An Introduction to Canada s National Public Cord Blood Bank

An Introduction to Canada s National Public Cord Blood Bank Dr. Heidi Elmoazzen Director, National Public Cord Blood Bank

Hematopoetic Stem Cells Hematopoetic stem cells are not yet mature (undifferentiated) cells that can divide and develop into any one of the three main types of cells found in the blood: Red blood cells, which carry energy-giving oxygen from the lungs to the entire body; White blood cells, important immune cells that play an important role in fighting bacteria and viruses that cause infection; and Platelets, which help blood to clot when bleeding occurs. 2

3 How are stem cells collected?

Stem Cell Transplants Adults and Children With Life Threatening Diseases Leukemia Lymphoma Aplastic Anemia Immune Dysfunctions Genetic Disorders 4

OneMatch Stem Cell and Marrow Network Canadian Blood Services national public cord blood bank is part of the OneMatch Stem Cell and Marrow Network, which is a national program that: recruits healthy, unrelated, volunteer blood stem cell donors conducts searches for patients who need an unrelated blood stem cell transplant coordinates the collection and delivery of blood stem cells when a match is found

Why Unrelated Donors? HLA Typing: inherited genetic markers Only 25% of patients have a match in family Unrelated donors are often from the same ethnic group as the patient Leila, OneMatch Registrant & whole blood donor 6

Increasing need for UCB With declining fertility rates in recent decades, fewer patients will have HLA-matched siblings There will be an increasing reliance on alternative sources of cells such as cord blood or unrelated donors Cord blood banking may represent an ideal strategy to embrace the evolving ethnic diversity in a given jurisdiction. Especially relevant given diverse immigration patterns over recent decades in Canada. HLA-compatibility in cord blood transplantation is less stringent than with bone marrow or peripheral blood progenitor cells

Reducing fertility rates = fewer matched related sibling donors Allan et al, BBMT 2009 Slide kindly shared by Dr. David Allan, Canadian Blood Services

Table. Calculating the chance of identifying an HLA-matched sibling donor depending on the year of birth of the donor. Donor/patient birth year Average birth rate (actual) Sibling Rate (calculated) Chance of 1 HLA-matched sibling donor (calculated)* 1951 1955 3.65 2.65 53.3% 1956 1960 3.88 2.88 56.3% 1961-1965 3.68 2.68 53.7% 1966 1970 2.61 1.61 37.1% 1971 1975 1.98 0.98 24.6% 1976 1980 1.73 0.73 18.9% 1981 1985 1.63 0.63 16.6% 1986 1990 1.62 0.62 16.3% 1991 1995 1.69 0.69 18.0% 1996 2000 1.56 0.56 14.9% 2001 2005 1.52 0.52 13.9% Allan et al, BBMT 2009 Slide kindly shared by Dr. David Allan, Canadian Blood Services

OneMatch Fast Facts May 2014 Searchable donors: 342,224 Canadian Transplant Centres: 12 Canadian Collection Centres: 8 International Registries: 73 Over 24,069,577 registrants worldwide International Cord Blood Banks: 47 Over 607,895 umbilical cord blood units Francis, OneMatch Registrant 10

11 OneMatch Registrants: May 2014 N=342,224

12 Ethnic composition of OneMatch database

WHY build a National Public Cord Unacceptable that we can only find matches for approximately 50% of our Canadian patients. Blood Bank now? This valuable resource is being discarded as medical waste. 13

March 14, 2011 Official Announcement Ministers of Health announce Canada's national, publicly-funded umbilical cord blood bank $48 million investment over eight years. The provincial and territorial governments recognized this as an important health need and signed a contract to provide operational funding for this new initiative to be led by Canadian Blood Services. Canadian Blood Services is committed to raise $12.5 million needed to cover start-up costs. April 1, 2011 National Public Cord Blood Bank project began in Ottawa, as per approved model by the Ministers of Health September 30, 2013 Go-live in Ottawa! July 7, 2014 Go-live in Brampton (Greater Toronto Area) End of 2014 Edmonton, Vancouver 14

