. What are Stem Cells? Not characteristics of specific tissues Divide for the lifetime of the organism Can replenish themselves Stem cells as “seed cells” for the body Stem cells may exist in all organs Serve in injury repair “trust fund” to replace cells as they die off Stem cells may circulate from one tissue reserve to another?

    6. Sources of Stem Cells Three main types of stem cells Adult stem cells Main reservoir in the bone marrow Cord blood stem cells Circulating stem cells in umbilical cord blood Embryonic stem cells Derived from fertilized embryos during early phases of development

    7. Adult Stem Cells Replenish cells lost through age or injury Largest reservoir in marrow Stem cells circulate in blood “Relocate” to fill empty stem cell slots in other tissues Harvested from bone marrow or peripheral blood in stem cell transplants since late 1970’s Stem cells isolated from: Skin, brain, prostate, muscle

    8. Umbilical Cord Blood Stem Cells Obtained from blood retained in the umbilical cord and placenta after delivery Has been used in stem cell transplants since the late 1980’s Most often used in children and small adults Potential role for double cord transplants in adults

    9. Indications for Stem Cell Transplants Cancer: Leukemia Myelodysplasia Lymphoma Breast cancer Testicular cancer Ovarian cancer Brain tumors Pediatric tumors Multiple myelomas Sarcomas Kidney cancers Non Cancers: Autoimmune diseases Rheumatoid arthritis Juvenile and adult Multiple Sclerosis Scleroderma Systemic Lupus Immune deficiency Sickle cell anemia Thalassemia

    10. Annual Numbers Of Blood And Marrow Transplants Worldwide 1970-2002

    11. Stem Cell Sources By Recipient Age 1997-2004

    12. Practical BMT Two main types based on source of stem cells Autologous: no immunologic conflict Stem cell infusion as “rescue” from high dose chemo “marrow lethal dose” Allogeneic: Minor HLA disparity Related Unrelated Cord blood High dose therapy with immunotherapy “rejection” of the cancer and building better immunity

    13. Elements of Stem Cell Transplants Selection of donor Based on tissue typing of 6-10 HLA antigens in allogeneic transplantation Tissue typing unnecessary in autologous transplantation Harvest of stem cells from donor Bone marrow harvest or pheresis of peripheral blood Preparative regimen Chemo-radiation for ablation and immune suppression Stem cell infusion Post-transplant supportive care Autologous 100 days Allogeneic 180 days or longer for tolerance to develop

    14. Patient Evaluation Recipient Age Autologous: “0” to 70 years Allogeneic: Matched Related 55-60 years Mismatched or Unrelated Donor: 50-55 years Risk of GVHD significantly increased age >45 Dose-Adjusted Transplantation for older, or ill patients Reduced intensity myeloablative Non-myeloablative Indicated based on extensive pre-transplant evaluation for candidacy Patients up to age 70 may be eligible for allogeneic transplant

    15. Preparation for BMT Immune suppression and myeloablation required Bone marrow failure states require more immunosuppression Immune deficiency without empty marrow leads to rejection. Chemotherapy induces aplasia to allow engraftment Additional merits of marrow ablation Provides marrow “space” Eradicates malignant cells Reset of the recipient immune system Preparative regimens before transplant provide aplasia and immune suppression

    16. HLA and Marrow Transplantation Histocompatibility Locus Antigens (HLA) are determinants of immunologic “self” and “not-self” Immunologic “password” Allows for effective immune response against infections, cancer T cell reaction to foreign HLA molecules (donor) is a major problem of transplantation (alloreactivity) Need good donor and recipient match for HLA sites Cause of acute rejection in organ transplant, and of GVHD in BMT.

    17. HLA Typing in BMT Family members typed with patient for HLA A, B and DR Likelihood of 6/6 or 5/6 match depends on frequency of recipient HLA haplotype Likelihood of unrelated donor match related to haplotype frequency in general population Some HLA combinations more frequently found among ethnic groups Ethnic sequestration phenomenon

    18. Ethnicity and Unrelated Donors

    19. Increasing Donor Pool Essential Time from search to unrelated donor: 4 months Often relapse prevents coming to transplant Greater efforts are needed to increase participation and minority representation in the volunteer donor pool (NMDP) Education regarding safety and need Increasing cord blood donation may help some Everyone has umbilical cord blood they won’t use No risk to donate Better reflects the local population demographics

    20. Harvesting Stem Cells Adult stem cells obtained by large volume marrow biopsy/aspiration (1-2L) Cord blood stem cells obtained at delivery by sterile emptying umbilical cord and placenta into blood donation bag Increasingly obtained by processing of peripheral blood of patients and healthy donors Isolated in “real time” from blood after stimulation with blood cell growth factors Stem cells can be frozen for up to 5-10 years

    24. Practical BMT Stem cells infused IV “Home” to micro-environment niches in marrow and spleen Recognition of arrays of adhesive and growth factors in marrow stroma Donor T lymphocytes are essential to engraftment

