Cord blood storage and stem cells

Keith Tsui

Outline

• Introduction• The state of cord blood in HK• Existing clinical applications• Potential therapies

Umbilical cord and stem cellsCord Blood Cord Tissue

Stem cells Hematopoietic stem cells Mesenchymal stem cellsCurrent treatments

Hematological, immunological and metabolic storage disorders

No

Storage Availability

Public and private Private only

Future potential Ex vivo expansion for adult useGene therapy?

Regenerative therapy?

Hong Kong

• Public– Hong Kong Red Cross (since 1998)– KWH only due to logistic reasons

• Private– Healthybaby– Cordlife– Cryolife

Public vs Private

• Public:– Allogenic donation

• Private:– Autologous use– Estimated 1 in 2700 to 1 in 20000 chance of cord

blood being used by family member or child– Cost of initial processing and annual storage fee

Sources of cord blood storageNon-directed Directed

Low risk

Donations, public “insurance?”, private

At risk Donations, public “savior sibling”, public/ private

QMH guideline1. Routine directed commercial cord blood collection and stem-

cell storage is not recommended at the present time because of insufficient scientific base to support such practice. Parents’ request should be refused because of logistic problems of collection of cord blood (for private banking) in H.A. hospitals.

2. Collection of cord blood for directed donations for at risk families (e.g. for siblings with β thalassaemia major) should be arranged with the prenatal diagnosis team. The mother requesting collection for directed donations should be referred to PDC for counselling if she is not a patient of the PDC.

How to collect?• When?During third stage or shortly thereafter

• Always focus on minimizing adverse neonatal outcome and postpartum hemorrhage first, Especially if there is prematurity, nuchal cord, C-section, multiple pregnancy

• RCOG recommendation: – There should be no alteration in usual management of the third stage– Collection should be made from the ex utero separated placenta– Collection should be by a trained technician (not midwife or obstetrician)

licensed by the Human Tissue Authority – Service should not be made available when attending clinician believes it to

be contraindicated (nuchal cord or maternal hemorrhage)

Procedure for ex utero collection• Placenta suspended from collection stand• Cord cleansed with antiseptic solution• 16 gauge needle inserted into umbilical vein• Blood allowed to drain into collection bag

with anticoagulant by gravity• Until cord appears empty and mostly white

usually after 2-4 minutes• Volume below 40ml is unlikely to be

sufficient

Follow up studies• Cord blood units should be tested, processed and stored

within 48 hours– Unit volume, weight, total nucleated cell count with differential,

hematopoietic potential (CD34+ cell count or colony forming unit)– ABO/Rh blood type, HLA class I and class II haplotypes– HBV, HCV, HIV, syphilis, CMV, bacterial culture– Hb electrophoresis

• Maternal blood sampling within 7 days for infection screen and maternal HLA type

• Shelf-life: retained viability and engraftment potential for >10 years

History of cord blood transplant

• First case in 1988 for Fanconi anemia• Estimated more than 7000 transplants done

up to 2008• Since 1998, 20% of stem cell transplants for

patients less than 20 years old are cord blood transplants (mostly for ALL and AML)– Data from international Bone Marrow

Transplantation Registry

On lists around the world

• >22.5 million potential adult bone marrow donors

• >601,000 cord blood units

HLA typing

• A suitably matched adult donor is defined as one matched with the patient at ≥7/8 HLA loci (HLA-A, -B, -C, and -DRB1).

• A suitably matched CBU is defined as one matched with the patient at ≥4/6 HLA loci (HLA-A, -B, and -DRB1)

Likelihood of finding an unrelated cord blood unitRange 95-99%: patients <20 years, adequate cell dose, Be The Match Registry®

White European

Middle Eastern/N. A

frican

African Americ

anAfric

an

Black South/Centra

l Americ

an

Black Carib

bean

ChineseKorean

South Asian

JapaneseFili

pino

Southeast Asia

n

Vietnamese

Hawaiian/Pacific Is

lander

Mexican

Hispanic S

outh/Central A

merican

Hispanic C

aribbean

Native North

American

Native South/Centra

l Americ

an

Native Carib

bean

Native Alaska

n0%

10%20%30%40%50%60%70%80%90%

100%

6/6 HLA match ≥5/6 HLA match ≥4/6 HLA match

Race or ethnic group of searching patient for hematopoietic cell transplantation

Mat

ch li

kelih

ood

Gragert L, et al. N Engl J Med. 2014; 371(4): 339-348.