Number of Patients Canadian Patient Searches- The demand and need continues to increase 1000 900 811 894 968 852 800 700 708 600 543 500 400 300 295 393 475 200 100 0 2004/2005 2005/2006 2006/2007 2007/2008 2008/2009 2009/2010 2010/2011 2011/2012 2012/2013 Total 15

Canadian Stem Cell Recipients Canadian Unrelated Transplants 2002-2012 450 400 350 300 250 369 International Donor 200 150 148 190 187 203 228 252 285 266 Canadian Donor 100 50 0 89 43 61 39 45 43 36 45 58 53 55 02/03 03/04 04/05 05/06 06/07 07/08 08/09 09/10 10/11 11/12 16

Number of Cord Units Procured Cord Units Selected for Canadian Patients 100 90 80 8 10 70 60 9 50 40 73 87 86 82 89 30 20 43 54 50 10 0 2005/2006 2006/2007 2007/2008 2008/2009 2009/2010 2010/2011 2011/2012 2012/2013 Fiscal Year International Cords Hema-Quebec Cords 17

1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 Number of HPC Cord shipped Number of Cord Blood Units provided for Unrelated Transplantation (Data courtesy of WMDA) Number of cord blood units provided for unrelated transplantation 4,500 4,000 2012 4,150 3,500 3,000 2011 4,093 2,500 2,000 1,500 1,000 500 0 Year No information provided Units provided for adults Units provided for children 18

Caucasian Patient Searches 600 500 400 300 Caucasian 200 100 0 2008/09 2009/10 2010/11 2011/12 2012/13 2013/14 Number of Patients 2008/09 2009/10 2010/11 2011/12 2012/13 2013/14 Caucasian 359 415 482 513 502 480 19

First Nations, Métis, Inuit Patient Searches 14 12 10 8 First Nation, Metis, Inuit 6 4 2 0 2008/09 2009/10 2010/11 2011/12 2012/13 2013/14 Number of Patients 2008/09 2009/10 2010/11 2011/12 2012/13 2013/14 First Nation, Métis, Inuit 7 6 14 13 12 12 20

Canadian Aboriginal Patients Number of Patients 2001/02 2002/03 2003/04 2004/05 2005/06 2006/07 2007/08 2008/09 2009/10 2010/11 2011/12 Active 0 1 1 1 3 6 4 6 4 12 13 Cancelled 0 39 42 43 49 50 61 71 75 79 95 Preliminary 0 0 0 0 0 0 0 1 2 2 1 Workup 0 0 1 1 0 0 0 0 1 1 0 16 14 Number of Aboriginal Patient Searches 14 13 12 10 8 6 4 3 6 4 7 6 2 0 1 1 2003/04 2004/05 2005/06 2006/07 2007/08 2008/09 2009/10 2010/11 2011/12 21

Aboriginal Patient Transplants (2005-2012) Canadian Donors, 5 International Donors Germany, 2 Belgium, 1 United States, 24 Spain, 1 22

Products Used for Aboriginal Patients (2005-2012) DLI 6% PBSC 23% Cord 53% Marrow 18% 23

Chinese and South Asian Patient Searches 40 35 Chinese South Asian 30 25 20 15 10 5 0 2008/09 2009/10 2010/11 2011/12 2012/13 2013/14 Number of Patients 2008/09 2009/10 2010/11 2011/12 2012/13 2013/14 Chinese 7 16 22 25 34 36 South Asian 14 20 23 34 40 36 24

Black and Multicultural Patient Searches 40 35 30 25 20 Black Mixed Culture 15 10 5 0 2008/09 2009/10 2010/11 2011/12 2012/13 2013/14 Number of Patients 2008/09 2009/10 2010/11 2011/12 2012/13 2013/14 Black 20 26 24 36 33 33 Multi Cultural 11 22 30 30 32 32 25

