Transcript Document
Transplant: Past Present and Future
John McCarty M.D. Medical Director Bone Marrow Transplantation Program Massey Cancer Center VCU Health Systems/MCV Hospitals and Physicians May 7, 2008
Introduction
• History of stem cell transplantation • Definition and biology of stem cells by source • Practical aspects of the transplant process • Future directions of BMT
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
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 Thomas et al J Clin Invest 1959
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?
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
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
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 QuickTime™ and a GI F decompressor are needed to see this picture.
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
Annual Numbers Of Blood And Marrow Transplants Worldwide 1970-2002
45,000 40,000 35,000 30,000 25,000 20,000 15,000 10,000 5,000 0 1970 1975 1980 Autologous 1985 YEAR 1990 Allogeneic 1995 2000
Stem Cell Sources By Recipient Age 1997-2004
100 80 60 40 20 0 1997-2000 2001-2004 Age
20 yrs 1997-2000 Age
>
20 yrs 2001-2004
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
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
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
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
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.
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
Ethnicity and Unrelated Donors
Growth of the Registry has Increased the Likelihood of Matching for All Patients
100% Caucasian 43,780 80% American Indian/AN, 243 60% Mult/Oth/Unk/Dec, 7,187 40% Hispanic, 3,784 Asian/Pacific Islander, 2,328 20% African American, 4,228 0% 1988 1990 1992 1994 1996 1998 2000 Year
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
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
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
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
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
Stem Cell Grafts are Complex
Stem cell graft components Facilitating Cells Dendritic Cells NK Cells Stem Cells, progenitors T and B Lymphocytes T Lymphocyte functions GVL, grafting GVHD
Pathophysiology of GVHD
• Essential factors necessary for GVHD to occur: – Immunologically competent donor graft – Histo-incompatibility between donor and host – Immunologically incompetent host
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
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
NST: Overview
.
NST: Graft versus Renal Cell Cancer
60 days post transplant Childs et al NEJM 2000 285 days post transplant
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
Cost of BMT
• Variable due to several factors: – Indication: AML
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
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
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
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
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”
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?
Stem Cells Repair Broken Hearts
Orlic et al PNAS 2001
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