Emerging Considerations for Cord Blood Transplantation · Flu 25 mg/m2 daily TBI 165 cGy twice...

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Emerging Considerations for Cord Blood Transplantation

Juliet Barker, MBBS

Joanne Kurtzberg, MD

Koen van Besien, MD, PhD

Moderators:

Janelle Olson, PhD, CHTC

Elizabeth Beduhn, CHTC

2

Cord Blood Unit Panel Discussion

Juliet BarkerOverview of CD34+ as a consideration in cord blood transplantation

Joanne KurtzbergEmerging uses of cords in non-malignant diseases

Koen van Besien

Use of dual haplo/cord blood transplants

12/4/2014

1

Juliet N. Barker, MBBS (Hons), FRACPAssociate Attending

Director, Cord Blood Transplant ProgramMemorial Sloan-Kettering Cancer Center

Using CD34+ Cell Dose in Cord Blood Unit Selection

CSA/ MMF

-3 -2 -1-4-6 -5 30 1000

Laboratory MedicineKatherine SmithRichard MeagherJoann Tonon Adult & Pediatric BMTDuncan PurtillCladd StevensDoris PonceParastoo DahiAndromachi ScaradavouSergio GiraltCBT Program ResearchMarissa LubinEmily LauerBiostatisticsSean Devlin

AcknowledgementsSearch CoordinatorsCourtney ByamEric DavisJen PaulsonMelissa SideroffDebbie Wells

12/4/2014

2

0

25

50

75

100

0 12 24 36 48 60Months Post BMT

Pro

bab

ilit

y of

DF

S

3-yr DFS 8/8 & 7/8 URD-T or dCBT

dCBT (n = 55): 68%

8/8 URD-T (n = 74): 59%

7/8 URD-T (n = 46): 40%

dCBT: higher 3-year DFS than 7/8 URD-T.

P = 0.043 N = 175.Adults16-60 yrs.Acute leukemiaor CML.

dCBT: Inf. CD34+ dose 1.3 + 0.7 x 105/kg.11% 7-8/8, 48% 5-6/8, 41% 2-4/8.

Ponce et al,ASBMT

2014

0

20

40

60

80

100

120

140

160

180

8/8 URD7/8 URDCBNo URD/CB

Patient Ancestry

Distribution of URD, CB & No URD / CB by Patient Ancestry (n = 884)

Nu

mb

er o

f P

atie

nts

Dahi et al, ASBMT 2015

Image unavailable due to copyright restrictions

12/4/2014

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Patient Ancestry

8/8 URD 7/8 URD dCB No 7-8/8 URD/ dCB

Europeans N = 605

397/605(66%)

97/605(16%)

103/605(17%)

8/605(1%)

Non-EuropeansN = 279

African (n = 95)W. Hispanic (n = 59)Asian (n = 66)

74/279(26.5%)

10/95 (11%)16/59 (27%)20/66 (30%)

55/279(20%)

24/95 (25%)17/59 (29%)8/66 (12%)

115/279(41%)

37/95 (39%)19/59 (32%)37/66 (56%)

35/279(12.5%)

24/95 (25%)7/59 (12%)1/66 (1%)

URD, CB & No URD / CB by Patient Ancestry (n = 884)

Dahi et al, ASBMT 2015

Only one quarter of Non-Europeans received 8/8 URD.Access for African ancestry patients most challenging.


Relevance of CB?(beyond extending access if no 7-8/8 URD)

• Decreases need to allograft with mismatched7/8 URD.

• Extends transplant access if no haplo.

12/4/2014

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CB: Approaches to Reduce TRM

• Unit selection• Conditioning• Immune suppression & GVHD• Speeding engraftment (beyond unit selection)• Preventing infections

How to Select Units?

• Dose (TNC, CD34+) & quality• HLA-match• RBC content (thaw & infusion)

12/4/2014

5

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

NYBC(n=149)

Other US (n=123)

International(n=94)

% Viable CD34+s Post-Thaw by Bank (n = 366 units)

Median 94%

(68-99)

Median 89%

(34-98)

Median 92%

(34-98)%

Via

ble

CD

34+

s

Variability in viability by unit & by bank: introduces unit quality as important variable in unit selection.