    25. Hematopoietic Reconstitution Bone marrow cellularity decreased months post transplant Immunologic reconstruction over 100 days post transplant Graft-vs.-host disease (GVHD) delays immune reconstitution Immune deficits expected: T cell and B cell dysfunction. Low Ig levels for three months, normal IgG and IgM by one year, IgA by two year Predisposes to fungal, viral and bacterial infection

    26. Transplantation Immunology In solid organ transplantation, the main relevant immunologic process is graft rejection In marrow transplantation, a novel immunologic condition arises due to the immunologic competence of the graft itself. Rejection is bi-directional Graft rejection Graft-vs.-host disease (GVHD) Tolerance develops, immunosuppression not lifelong

    27. Stem Cell Grafts are Complex

    28. Pathophysiology of GVHD Essential factors necessary for GVHD to occur: Immunologically competent donor graft Histo-incompatibility between donor and host Immunologically incompetent host

    29. Graft-versus Malignancy Effect Lower incidence of leukemic relapse in patients who get acute or chronic GVHD Higher relapse rates in syngeneic vs. allogeneic BMT High relapse rates in T cell depleted BMT Cytogenetic remission induced after post BMT relapse of CML by infusion of donor leukocytes

    30. Nonmyeloablative Stem Cell Transplants as Immunotherapy “Mini transplants”: less cytoablative therapy host/donor marrow chimerism prominent early studies effective in CML in patients up to 75 yrs low level GVHD if chimerism present, malignancy detectable (PCR): reduction in immunosuppression donor lymphocyte infusion high remission re-induction rate lower mortality/morbidity

    31. NST: Overview

    33. . NST: Graft versus Renal Cell Cancer

    35. Tandem Transplantation Refers to the deliberate performance of two stem cell transplants within 3-4 months of each other By intention, rather than by failure to respond May consist of autologous-autologous or autologous-allogeneic The latter allows separation of the high dose component from the immunotherapy component Most often utilized in myeloma, testicular cancer, medulloblastoma, neuroblastoma Response and risk adaptive approach used in myeloma

    36. Cost of BMT Variable due to several factors: Indication: AML<CML<NHL<AA Complications: hospital days, blood products most $$ Stem cell source: PBSC<Marrow (faster engraftment) Preparative regimen: TBI expensive Unrelated>>Allogeneic>Autologous Average ABMT 84k-175k Average AuBMT 70k-100k

    37. Cost Effectiveness of BMT Welch (NEJM 1989): 41 patients with ALL 17 w/ matched related donor 19 w/ no donor; standard consolidation/maintenance Costs for survivors (both arms) less than non-survivors Incremental cost effectiveness (difference in cost/yrs survival): BMT: survivor $166k, nonsurvivor $232k Chemo: survivor $79k nonsurvivor $157k More patients surviving after BMT ICE of BMT $10k per year of life gained Rx of moderate HTN $13.5k per year of life gained

    38. Long Term Complications Infection risk prolonged with GVHD Infertility (Women>>men, TBI>>HD Cytoxan) Hypothyroid 15-25%; (TBI) Cataracts (TBI, steroids) AVN bone: (steroids) Autoimmune dysfunction: (GVHD) Dental: dry mouth, caries (GVHD, TBI) Malignancy 5-6x increased risk PTLPD Non hematologic cancer risks from TBI, Cytoxan

    39. New Directions I Autoimmune diseases heterogenous with variable course All have a basis in the stem cell Main intervention is immunosuppression Safety and side effect profile improving for stem cell transplant Transplant considered in patients with severe AID Life-threatening disease Disease of major morbidity (diffuse Scleroderma) unresponsive to standard therapy (Systemic Lupus) Early in progressive relapse (Multiple Sclerosis) Preparative regimens to include BU/CY/ATG avoiding TBI reduces risk of secondary malignancy

    40. New Directions II Stem cell transplantation as platform for directed therapies Dendritic cell/NK cell immune therapy Vehicle for cancer vaccine delivery Use of specifically generated cytotoxic T cell lymphocyte responses Against malignancy Against infection Enhance autologous Graft versus malignancy effect

    41. Developing Applications I Induction of solid organ graft tolerance In living donor solid organ transplants Orthotopic liver Kidney Pancreatic islet cell Tolerance to solid organ by subsequent NST transplantation Patient as mixed chimera Transplanted marrow and lymphocytes tolerate patient and recognize transplanted organ as “self”

    42. Developing Applications II Heart disease Heart muscle damaged by coronary heart disease or viral injury Injection of stem cells into area of dead heart muscle regenerates viable muscle Injection of stem cells promotes formation of new blood vessels in injured heart muscle Can intracoronary or intravenous purified stem cell populations be given during cardiac catheterization?

    43. Stem Cells Repair Broken Hearts

    44. Conclusions Stem cells can be derived from adult, cord blood and eventually embryonic stem cells Stem cell transplantation can both support highly intensive chemotherapy and promote highly effective immunotherapy Recent advances in stem cell transplantation allow therapy more tailored to disease and patient Improved supportive care measures expand transplant to more patients Expanded applications capitalizing on stem cell plasticity are feasible

More Related