Current and Future Applications of Umbilical Cord Blood Cell Transfusion

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Current and Future Applications of Umbilical Cord Blood Cell Transfusion

  1. 1. Current and Future Applications of Umbilical Cord Blood Transfusion Red Blood Cell Antigens SSC 2014 Done By: Ivan Seah
  2. 2. Objectives • To explain the concept of hematopoietic stem cell transfusion • To compare the various sources of hematopoietic stem cells available, in particular the bone marrow and umbilical cord blood • To outline the current applications of umbilical cord blood transfusion • To discuss the future applications of umbilical cord blood and the challenges they face
  3. 3. What exactly is a hematopoietic stem cell?
  4. 4. The Haematopoietic Stem Cell • Immortal • Multipotent • Resides in bone marrow of adults • Circulates around the blood during foetal stage
  5. 5. Where can we find these HSCs?
  6. 6. Sources of Haematopoietic Stem Cells Mobilized Peripheral Blood Adult Bone Marrow Umbilical Cord Blood
  7. 7. What are the current applications of UCB transfusions?
  8. 8. UCBT: Past and Present 1st Success Paris 1988 5 year old boy with Fanconi’s Anemia 600,000 units have been stored and more than 300,000 UCBTs have been performed… As of date, more than
  9. 9. Bone Marrow VS Umbilical Cord Blood Bone Marrow Requires Surgery Shelf life measured in hours Common Umbilical Cord Blood Collection Usage Time of Latent Virus Infection Obtained from delivered placenta and umbilical cord Shelf life can be more than 20 years Rare Uncommon and less severe Common in mismatched grafts Graft VS Host Disease even if there is GVHD 1 or 2 allele mismatches Requires a perfect HLA-match proven to be successful HLA-Matching Possible High  Better engraftment Second Transplant HSC Volume Not possible Low  Poorer engraftment
  10. 10. To date, over 80 diseases utilize UCBT as a standard therapy… However, most of them are blood-related diseases
  11. 11. Current Applications of UCB • Leukaemia • Lymphoma Paediatric Hematologic Malignancies Other Blood Disorders • Anaemia • Inherited RBC Abnormalities • Inherited platelet Abnormalities • Inherited Immune System Disorders • Myeloproliferative Disorders • Phagocyte Disorders UCB Treatable Diseases Solid Tumours • Neuroblastoma • Retinoblastoma Inherited Metabolic Disorders • Mucopolysaccharidoses (MPS) Storage Diseases • Leukodystrophy Disorders • Lysosomal Storage Diseases
  12. 12. Paediatric Haematological Cancers Leukaemia Lymphoma • Cancer of WBCs in the bone marrow • Increase of immature WBCs (Blasts) • Cancer of WBCs in the lymphatic system • Increase of B and TLymphocytes Acute Lymphoblastic Leukaemia T-Cell Lymphoma Blasts Blasts B-Cells Blasts T-Cells T-Cells Blasts Blasts T-Cells Blasts B-Cells B-Cells
  13. 13. Paediatric Haematological Cancers In 2000, “Graft-Versus-Host Disease in Children Who Have Received a Cord-Blood or Bone Marrow Transplant from an HLA-Identical Sibling” By Rocha et al
  14. 14. Paediatric Haematological Cancers The study compared 113 children who received UCBTs and 2052 children who received BMTs… Bone Marrow 24% Umbilical Cord Blood % Patients developing 14% Graft VS Host Disease (Day 100) 18  Engraftment Days to Neutrophil 26
  15. 15. Paediatric Haematological Cancers Most surprisingly, the 3-year survival rate was around the same! BONE MARROW TRANSPLANT Alive UMBILICAL CORD BLOOD TRANSPLANT Dead Dead 34% Alive Dead Dead 36% Alive 66% Alive 64% Hence, the suitability of UCB for treatment of paediatric haematological cancers was confirmed.
  16. 16. Hurler Syndrome • Belongs to a group of genetic disorders (mucopolysacchraidoses) • Absence or malfunctioning of lysosomal enzymes required to breakdown glycosaminoglycans (GAGs) Although also known as gargoylism, skeletal deformities are the least of the patient’s concern… + Hepatosplenomegaly + Cardiomegaly = Neurological Disorders  Median Lifespan 11.6 years