PROBLEM:Delayed or failed engraftment

increased TRM

SOLUTIONS

• Ex vivo expansion• 3rd party cells• Facilitate homing

• Improved unit selection*

12/4/2014

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Is infused viable CD34+ dose better than TNC dose?

Cell Dose

Analysis of dCBT Neutrophil EngraftmentN = 129: Engraftment 95%

Univariate Variable* HR P value

Recipient Age (continuous, per decade) 0.90 0.031

Dominant Unit Dose: Bank

Pre-freeze TNC 1.19

All< 0.001

Pre-freeze CD34+ 1.39

Dominant Unit Dose: Post-thaw

Inf. TNC 1.28 Inf. Viable CD34+ 1.88 Inf. CFU 1.08 0.001Inf. Viable CD3+ 1.09 0.006

Multivariate analysis: only significant factorinfused viable CD34+ cell dose of dominant unit:

HR 1.95 (95%CI: 1.30-2.90), p < 0.001.

* Diagnosis, CMV serostatus, prep. regimen intensity & HLA match: NS

Purtill et al, Blood 2014

12/4/2014

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Cu

mu

lati

ve I

nci

den

ce

Days Post-Transplant

> 1.40

< 0.5

< 0.50 (n = 32) 1.00 Ref.0.5-0.91 (n = 32) 2.15 0.0040.92-1.4 (n = 32) 1.70 < 0.001> 1.4 (n = 33) 1.86 < 0.001

0.92-1.39

0.5-0.91

Inf. viable CD34+ cell dose


MSKCC dCBT: Neutrophil Engraftment by Dominant Unit Infused Viable CD34+/kg (n = 129)

Winning unit infused viable CD34+ dosedetermines

speed & success.

Pre-freeze CD34+ count

Post-thaw CD34+ recovery

CD34+ viability*

What Determines Infused Viable CD34+ Cell Dose &

Can it be Predicted at Unit Selection?

* Tested at MSKCC by flow cytometry & 7-AAD exclusion


Analysis of 3 Factors in 402 Units

12/4/2014

8

Bank pre-freeze total CD34+ cell count

Pos

t-th

awto

tal C

D34

+ c

ell c

oun

t

Pre- vs Post-Thaw CD34+ Cell Recovery (n = 402)

Overall correlation: r2 = 0.73Median recovery: 101% (range 12-1480)

Low recovery (< 65%): 39 CB units (11%)• Netcord-FACT accredited: 8% • Non-Netcord-FACT accredited: 29%


Pos

t-th

awto

tal C

D34

+ c

ell c

oun

t

p < 0.001

Post-Thaw CD34+ Cell Recovery

12/4/2014

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Median viability: 92% (range 34-99%)< 75% viability: n = 33 (8%)

Pos

t-th

awto

tal C

D34

+ c

ell c

oun

t

Post-thaw CD34+ Cell Recovery & Viability


< 75% viability

Variable (N)N (%) < 75%

CD34+ ViabilityOR*

(95% CI)Multivariate

p value

Netcord-FACT accreditationYes (n = 350) 15 (4%) Reference

0.002No (n = 52) 18 (35%) 4.9 (1.8-13.3)

Cryopreservation year1997 – 2004 (n = 119) 17 (14%) 1.47 (0.6-3.7)

0.4082005 – 2012 (n = 283) 16 (6%) Reference

Cryopreservation volume per bag (ml)< 24.5 (n = 14) 5 (36%) 8.8 (1.9-41.7)

< 0.00124.5 – 26.0 (n = 298) 8 (3%) Reference26.1 – 30.0 (n = 45) 7 (16%) 8.5 (2.6-28.0)> 30.0 (n = 45) 13 (29%) 7.5 (2.5-22.0)

Processing methodManual (n = 187) 24 (13%) 2.3 (0.8-6.5)

0.131Automated + semi-automated (n = 215)

9 (7%) Reference

Factors Associated with Low CD34+ Cell Viability

12/4/2014

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• Infused viable CD34+ cell dose of dominant unit is critical determinant of engraftment after dCBT.