Canadian Black Patients Number of Patients 2001/02 2002/03 2003/04 2004/05 2005/06 2006/07 2007/08 2008/09 2009/10 2010/11 2011/12 Active 0 6 9 14 15 22 19 21 31 31 44 Cancelled 0 82 87 91 101 105 119 128 137 152 164 Preliminary 0 0 0 1 1 0 2 2 0 3 3 Workup 0 0 1 1 0 0 1 0 0 1 2 26

Why Cord Blood? Cord blood has distinct advantages over bone marrow or PBSCs: More lenient HLA matching requirements Units are available immediately Lower risk of graft-vs.-host disease (GvHD) Minimal risk to donor (mother and baby) More likely to find a match from someone of similar ethnic background. Today all cord blood units supplied by Canadian Blood Services for unrelated transplant are imported from international sources at significant cost. 27

National Public Cord Blood Bank Model Five collection sites and two manufacturing facilities for processing, storage and distribution. Canadian Blood Services Medical and Scientific Advisory Committee Searching, Matching OTTAWA Manufacturing Facility (Sept. 2013) EDMONTON Manufacturing Facility (2014) CBS Support HLA Testing Transmissible Disease Testing CBS Research Ethics Committee (units unsuitable for transfusion) Marketing & Recruitment Canadian Transplant Programs OTTAWA Collection Sites (2) (Sept. 2013) EDMONTON Collection Site (2014) Canadian Research Scientists International Registries BRAMPTON Collection Site (2014) VANCOUVER Collection Site (2014) 28

Cord Blood and Research Approximately 15% to 40% of the cord blood units collected are of sufficient volume and/or cell count to be used for transplantation. Mother s in Ottawa will have the option to donate their baby s cord for research in Canada if it cannot be used for transplantation. 29

Cord Blood for Research Program The Cord Blood for Research Program mission is to facilitate research that promotes advances in the fields of transfusion, cellular therapies and transplantation medicine in Canada. Canadian Blood Services Cord Blood for Research Program distributes to approved research projects, and with the mother s consent, cord blood products collected at the Ottawa Hospital that do not meet the criteria for storage in Canadian Blood Services National Public Cord Blood Bank. The program began on 2014-08-05 Research projects are being approved and cord blood units are being distributed for research 30

Cord Blood Banking Process Seven key processes for cord blood will include capturing and centralizing data on a per unit basis for traceability, searching and matching, information management, ad-hoc queries, reporting, data export and modeling for optimization. Awareness Recruitment Collection Receiving, Assessing, Processing, Testing, Storage Searching, Matching Distribution Transplant, Follow-up Stem Cell National Systems Solution 31

Awareness Marketing Objectives 1. To develop strategy to raise awareness of the public cord blood bank among prospects to facilitate recruitment 2. To implement tactics to support recruitment 3. To develop strategy for donor recognition 32

Recruitment Our target group is specific and localized, i.e., healthy pregnant women who plan to deliver at the designated collection hospitals: Discussions begin during the antenatal period with their health care professional Education, information gathering, questions (becoming informed of process in advance of day of delivery) Arrive on special day with Permission to Collect form ready No advance registration 33

Maternal Information Booklet 34

Who Can Donate? Healthy pregnant women, 18 years of age or older, can donate cord blood with their signed consent. A mother qualifies to donate her baby s cord blood if neither she nor her infant has any diseases or medical conditions that could be passed on to a patient who receives a cord blood stem cell transplant. Eligibility criteria have unique differences from whole blood. Mothers reaching 34 weeks or later who are not having a multiple pregnancy, may consider donating their baby s cord blood. A mother must deliver at one of our designated collection hospitals in order to donate her baby s cord blood to Canadian Blood Services national public cord blood bank. 35

Collection Two Collection Methods 1. Ex-utero: Fully supported by CBS NPCBB designated staff 2. In-utero (supported): All aspects of collection, labelling, packing/shipping by hospital staff CBS NPCBB Nurse Specialist for maternal interview The Ottawa Hospital September, 2013 General Campus: Ex-utero Civic Campus: In-utero, CBS supported Remaining Collection Hospitals, 2014 Edmonton, Vancouver, Brampton (Greater Toronto Area): Ex-utero 36 36