  17. 17. Treatments for Hurler Syndrome Medical treatment relies on Laronidase, an enzyme replacement therapy… However, enzyme cannot treat CNS affected disease due to the blood-brain barrier…
  18. 18. Hurler’s Syndrome In 2004, “Cord-Blood Transplants from Unrelated Donors in Patients with Hurler’s Syndrome” By Staba et al
  19. 19. Hurler’s Syndrome From December 1995 – October 2002, 20 children with Hurler’s Syndrome were treated with UCBT… 17/20 Survived by September 2003  Arrested progression of disease  Normal growth velocities  Correction of certain growth deformities (Odontoid dysplasia)  Improved neurocognition  1-3 HLA-loci mismatched UCBs used  No deaths due to GVHD
  20. 20. What else will umbilical cord blood be used for in the future?
  21. 21. Organ Regeneration The most exciting application yet… Is there a difference in the regenerative potential of UCBderived MSCs as compared to BMderived MSCs? Are there enough MSCs in the UCB for regeneration purposes? However, the concept is still preliminary
  22. 22. UCBT in Adults The low HSC volume in UCB has been its most limiting factor yet… Adult Disease Paediatric Disease x x P In a 2001 NEJM study, 40% adult patients who underwent unrelated UCBT passed away before Day 100…
  23. 23. Methods of Increasing HSC Counts Ex-Vivo Expansion Double UCBT Notch-1 • Larger clinical trials required to evaluate overall survival and infection rates • Little is known of the biology or the factors deciding unit dominance
  24. 24. Paediatric Autoimmune Diseases Paediatric autoimmune diseases are rare… Systemic Lupus Erythematosus Juvenile Idiopathic Arthritis However, treatment is difficult when they occur…
  25. 25. Paediatric Autoimmune Diseases Concept of UCBT Treatment: MOSTLY ANIMAL DATA! CLINICAL DATA DIFFICULT TO INTERPRET! Step 1: Chemotherapy to Step 2: Transfuse UCBT eradicate immune cells (allogeneic/autologous) Step 3: New immune system develops
  26. 26. Gene Therapy Trials for gene therapy have mainly been aimed at cancer and immune deficiencies… RNAi Oligoneucleotides HSCs Zinc-finger Nucleases Step 1: Remove HSC Step 2: Genetically alter from patient/autologous the HSCs UCB Step 3: Reintroduce HSCs into patient
  27. 27. Autologous UCBT Gene Therapy UCB is a good choice for gene therapy because…  Cells are well characterised  Clinical transplantation protocols are established  Can be used to correct genetic deficiencies at birth  Possible higher efficiency of gene transfer as compared to adult HCT Will introducing autologous cells cause a higher risk of the same disease occurring again?
  28. 28. Tolerance Induction Although graft rejection can be reduced by immunosuppresants… Only 40-60% of grafts continue to function after 10 years…
  29. 29. Tolerance Induction Concept of HSC tolerance induction Recipient HSCs Donor HSCs Donor Step 1: Irradiation or preparative regimens to make space for donor HSCs Step 2: Infuse solidorgan donor HSCs Step 3: Mixed chimerism is achieved. Tolerance is induced.
  30. 30. Tolerance Induction Although proven to work in certain studies, Is the risk of patient dying of infection worth the benefit of tolerance induction by HCT? HCT tolerance induction is associated with high mortality and morbidity…
  31. 31. Conclusion • Since its initial success, UCBT has become popular as an alternative source of HSCs in the paediatric setting. • There is a lot of ongoing research on how to increase the HSC volumes of UCB for the treatment of adult diseases. • Aside from blood diseases, UCB has the potential for many other applications (organ regeneration, autoimmune disorders, tolerance induction)

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