• Post-thaw CD34+ recovery is Bank-dependent:

– Non-Netcord-FACT Banks associated with

lower recovery.

• Post-thaw CD34+ viability is dependent on Banking practices:

– Non-FACT accredited

– < 24.5 ml or > 26 mllower post-thaw

viability

CD34+ Conclusions: Engraftment & Unit Quality Analysis

CD34+ Conclusions:Relevance in Unit Selection

• Pre-freeze CD34+ cell dose can be used for unit selection: more reliable than TNC. Ideally > 1 x 105/kg.

• Quality: another factor in unit selection: Netcord-FACT accreditation, processing & cryovolume.

• Applies to both units of double unit graft.

• Post-thaw testing (with back-up) warranted if lowunit - esp. if single unit CBT.

12/4/2014

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If units can be selected based on likely post-thaw viable CD34+ dose

are 2 units needed?

What is an adequate single?

Graft VariableMultivariate

HR (95%CI) p valueDominant unit viable CD34+ cell dose (continuous)

1.72(1.41-2.10) < 0.001

Dominant unit % viable CD34+ cells (by decile)

1.31(1.03-1.65) 0.026

Non-dominant unit TNC dose (continuous)

1.19(1.01-1.40) 0.035

MSKCC dCBT: Role of Non-Dominant Unit (n = 129 myeloablative dCBT)

Purtill / Barker, ASH 2014

Winner determines speed & success of engraftment,but non-dominant unit may have facilitation effect- role in

overcoming allogeneic barrier to engraftment ???


12/4/2014

12

8 Allele Donor-Recipient HLA-Match

Nu

mb

er o

f C

B U

nit

s (C

BU

)

Selection based on high resolution typing now standard & selection of better matched units possible.

Dahi et al, BMT 2014

Recognition of HLA-Allele Mismatch

4/6 units: 2/8 - 6/8

1

Novel Applications of Cord Blood Therapies

Joanne Kurtzberg, MDJerome Harris Distinguished Professor of Pediatrics

Professor of PathologyPediatric Blood and Marrow Transplant Program

Carolinas Cord Blood BankJulian Robertson Cell and Translational Therapy Program

2

Early Observations• Cord blood could substitute for bone marrow as a donor for

HSCT for all standard allogeneic indications

• Hematological malignancies, marrow failure, immunodeficiencies, hemoglobinopathies, certain inherited metabolic diseases

• Cell dose matters and single cord blood unit may be on the cusp or too small for larger individuals

• HLA matching also matters, but lesser matches can be utilized when higher cell doses are administered

• Immune reconstitution is delayed

• GvHD is decreased as compared to adult HSCT sources

• ?Relapse may be lower post CBT versus other HSCT sources

3

7 14

UCB 2

HLA

<3 ag mm

HLA < 2 ag mm TNC >1.5 x 107/kg

HLA < 2 ag mm TNC >2.5 x 107/kg

0 100

TIME

UCB 1

0501 Treatment Schema

‐3

CY

‐10

FLU

‐9

FLU

‐8

FLU

‐7

TBI

‐6

TBI

‐5

TBI

‐4

TBI

‐2

CY

‐1

REST

CSA

MMF

G‐CSF

Flu 25 mg/m2 dailyTBI 165 cGy twice daily Cy 60 mg/kg daily

100

0

20

40

60

80

0

100

20

40

60

80

Pro

babi

lity,

%

Months 0 3 6 9 12Number at riskDouble UCB 111 95 76 68 62Single UCB 113 102 88 77 71

Double UCB: 65% (55 – 73)

Single UCB: 71% (62 - 79)

Overall Survival- Intent-to-Treat -

P=0.13

4

Engraftment (ANC 500)

Partially Matched, Fresh

(med = 13 days)

NON‐matched, Cryopreserved(med = 19 days)

ConventionalCBT

(med = 25 days)

