Hematopoietic Stem Cell Cells Mobilized Peripheral Blood Stem - - PowerPoint PPT Presentation

10/24/2013 1

• Relevant Disclosures
• Medical Director, ViaCord Processing

Laboratory

• Medical Director, AllCells, Inc,

Sources of Hematopoietic Stem Cells

Marrow

Mobilized Peripheral Blood Stem Cells

Cord Blood

Hematopoietic Stem Cell

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Diseases Treatable by Hematopoietic Cell Transplantation

• Leukemia/pre-leukemia
• Non-Hodgkin’

’ ’ ’s and Hodgkin’ ’ ’ ’s Lymphoma

• Multiple Myeloma
• Solid tumors
• Hemoglobinopathies
• Congenital bone marrow failure

syndromes

• Congenital immunodeficency

syndromes

• Inborn errors of metabolism
• Wiskott-Aldrich syndrome

Malignant disorders Hereditary disorders

Umbilical cord blood

stem cell biology

• Higher number of stem cells than adult

peripheral blood

• Myeloid precursor numbers similar to

marrow

• Earliest stem cells (CD34+) show high self-

renewal capacity

• Plasticity of stem cells – possibility of tissue

repair?

Umbilical cord blood

immunology

• Compared to adult blood, cord blood has more abundant

naïve T cells, fewer suppressor T cells, and similar NK and LAK activity

• Cord blood T cells:
• proliferate in response to antigen
• show decreased cytotoxicity
• Alloantigen priming induces state of unresponsiveness
• Reduced risk of Graft-versus-Host Disease

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UCB and Marrow from URD

Bone Marrow UCB US Availability* 10.5 million donors 185,000 CBUs Acceptable Mismatch 1-HLA allele 2 HLA antigens Search time 6 weeks – 6 mos. <1 month 2nd stem collection? Yes No Ease of delivery Often difficult Easy CMV/EBV Yes No Risk to donor Minimal None

* 14 million marrow and 400,000 CBUs available worldwide

NMDP transplantations by hematopoietic cell source.

Effect of cell dose on recovery after HLA-ID sibling UCBT for malignancies

Herr A et al. Blood 2010;116:1849-1856

Effect of cell dose transplant-related mortality after URD UCB transplantation

Barker J N et al. Blood 2010;115:1843-1849

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Private Cord Blood Banking – Academy Recommendations

ACOG Opinion – February 2008

• If a patient requests information on umbilical cord banking, balanced and

accurate information regarding the advantages and disadvantages of public versus private umbilical cord blood banking should be provided

• Discussion may include information regarding maternal infectious disease

and genetic testing, the ultimate outcome of use of poor quality units of umbilical cord blood

• Some states have passed legislation requiring physicians to inform their

patients about umbilical cord blood banking options

• Directed donation of umbilical cord blood should be considered when there

is a specific diagnosis of a disease known to be treatable by hematopoietic transplant for an immediate family member

• The collection should not alter routine practice for the timing of umbilical

cord clamping.

• Physicians who recruit pregnant women and their families for for-profit

umbilical cord blood banking should disclose any financial interests AAP Recommendations regarding UCB storage (January 2007)

• Cord blood donation should be discouraged when cord blood stored in a bank is

to be directed for later personal or family use, because most conditions that might be helped by cord blood stem cells already exist in the infant’s cord blood (ie, premalignant changes in stem cells)

• Directed cord blood banking should be encouraged when there is knowledge of a

full sibling in the family with a medical condition (malignant or genetic) that could potentially benefit from cord blood transplantation

• Cord blood donation should be encouraged when the cord blood is stored in a

bank for public use

• Because there are no scientific data at the present time to support autologous

cord blood banking private storage of cord blood as “biological insurance” should be discouraged (est 0.04% to 0.005% chance of using own cord blood by 21 years – Ballen et al BBMT, 14:356, 2008)

