APBMT 2016: 28 October - 30 October

1. Public cord blood banks are important
and remain relevant in this era
Sergio Querol MD, PhD
Head, Cell Therapy Services
Catalan Blood and Tissue Bank
Barcelona, Spain
APBMT 2016, Singapore

2. Preliminary questions
• Is CB still used?
• Why did patterns change?
• Could CB banking improve?
• What is unique in CB?
• New paradigm for CBT

3. Is CB still used?
17%22%

4. Adult unrelated registries are unable to provide a donor
for everyone in need
Gragert et al. N Engl J Med 371;4 July 24, 2014
0.2 1 3.6 6.2 8.1 9.9 11.5 18.6 25.5 Donors in Millions
6%/100K 1%/1M

5. 97 (90-99)
83 (66-97)
37 (16-75)
Volunteer HPC donor registry:
Integral A. Donor + Cord
Gragert et al. N Engl J Med 371;4 July 24, 2014

6. Why did patterns change?
• Donor centres and Registries increased their efficiency
• Haplo-postCY
• Randomized single vs double (favouring single)
• CB no completely solved its classical problems:
– Quality issues
– Access: poor international inventory, slow turn over
– Provision cost
– Delay engraftment
– Prolonged immuno reconstitution
– Lack of DLI

7. Europe: BMT Activity 2014
Passweg JR, et al Hematopoietic stem cell transplantation in Europe 2014: more than 40 000
transplants annually.
Bone Marrow Transplant. 2016 Feb 22. doi: 10.1038/bmt.2016.20.
Unmet
needs

8. 76% samples shipped within 2 weeks for CBU
69% samples shipped within 2 weeks for donors
Adult donor registries have increased efficiency

9. Alternative donors: Haplo vs Cord
Brunstein et al. Blood.
2011 Jul 14;118(2):282-8

10. One-unit versus two-unit cord-blood
transplantation for hematologic cancers.
Wagner et al. N Engl J Med. 2014 Oct 30;371(18):1685-94

11. NMDP Cord Blood Transplants
• Multicord transplants are showing the largest negative
variance when compared to the prior year – down 30%
• Single cord transplants are down 6%
• This brings overall cord blood transplants down 20% as
compared to 2015.
11

12. Could CB banking improve?
• Japan as a model
• HQU for off-the-shelf therapies
• Confronting costs

13. 0
5000
10000
15000
20000
25000
30000
35000
0
200
400
600
800
1000
1200
1400
1600
1800
BMT + PBSCT (total 19,397)
CBT (total 13,275)
Total SCT 1,266
Trends in unrelated stem cell transplantation coordinated by the JMDP & CBBs
Year
No.ofBMT+PBSCTorCBT
CBT
52%
The number of transplants via the JMDP includes 165 PBSCT cases. 13
(to April 30th)
Totaltransplantations
421

14. Lessons to learn
• First, size calculation …

15. Cord Blood Bank Size
(Takanashi M., et al., Bone Marrow Transplant. 2011;46:1014-1015) 15
The minimum is 1,600 units with a sufficient cell number for adults.
Hopefully more than 10,000 units to enable better HLA matching.

16. JRC Hokkaido
(1,470 units)
JRC Kanto-Koshinetsu
（3,965 units）
Chubu
(2,621 units)
Hyogo
(368 units)
JRC Kyushu
(1,413 units)
JRC Kinki
(1,501 units)
16
Six CBBs (three organizations) were licensed on April 1st, 2014.
Cord Blood Banks in Japan
The number of cord blood units ready for transplantation as of May 23, 2016:
11,338

17. Lessons to learn
• Then, focus on quality requirements …

18. 18
0
5,000
10,000
15,000
20,000
25,000
30,000
35,000
2008 2009 2010 2011 2012 2013 2014 2015 2016
≥20
≥18, >20
≥16, <18
≥14, <16
≥12, <14
≥10, <12
<10
TNC distribution in CB units available for transplantation at the beginning of the year
TNC (x10^8)
NumberofCBunits
Year
Shrinking bank size: the decrease in the units of TNC ≥10x108 is relatively slight.