Expanded Unit CD34 Cell Dose

Average: 6.8 million/kgMedian: 6 million/kgRange: 3.1 to 11.6 million/kg

Expanded Unit CD34 Cell Dose

Average: 12.5 million/kgMedian: 8.3 million/kgRange: 0.9 to 49 million/kg

NiCord® Product for BMT

The CD133 positive cell fraction ‐Cultured for 3 weeks using

NAM technology

The CD133 negative cell fraction ‐Kept frozen till the day of

transplantation

Cultured fraction (CF) Non‐cultured fraction (NF)

+

NiCord®

CliniMACS separation:Enrichment of CD133+ cells

Cord Blood Unit

5

CONFIDENTIALCONFIDENTIAL

I. NiCord® cultured fraction (CF)Day ‐21:Cultured with cytokines (FLT3, SCF, TPO, IL‐6)+ Nicotinamide in cultured bags for 21 daysDay 0:

Cells harvested, safety and quality tested

Hand delivery to clinical site (18hr stability)

NiCord® Graft Processing and Transplantation SchemaNiCord® Graft Processing and Transplantation Schema

‐4‐21 ‐7 1800

ARRIVAL OF NiCord® CF

TO CLINICAL SITE

ARRIVAL OF NiCord® NF

TO CLINICAL SITE

TRANSPLANTATION

I. NiCord® CF

II. NiCord® NF

III. Unmanipulated CBU

‐14

CD133+CD34+ Fraction

II. NiCord® non‐cultured Fraction (NF) Day ‐21: cryopreserved

CD133‐CD34‐ Fraction

CONDITIONING: Day ‐9 to 0 FOLLOW UP

MMFTacrolimus

60‐9



Patients engrafted with NiCord®: 23.5 (Day 14 post transplant discharge)

Patients engrafted with the UM CBU: 40 (Day 31 post transplant discharge)

Duke control cohort (n=17) average 36 (Day 24 post transplant discharge)

Avg. hospitalization days

Rapid PB WBC Reconstitution in Patients Engrafted with NiCord®

NiCord (n=8)

UM (n=2)

Cont. (n=17)

0.00

0.50

1.00

1.50

2.00

2.50

3.00

3.50

4.00

4.50

5.00

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

ANC>500(median)

ANC>500(average)

ANC>500(median)

Days post transplantation

WBC

NiCord® Rapid Engraftment Shortens Hospitalization

Horwitz M et al J Clin Invest. 2014;124(7):3121–3128.


6

CONFIDENTIALCONFIDENTIALStable Donor Derived Chimerism, Over Three Years, Provided by NiCord® HSC’s

Horwitz M et alJ Clin Invest. 2014;124(7):3121–3128.



I. NiCord® cultured fraction (CF)Day ‐21:Cultured with cytokines (FLT3, SCF, TPO, IL‐6)+ Nicotinamide (2.5mM) in cultured bags for 21± 2 daysDay 0:

Cells harvested, safety and quality tested

Hand delivery to clinical site (18hr stability)

‐4‐21 ‐7 1800

CF®ARRIVAL OF NiCord

TO CLINICAL SITE

NF®ARRIVAL OF NiCord

TO CLINICAL SITE

TRANSPLANTATION

.ICF®NiCord

.IINF®NiCord

.IIIUnmanipulated CBU

‐14

CD133+ Fraction

cultured ‐non®II. NiCordFraction (NF) Day ‐21: cryopreserved

CD133‐ Fraction

CONDITIONING: Day ‐9 to 0 FOLLOW UP

MMFTacrolimus

60‐9

NiCord Single Expanded Cord Blood Transplantation


7


First 5 SC Patients, Preliminary Results

Five patients enrolled to date

ANC engraftment on day 9, 11 and 6, 7, 26

aGvHD – grade II in two patients

NiCord® Phase I/II Study – Single Cord Configuration

Myeloablative conditioning regimen: TBI/Flu, Cy optional

GvHD prophylaxis: tacrolimus/mycophenolate mofetil

DC/NICORD Transplantation in patients with Sickle Cell Disease• 5 patients ages 4‐17 years• Severe manifestations• Bu/CY/ATG or Flu/BU/CY• Median day to ANC 500 – day +8• 4 patients engrafted and surviving long term: 8 months‐2 years• 2 with unmanipulated unit, 1 nicord, 1 mixed nicord/UMU


How does SCT correct inborn errors of metabolism?

