Current and Future Applications of Umbilical Cord Blood Transfusion

Red Blood Cell AntigensSSC 2014Done By: Ivan Seah

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

What exactly is a hematopoietic stem cell?

• Immortal• Multipotent• Resides in

bone marrow of adults• Circulates

around the blood during foetal stage

The Haematopoietic Stem Cell

Where can we find these HSCs?

Sources of Haematopoietic Stem Cells

Adult Bone Marrow

Mobilized Peripheral

Blood

Umbilical Cord Blood

What are the current applications of UCB transfusions?

UCBT: Past and Present

As of date, more than 600,000 units have been stored and

more than 300,000 UCBTs have been performed…

1st SuccessParis 19885 year old boy with Fanconi’s Anemia

Bone Marrow VS Umbilical Cord BloodBone Marrow Umbilical Cord

BloodCollection

Requires SurgeryObtained from delivered placenta and umbilical cord

Time of UsageShelf life measured in hours Shelf life can be more

than 20 years

Latent Virus InfectionCommon Rare

Graft VS Host DiseaseCommon in mismatched grafts

Uncommon and less severe even if there is GVHDY Y

YY

HLA-MatchingRequires a perfect HLA-match

1 or 2 allele mismatches proven to be successful

Second TransplantPossible Not possible

HSC VolumeHigh Better engraftment Low Poorer

engraftment

However, most of them are blood-related diseases

To date, over 80 diseases utilize UCBT as a standard therapy…

Current Applications of UCB

• Mucopolysaccharidoses (MPS) Storage Diseases

• Leukodystrophy Disorders

• Lysosomal Storage Diseases

• Neuroblastoma• Retinoblastoma

• Anaemia• Inherited RBC

Abnormalities• Inherited platelet

Abnormalities• Inherited Immune

System Disorders• Myeloproliferative

Disorders• Phagocyte Disorders

• Leukaemia• Lymphoma

Paediatric Hematologic Malignancies

Other Blood Disorders

Inherited Metabolic Disorders

Solid Tumours

UCB Treatable Diseases

Paediatric Haematological Cancers

Acute Lymphoblastic Leukaemia T-Cell Lymphoma

Blasts

Blasts

Blasts

Blasts

Blasts

Blasts

Leukaemia• Cancer of

WBCs in the bone marrow

• Increase of immature WBCs (Blasts)

T-Cells

B-Cells

T-Cells

B-Cells

B-Cells

T-Cells

Lymphoma• Cancer of

WBCs in the lymphatic system

• Increase of B and T-Lymphocytes

Paediatric Haematological Cancers

“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

In 2000,

Paediatric Haematological Cancers

The study compared 113 children who received UCBTs and

2052 children who received BMTs…

Bone Marrow Umbilical Cord Blood

% Patients developing

Graft VS Host Disease

(Day 100)

14%24%

Days to Neutrophil

Engraftment

2618

Paediatric Haematological CancersMost surprisingly, the 3-year survival rate was around the same!

Alive64%

Dead36%

Umbilical Cord Blood TransplantAlive Dead

Alive66%

Dead34%

Bone Marrow TransplantAlive Dead

Hence, the suitability of UCB for treatment of paediatric haematological cancers was confirmed.

Hurler Syndrome

Although also known as gargoylism, skeletal deformities are the least of the patient’s concern…

Hepatosplenomegaly

Cardiomegaly

+Neurological

Disorders

+ = MedianLifespan

11.6 years

• Belongs to a group of genetic disorders (mucopolysacchraidoses)

• Absence or malfunctioning of lysosomal enzymes required to breakdown glycosaminoglycans (GAGs)

Treatments for Hurler Syndrome

However, enzyme cannot treat CNS affected disease due to the blood-brain barrier…

Medical treatment relies on Laronidase, an enzyme replacement therapy…

Hurler’s Syndrome

“Cord-Blood Transplants from Unrelated Donors in Patients with Hurler’s Syndrome”

By Staba et al

In 2004,

Hurler’s SyndromeFrom December 1995 – October 2002, 20 children with Hurler’s Syndrome were treated with UCBT…

17/20Survived 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

What else will umbilical cord blood be used for in the future?

Organ RegenerationThe most exciting application yet…

However, the concept is still preliminary

Are there enough MSCs in the UCB for regeneration

purposes?

Is there a difference in the

regenerative potential of UCB-derived MSCs as compared to BM-derived MSCs?

UCBT in AdultsThe low HSC volume in UCB has been its most limiting factor yet…

Paediatric Disease x xP

Adult Disease

In a 2001 NEJM study, 40% adult patients who underwent unrelated UCBT passed away before Day 100…

Methods of Increasing HSC Counts

Double UCBTEx-Vivo ExpansionNotch-1

• Little is known of the biology or the factors deciding unit dominance

• Larger clinical trials required to evaluate overall survival and infection rates

Paediatric Autoimmune DiseasesPaediatric autoimmune diseases are rare…

However, treatment is difficult when they occur…

Systemic Lupus Erythematosus

Juvenile Idiopathic Arthritis

Paediatric Autoimmune DiseasesConcept of UCBT Treatment:

Step 1: Chemotherapy to eradicate immune

cells

Step 2: Transfuse UCBT (allogeneic/autologous)

Step 3: New immune system develops

MOSTLY ANIMAL DATA!

CLINICAL DATA

DIFFICULT TO INTERPRET!

Gene TherapyTrials for gene therapy have mainly been aimed at cancer and immune deficiencies…

Step 1: Remove HSC from

patient/autologous UCB

HSCs

Step 3: Reintroduce HSCs into patient

Step 2: Genetically alter the HSCs

RNAi

Zinc-finger

Nucleases

Oligoneucleotides

Autologous UCBT Gene TherapyUCB 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?

Tolerance InductionAlthough graft rejection can be reduced by immunosuppresants…

Only 40-60% of grafts continue to function after 10 years…

Concept of HSC tolerance induction

Tolerance Induction

Donor

Step 2: Infuse solid-organ donor HSCs

Step 3: Mixed chimerism is

achieved. Tolerance is induced.

Recipient HSCsDonor HSCs

Step 1: Irradiation or preparative regimens

to make space for donor HSCs

Tolerance InductionAlthough 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…

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)