Collection Five Collection Sites: TNC cutoff 1.5 X 10 9 Caucasian TNC cutoff 1.3 X 10 9 Ethnically diverse 37

Manufacturing Stem Cell Manufacturing Facility: Peripheral Blood Apheresis / Bone Marrow: Processing, testing, storage, distribution FACT Accredited / GMP Guidelines Staffing: Charge Technologists and MLTs Manufacturing Equipment 38

Processing Sepax System Fully-automated, mobile, GMP compliant system for the efficient and reproducible processing of umbilical cord blood, bone marrow and peripheral blood Hands-free operation automated, closed, sterile system Quick, accurate data tracking Consistently high mononuclear cell recoveries 39

Testing Blood cell counts (Pre and Post) Purity, Potency, Safety Purity: Microbiology Potency: Stem Cell Counts Flow Cytometer (CD34+ count) CFU Assay (stem cell culture) Safety: Genetic screening, infectious disease testing HLA NIMA ABO QC samples storage 40

The IPA/NIMA effect Mother IMA/NIMA Father IPA/NIPA NIMA = non inherited maternal antigens NIPA IMA IPA = non inherited paternal antigens = inherited maternal antigens = inherited paternal antigens The mother develops B and T cell immunity against the IPA of the fetus, which is controlled by T reg. PNAS 2012 Likewise, the foetus develops immunity and Tregs against the NIMA. CTL s and Tregs identified in foetus, cord blood and adults. Foetus IMA/IPA Immunity and regulation can be lifelong in both mother and child. PNAS 2009 Slides courtesy of Jon J. van Rood, Leiden University Medical Center and Europdonor Foundation

Identification of an acceptable mismatch with the help of NIMA van Rood et al. Pnas: 2009, 106, pp 19952 Patient cord blood A1, A2 - B7, B44 A1, A3 - B7, B44 mother of CB A1, A2 - B7, B8 NIMA=A2 and B8 Combining the NIMA A2 and/or B8 with the CB phenotype can create e.g. the Virtual CB phenotype: A1, A2 / B7, B44 and 5 other Virtual Phenotypes (VP) if there is 1 substitution, 12 when there are 2 and 8 when there are 3. HLA typing of the mother can create 26 up to different VPs!! Slides courtesy of Jon J. van Rood, Leiden University Medical Center and Europdonor Foundation

Transplant-Related Mortality (Patients 10 Years Old) 80 % with TRM (Cum. Incid.) 60 40 20 2 MM, No NIMA Match Reference N= 357 2 MM, 1NIMA Match N= 31 1 MM, No NIMA Match Reference N=131 1 MM, 1NIMA Match N=10 0 0 1 2 3 Years Post-Transplant 0 Mismatch 4/22 RR=0.3 P = 0.011 1+2 MM, 1 NIMA 20/41 RR=0.6, P= 0.012 PNAS 2009 106 (47) p10952

Cryopreservation Volume reduced cord blood unit Cryo-protectant added (DMSO) Controlled rate freezing using ThermoGenesis BioArchive freezer Holds up to 3,636 units Liquid nitrogen storage (-196 C) Inventory controlled / tracked Must be stored within 48 hours of collection; can be stored indefinitely 44

Searching and Matching Listed on OneMatch Registry Banked inventory of cord blood units Cords listed, searched and requested Searched both nationally and internationally Stem Cell National Systems Solution (IT system) Physicians / Clinical Transplant sites request banked cord blood unit Build on current OneMatch process 45

Distribution Requested Cord Blood for Transplant Manufacturing selects, releases, packs and ships Transport courier 46

Transplant and Follow-up Transplant Follow-up: Outcome Measurement Build upon the current OneMatch process Infusion Reactions Engraftment Data 100 day follow-up Family History Genetic 47

What Transplant Physicians Want Want to know about factors that influence the graft potency (i.e. volume, TNC, CD 34 + ) Want to know IDM are negative Want to be ensure the unit is matched Want to know the unit comes from an accredited bank Want to know their patient will not acquire a genetic or serious disease The Selection and Acquisition of Unrelated Cord Blood Grafts Dr. Juliet Barker et al, Blood 2011; 117:2332-9. 48