Marrow and immunoablation

Replacement with donor cells

Donor leukocytes produce enzyme

Enzyme distributed through blood circulation

Cells migrate to brain, cross blood brain barrier, replace enzyme in brain “Cellular Enzyme Replacement Therapy”

Non‐hematopoietic cell engraftment

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Differentiation of Donor Cells into Cardiac Myocytes

A

C

B

A = troponinB = StackingC = myosin

Engraftment of donor‐derived insulin‐expressing beta cells in a recipient of UCBT

Huang et al. Diabetologia (2011) 54:1066‐74

Donor‐derived islet in a 1.5 year old, MPS 1, female recipient of a male UCBT surviving 161 days post transplant

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SCT for Krabbe Disease: Early transplantation is critical!

Escolar et al, NEJM, 2005

Newborn Screening: New York State 2008Now 7 other states

Some newborns with Krabbe Disease have sustained prenatal damage to their cortical spinal tracks

M Escolar, CDL, NFRD, UNC-CH

VP3

VP3 aLL 2-3 DAYS OF AGE tIERNEY, bORRASSA, Degan Miles;Cerebral pudencle - k4 and k6 are normal (yellow is myelination) Middle - Bourassa - less fibres, no myelin; the outcome of the motor function worse in the middle child.Vinod Prasad, 4/12/2007

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Donor Cells engraft in the brain after IV UCBT

DUOC‐01

DUOC‐01 –Initial Description• E Tracy, J Aldrink, J Panosian, D Beam, J Thacker

and M Reese and J Kurtzberg, Isolation of oligodendrocyte‐like cells from, human umbilical cord blood, Cytotherapy (2008) 10, 518‐525.

• ET Tracy, CY Zhang, T Gentry, KW Shoulars and J Kurtzberg, Isolation and expansion of oligodendrocyte progenitor cells from cryopreserved human umbilical cord blood, Cytotherapy (2011)13, 722‐729.

• Completed preclinical toxicology, biodistribution, animal toxicology, validation of manufacturing, stability, development of release criteria, clinical protocol for IND submission

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Robertson CT2

CT2RP2

CCBB

GMP

Clinical Trials

Regulatory / QSU

Stem Cell Lab

100 employees

www.DukeGMP.org

• Flexible manufacturing spaces.

• Three class 10,000 (ISO class 7) suites available

• Aseptic processing, fill, and finish for cellular product

• cGMP sample storage

• Controlled receipt, storage and release of raw materials and supplies

• Environmental monitoring using industry standard equipment with quality audit and trending

GMP Cell Manufacturing Facility

24

13

DUOC‐01‐Manufacturing (GMP)More than Minimally Manipulated

• Thaw 20% fraction of licensed CBU, wash

• Deplete RBC

• Culture, NCS proliferation conditions, demi‐depleting non‐adherent cells in feeding

• Differentiation medium d14‐17

• Trypsinize, wash d21

• Formulate for IT injection in syringe

• Release: viability, sterility, endotoxin, flow

E. Tracy, T. Gentry, GMP Lab

Tissue distribution of DUOC‐01 cells

frequency pg huDNA/reaction Total huDNA (ng/tissue)

day 1 4 of 5 3.4 – 107 pg 9.9 – 539 ng

day 14 4 of 8 0.6 – 18.6 pg 3.7 – 9.8 ng

day 28 3 of 7 1.2 – 7 pg 4.5 – 22.3 ng

day 56 2 of 2 1.8 – 10 pg 4.6 – 32.4 ng

frequency pg huDNA/reaction Total huDNA (ng/tissue)

day 1 5 of 5 0.7 – 104 pg 0.35 – 493 ng

day 14 4 of 8 0.8 – 4.7 pg 0.41 – 6 ng

day 28 4 of 8 0.8 – 6.5 pg 0.44 – 5.1 ng

day 56 1 of 2 1 pg 0.56 ng

Brain

Spine

R. Storms – RP2 Lab


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Activity* of 11 lysosomal enzymes in 5 cGMP batches of DUOC‐01 UCB Number