Private Cord Blood Banking – Academy Recommendations

Families with children who have disorders treated by Hematopoietic Cell Transplantation Prospective, full sibling pregnancies Resource to collect, transport, characterize and cryopreserve sibling cord blood units in a central Umbilical Cord Blood Banking Facility Remote sites & community hospitals

Sibling Cord Blood collections by state (Jan. 2012)

10/24/2013 5 55% 1% 14% 25% 5%

Total Sibling Collections= 3448

Oncology Other Rare Sickle Cell Thalassemia

Oncology, 48 Rare, 32 Sickle Cell disease, 39 Thalassemia, 32

Sibling UCBT by Indication (N=151) (Jan. 2013) Number and indications for sibling CBU Releases by year

5 10 15 20 25 30 35 40 45 50 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 Thalassemia Sickle Cell disease Rare Oncology Autologous

Sibling Cord Blood Bank: Fraction of CBUs released for UCBT

• Malignant Diseases

47 Sickle Cell 37 Other/Rare 27 Thalassemia 30

4%

Jan 2012

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STEM CELL PLASTICITY AND TISSUE REGENERATION?

Future applications of UCB and cord tissue

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Animal models of brain injury suggest a benefit in neurologic outcome and survival after UCB infusion

10/24/2013 7 Phase I Investigation of Autologous UCB in Children with acquire CNS injury

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Phase I Investigation of Autologous UCB in Children with acquire CNS injury

Visit 2 (1st Year) Visit 2 (1st Year) Visit 1 (time 0) Visit 1 (time 0) Visit 3 (2nd Year) Visit 3 (2nd Year) Phone Screen Phone Screen CBU Screen and Shipment to Duke CBU Screen and Shipment to Duke Qualifying Visit Qualifying Visit R A N D O M I Z E D R A N D O M I Z E D Enrolled On Study Enrolled On Study Arm 1 Arm 1 Arm 2 Arm 2 UCB UCB Placebo Placebo Evaluation Evaluation Placebo Placebo UCB UCB Evaluation Evaluation Evaluation Evaluation

Mesenchymal Stem Cells

Osteoblast Chondrocyte Myoblast Stromal Fibroblast Tendoblast Osteocyte Chondrocyte Myocyte Stromal Cells Tendocyte Adipocyte Muscle Cartilage Bone Stroma Tendon Adipose Pereadipocyte After Caplan

MSC activities

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10/24/2013 8 Umbilical Cord Tissue is a rich source of stem cells

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HUCPVCs Meet All the MSC Criteria MSCs in Liver Regeneration

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Stroke and MSCs

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UC-MSC–treated group PBS-treated group Sham group

Day(s) After Treatment 3 10 17 24 31

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8 6 4 2 10 12 14 16 18 Score *P < 0.05 **P < 0.01 baseline * ** * * Lower scores = less impairment 50 UC-MSC–treated group PBS-treated group P = 0.026 Ratio of Injury Volume, % 40 30 20 10

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Number and Potency of MSCs Decreases with Age

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Hematopoietic Stem Cell Gene Therapy

• UCB is a source of cells for Replacement Gene Therapy
• Mesechymal/Endothelial cell progenitors in UCB are

targets of transduction; hVEGF expression in transduced UCB improved blood flow in a rat hind- limb ischemia model

• Foamy virus vectors transduce 65% human UCB-

derived primitive long-term repopulating cells in a NOD/SCID xenotransplantation model compared to 34% of mobilized peripheral blood progenitor cells

Josephson NC, et al, Hum Gene Ther. 2004 15:87-92, Ikeda Y, et al, Hypertens Res. 2004;27:119-28

Summary

• Cord Blood Transplants can cure children with

genetic or malignant disease.

• Cord blood collection and storage should be

encouraged for all families who currently have a child with a transplantable disease who are having another child.

• Research applications hold promise in the

areas of stem cell plasticity and injury repair, and in gene therapy applications