Likelihood of finding an unrelated cord blood unitRange 81-96%: patients ≥20 years, adequate cell dose, Be The Match Registry®

White European

Middle Eastern/N. A

frican

African Americ

anAfric

an

Black South/Centra

l Americ

an

Black Carib

bean

ChineseKorean

South Asian

JapaneseFili

pino

Southeast Asia

n

Vietnamese

Hawaiian/Pacific Is

lander

Mexican

Hispanic S

outh/Central A

merican

Hispanic C

aribbean

Native North

American

Native South/Centra

l Americ

an

Native Carib

bean

Native Alaska

n0%

10%20%30%40%50%60%70%80%90%

100%

6/6 HLA match ≥5/6 HLA match ≥4/6 HLA match

Race or ethnic group of searching patient for hematopoietic cell transplantation

Mat

ch li

kelih

ood

Gragert L, et al. N Engl J Med. 2014; 371(4): 339-348.

White

Euro

pean

Middle Ea

stern

/N. A

frica

n

Africa

n America

n

African

Black S

outh/C

entra

l Ameri

can

Black Cari

bbean

Chinese

Korean

South

Asian

Japan

ese

Filipino

South

east Asia

n

Vietnam

ese

Hawaiian

/Pac

ific Isla

nder

Mexican

Hispan

ic So

uth/C

entra

l Ameri

can

Hispan

ic Cari

bbean

Native North

America

n

Native

South

/Cen

tral A

merican

Native

Caribbea

n

Native Alas

kan

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

8/8 HLA match ≥7/8 HLA match

Race or ethnic group of searching patient for hematopoietic cell transplantation

Mat

ch li

kelih

ood

Likelihood of finding matched unrelated adult donorRange 66-97%: Available suitable match, by race/ethnic group, Be The Match Registry®

Gragert L, et al. N Engl J Med. 2014; 371(4): 339-348.

Cord blood vs Bone marrow• Advantages of cord blood

– Greater degree of HLA mismatch toleration by recipient– Decreased incidence of GVH disease

• Less CD8+ T cells in cord blood– Lower incidence of CMV and EBV transmission– Available in shorter time interval (already tested and banked)

• Around 2 weeks compared with 11-13 weeks in BM transplant– Greater proliferative and colony forming capacity

• More responsive to growth factors

• Disadvantage of cord blood– One log fewer number of stem cells acquired per unit

• Overcame by combined units of cord blood for volume expansion– Ex vivo expansion studies underway

– Slower engraftment

Limitations of autologous cord blood transplant

• Inborn errors of metabolism or other genetic diseases – Genetic mutations already present in autologous stem

cells• Somatic gene therapy research underway

• Childhood leukemia– Chromosomal translocations in fetal blood have been

detected– Negate the beneficial effect of graft vs leukemia effect in

allogenic stem cell transplants

Potential of cord tissue

• Mesenchymal stem cells– Bone– Cartilage– Myocardial muscle– Neural tissue

Biological effects of MSCs in preclinical models of disease

Research underwayNeurological• Intracranial hemorrhage• Amyotrophic lateral sclerosis• Spinal cord injury• Alzheimer's• Parkinson’s• Multiple sclerosis• Cerebral palsy

Others• Myocardial infarction• Osteoarthritis• Rheumatoid arthritis• Inflammatory bowel disease• Lung cancer

No treatment approved yet

Summary

• Non-directed donations • Directed donations for at-risk families• Personal commercial banking for low-risk

families• No alteration in usual management of the

third stage• Cord blood vs Bone Marrow• Potential of MSCs and cord tissue

Reference• Umbilical Cord Blood Banking: Scientific Advisory Committee Opinion

Paper 2, June 2006, Royal College of Obstetricians and Gynaecologists. (reaffirmed 2011)

• ACOG Committee Opinion: Umbilical cord Blood Banking, Number 399, February 2008 (Reaffirmed 2012)

• Moise KJ Jr. Umbilical cord stem cells. Obstet Gynecol 2005;106:1393-407• Antonio Uccelli, Lorenzo Moretta & Vito Pistoia Mesenchymal stem cells in

health and disease Nature Reviews Immunology 8, 726-736 (September 2008) | doi:10.1038/nri2395

• QMH OG guideline• Uptodate.com• Bethematch.org