19. Lessons to learn
• Then, adjust renewal to use …

20. 20
0
200
400
600
800
1,000
1,200
1,400
1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
≥20
≥18, <20
≥16, <18
≥14, <16
≥12, <14
≥10, <12
<10
Fiscal year (from April 1st to March 31st)
TNC (x10^8)
NumberofCBunits
Cord blood units are selected by total cell count.
Yearly shipping of CB units to transplant centres, with TNC counts

21. 21
0
1,000
2,000
3,000
4,000
5,000
6,000
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
≥20
≥18, <20
≥16, <18
≥14, <16
≥12, <14
≥10, <12
<10
Fiscal year (from April 1st to March 31st)
TNC (x10^8)
NumberofCBunits
Yearly registration of new CB units in the donor search system
CBBs are trying to register CB units with large TNC counts.

22. Towards trully off-the-shelf High Quality Units:
• Upgrade of the already available “good” inventory and disclose “grand-
father” units
• Upfront test of the new inventory including high resolution typing for HLA-
A, -B, -C, -DRB1 and potency assays
• Focus on renewal of released CBUs (>1.5E9) (increase efficiency of
collection programmes and banks) to reduce costs

23. Costs (divided in two phases)
• Establishment phase: Grant
– Define size (5 to 10,000 CBUs)
– Focus on quality (>4E6 CD34+ cells)
– €10M grant
• Maintenance phase: Fee-per-transplant
– Balanced new storage/use (5:1)
– Concentrate in upgrade quality and extend HLA
phenotypes
– Self-sustained (cost could be in the region of €10K)

24. Production cost (Barcelona CBB)
MANUFACTURING COST € Corrected
Collection 15% 347
Disposable 12
Transport 20
HRs 20
Subtotal C 52
Processing 85% 218
VR disposable 135
Cryopreservation disposable 50
Subtotal P 185
Testing 85% 182
HLA (A,B,C,DRB1,ABO) NGS 50
Virology 35
Sterility 15
Haemoglobin 10
Cell Counting 5
Flow Cytometry 30
CFU 10
Subtotal T 155
Fix costs (x1000) 965 965
Amortization (215K/year) 215
Maintenance (170K/year) 170
HRs (12FTE) (580K/year) 580
Subtotal M 965
Total (€) 1712
Overheads and structure (20%)(€) 342 2054
Diversify activities to confront
high fix costs (65%):
•From CB Bank to HPC Donor
Centre to Cell Therapy Service
Optimise production costs (35%):
•Rationalise collection
•Outsource testing
•Automate processing
•Lean management
•Merge competitive institutions

25. What is unique for CB?
Exploting CB Immunology
• Immunogenetics
– Beneficial mismatch
– Balanced GVL / GVHD
• Immunobiology
– Post-thymic CB T cells

26. “Among patients with pretransplantation minimal
residual disease, the probability of overall survival after
receipt of a transplant from a cord-blood donor was at
least as favorable as that after receipt of a transplant
from an HLAmatched unrelated donor and was
significantly higher than the probability after receipt of a
transplant from an HLA-mismatched unrelated donor.
Furthermore, the probability of relapse was lower in the
cord-blood group than in either of the other groups.”

27. New project: CB FIT Panel
• 1.5E9 & 4E6 (Magalon et al, Plos One 2015)
• Full QC, FACT-Netcord Standards compliant
• NGS typing of CB and Maternal Blood
– NIMA/IPA
– PIRCHE
– KIR genomic typing
• International network of 150,000 HQU for HLA
diversity might be sufficient (Van der Zanden et
al, Biol Blood Marrow Transplant 2014)

28. Virtual matching using NIMA
Van der Zanden et al, Biol Blood Marrow Transplant. 2014 Nov;20(11):1791-5.

29. Towards a “personalized” CB selection
1. NIMA virtual match (cord blood T regs) (van Rood et al, PNAS 2009)
– Improving engraftment
– Decreasing TRM
2. IPA (maternal microchimerism) (van Rood et al, PNAS 2012)
– Decreasing relapse
3. KIR genomics and function (NK alloreactivity) (Sekine et al, Blood 2016)
– Decreasing relapse
4. PIRCHE (Bioinformatic prediction of Indirect recognition)(beneficial
mismatching) (Thus et al, Biol Blood Marrow Transpl 2016)
– Decreasing relapse (class I)
– Decreasing GVHD (class II)

30. Preliminary answers
• Is CB still used? A group of patients benefit for CBU
• Why did patterns change? Decrease unmet needs
• Could CB banking improve? Design sustainable CBBs
• What is unique in CB? Exploit neonatal immunology
• New paradigm for CB= Personalised transplantation

31. Conclusion
Public cord blood banks are important and
remain relevant in this era