Enzyme 600661 601558 601217 220058 220115 MEAN SD

β‐galactosidase 914.4 902 281.2 1184.2 974 851.2 302.5

β‐mannosidase 72.8 75.8 54.9 98.7 66.2 73.7 14.4

α‐L‐fucosidase 1819 1661 5452 2171 3409 2902.4 1414.7

α‐mannosidase 503.8 574 377.5 636 757.6 569.8 127.3

β‐glucuronidase 1493 1620 943.7 1754 1429 1447.9 275.7

β‐N‐acetyl‐glucose sulfatidase 2351 2173 1647 3246 2684 2420.2 532.0

arylsulfatase A 119.6 52.2 200.1 115 79.3 113.2 49.9

galactocerebrosidase 1.5 6.9 14.3 9.46 6.51 7.7 4.2

sphingomyelinase 16.4 22.6 30.1 27.1 20.6 23.4 4.8

glucocerebrosidase 127 255.9 428.9 307 373.9 298.5 103.9

α‐L‐iduronidase 48.6 65.5 43.3 28.3 36.4 44.4 12.5

*nmol/h/mg protein

Analysis done by Lysosomal Disease Testing Laboratory, Jefferson Medical College

LSD enzyme production

D. Wenger


Cytokines secreted by DUOC‐01 in response to TNF‐α

A Balber RP2 lab


15

Anti-MBP

Ringers

DUOC‐0172 tiled images of

representative section

Myelin basic protein expression one week after return to normal diet and treatment with DUOC-01 or Ringer’s solution

A. Saha RP2 Lab

DUOC‐01 First in Humans Trial Design

21 days

IT 1-5 X106 cells DUOC-01

CBT provides enzyme permanently

Cells from CBT in

CNS

IND 9/2014

16

Our Roadmap

Allo UCBT in IMD

Allo UCBT in IMD

Donor cells engraft in brain

Donor cells engraft in brain

Further injury

prevented, some repair

Further injury

prevented, some repair

What about auto cells for brain injury?

What about auto cells for brain injury?

What about an allo cord‐derived

product for Brain Injury?

What about an allo cord‐derived

product for Brain Injury?

Autologous UCBT at Duke

Safety

HIE Study “Babybac”Cooling +/‐ UCB infusion

Auto UCB infusion (volume reduced, fresh CB)

Congenital Hydrocephalus

HLHS/ECMOCryopreseved cord blood

CP ages 1‐6 Cryopreserved cord blood

Autism

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HIE (babybac) Pilot StudyMike Cotten, Ron Goldberg, Amy Murtha, STCL, CCBB

• Term Newborns with HIE meeting diagnostic criteria for moderate to severe encephalopathy

• Eligible for cooling

• Collected autologous cord blood

• Cooled per SOC

• Informed consent

• Given autologous CB infusions at <24 and <48 hours of age

• Followed for infusional toxicity, survival and functional outcomes at 1 and 2 years of age

Cotton et al, J Peds, 2014

Survival with 1 yr Bayley III scores> 85 in 3 domains

CellsN = 18

Cooled onlyN = 46

p

*Survived to 15 months

16 (89) 35 (76) 0.25

Survival with all 3 Bayley domain scores > 85

13 (72) 19 (41) 0.05

NEXT STEPS: PHASE II RANDOMIZED TRIAL:240 patients, 8-10 centers~$5-6M

? Standard Rx vs Placebo (RBC pellet)or 1 versus multiple (and later) infusions

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“CP‐AC” (IND)Jessica Sun, Allen Song, Anne Fitzgerald, Colleen Mclaughlin

• Randomized, placebo‐controlled trial of autologous CB in children with spastic CP– Ages 1‐6 yrs– Eligible cord blood– GMFM level (II‐IV)

• Blinded/cross‐over design– Baseline, 1 yr, 2yrs

• Evaluations by exam, neurocog/fxnl testing, MRI (functional in older pts), TMS, CB microarrays, QOL

• Primary Endpoint: >30% increase in predicted GMFM score at 1 year

• Activated 7/2010; completed accrual 2/2013• First analysis planned 3/2015

Phone screen

Qualifiyingvisit

CBU screen and CBU screen and shipment to

duke

*Placebo = TC199 + 1% DMSO

19

Assessing Change in Changing Subjects

Assumptions:– Mean increase of 6 points/year without intervention– ~30% additional increase (7.8 total points/year) would be clinically significant

Gra

ham

HK

. Cla

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l pa

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J P

edia

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2005

;25:

128

.