Operations Update Ottawa & Brampton

Ottawa Monthly Collections by Site 120 113 TOH - General TOH - Civic 107 105 100 80 60 77 79 67 92 81 79 71 63 65 83 59 91 68 68 66 88 69 70 40 34 20 0 October* November December January February March April May June July August ** 2013-2014 *Note that this figure includes September 30 th. **Note that this is an ongoing month. Figure includes Aug 1-17. 50

Volume (ml) Ottawa Average CBU Volume (ml) by Month and by Site 140 TOH - General TOH - Civic 120 118 100 80 101 103 93 88 88 90 97 101 91 94 84 83 85 81 83 88 96 89 82 87 99 60 40 20 0 October* November December January February March April May June July August** *Note that this figure includes September 30 th. **Note that this is an ongoing month. Figure includes Aug 1-17. 51

Ottawa Cumulative Average of Pre-Production TNC 1.3 Caucasian 1.27 Non-Caucasian 1.25 1.2 1.15 1.1 1.16 1.1 1.07 1.21 1.09 1.05 1 0.95 TOH - General TOH - Civic Both 52

Brampton Average of Pre-Production TNC 1.1 1.08 1.09 1.06 1.04 1.02 1 0.98 0.99 0.96 0.94 Caucasian Non-Caucasian 53

Ottawa Ethnicity of All Cord Blood Units Collected 60% 50% 40% 30% 20% 10% 0% 1849 units collected between 2013-09-30 to 2014-09-14 49% 18% Caucasian Multi-Ethnic 15% None Listed 8% 5% 4% 0.38% Other Asian Black Aboriginal Caucasian 49% Multi-Ethnic 18% None Listed 15% Other 8% Asian 5% Black 4% Aboriginal 0.38% Arab 69% Hispanic 15% Jewish-Ashkenazi 3% Jewish-Sephradic 1% Pacific Islander 0% Other 12% Central Asian 11% Chinese 24% Filipino 10% North Asian 1% Northeast Asian 6% South Asian 28% Southeast Asian 20% African 61% Caribbean 28% Other 11% First Nations 43% Inuit 43% Métis 14% 54

Brampton Ethnicity of All Cord Blood Units Collected 60% 50% 40% 30% 20% 10% 0% 163 units collected between 2013-07-07 to 2014-09-14 48% 23% 12% 10% 4% 3% 0% Asian Caucasian Multi-Ethnic Black Other None Listed Aboriginal Asian 48% Caucasian 23% Multi-Ethnic 12% Black 10% Other 4% None Listed 3% Aboriginal 0% Central Asian 0% Chinese 1% Filipino 4% North Asian 5% Northeast Asian 6% South Asian 71% Southeast Asian 13% African 25% Caribbean 63% Other 13% Arab 17% Hispanic 50% Jewish-Ashkenazi 0% Jewish-Sephradic 0% Pacific Islander 0% Other 33% First Nations 0% Inuit 0% Métis 0% 55

Phase II Project Update Edmonton, Vancouver

Phase II Update PV started on 2014-08-05, as scheduled 12 bankable units required Proposed Go-live for Edmonton/Vancouver Collections and Edmonton Manufacturing is on track for December, 2014.

Phase II Vancouver Collections BC Women's Hospital and Health Centre First collection for validation/training purposes took place on February 18, 2014 58

Phase II Edmonton Collections Lois Hole Hospital for Women First collection for validation/training purposes took place on February 24, 2014 59

Phase II Edmonton Manufacturing Vestibule/Entrance 60

Phase II Edmonton Manufacturing Processing 61

Phase II Edmonton Manufacturing Testing 62

Phase II Edmonton Manufacturing Cryopreservation 63

Fundraising- For All Canadians Over $9.19 million raised to date 64

heidi.elmoazzen@blood.ca 65

www.blood.ca/cordblood 66