GMFCS Level I GMFCS Level II GMFCS Level III

GMFCS Level IVGMFCS Level V

GMFM‐66 Percentiles by Age

Han

na S

E, e

t al.

Tabu

late

d re

fere

nce

perc

enti

les

for

the

66‐i

tem

Gro

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20

Longitudinal Assessment

Age = 1yr4mo, GMFCS = 2 Total Streamline Count = 145849 Total Tract Voxel Count = 201506

WM Fraction = 26.88%

Age = 3yr4mo, GMFCS = 1Total Streamline Count = 166743 Total Tract Voxel Count = 291097

WM Fraction = 30.61%

Year 0 Year 2

(Left Hemiplegia)

A Song BIAC

cp010 (T(Left UE)) cp009 (H(Rh))cp011 (H(Lh))

cp025 (Q) cp002 (Q) cp005 (Q)

LR LR LR

LR LR LR

GM

FM

ch

an

ge <

10

Increased normalized connection volume

Decreased normalized connection volume

GM

FM

ch

an

ge >

= 1

0

21

Cell therapies for brain diseases

Genetic Diseases

• Allogeneic cells

• Permanent engraftment– Including brain

• Enzyme replacement

• Requires chemotherapy

Acquired Brain Injuries

• Autologous cells

• Transient presence

• Paracrine/trophic effects

• Signaling of endogenous cells

• No chemotherapy

What about allogeneic cells for treatment of brain injuries?

Allogeneic cells for Acquired brain injuries and other cellular therapies?

• Most patients do not have their cord blood banked.

• A donor derived, readily available product is needed:– Administration without chemotherapy.– Will immunosuppression be needed?– Should the product be HLA matched?

• Therapeutic effects through paracrine signaling

• Durable engraftment not necessary

22

The Marcus Foundation GrantJK and Geri Dawson

• Cord blood derived cellular therapies for treatment of autism, stroke, CP

• Autologous and allogeneic products– Non homologous use

• Minimally manipulated and more than minimally manipulated cells

• Preclinical development, animal models, INDs, 11 clinical trials

FDA LICENSURE‘hematopoietic reconstitution after

myeloablative chemotherapy’

23

Pediatric Blood and Marrow Transplant Team

MDs, APNs, NCs, SC, SW, FA, FSP

Stem Cell Laboratory

Carolinas Cord Blood Bank

CT2: Andy Balber and team

Allen Song and Jim Provenzale

Jessica Sun/Mohamad Mikati/Gordon Worley

Katie Gustafson/Laura Case and ND Team

Amy Murtha, Haywood Brown

Sid Tan, Mike Cotten, Ron Goldberg, RickiGoldstein

Geri Dawson and team

NHLBI, HRSA, NMDP, The EMMES corp

The Julian Robertson Foundation

The Legacy of Angels Foundation

The Katz Foundation

The Marcus Foundation

Acknowledgements

Our Patients and their parents and families

1

Koen van Besien, MD, PhD

NYP‐WCMC

New York, NY

Thanks to: U Chicago

– Hong Tao Liu– Andy Artz– John Cunningham– Lucy Godley– Elizabeth Rich– Justin Kline– Richard Larson– Vu Nguyen– Toyosi Odenike– Wendy Stock– Amittha Wickrema

WCMC– Tsiporah Shore– Usama Gergis– Sebastian Mayer– Melissa Cushing

Transplant Unit StaffResearch CoordinatorRN, PA, Pharm DRehab MedicineBiostatisticsChimerismHLA

2

NATIONAL MARROW DONOR PROGRAM®

Entrusted to operate the C.W. Bill Young Cell Transplantation Program, including the Be The Match Registry®

8/8 Allele, Available-Match Rates in the Adult Donor Registry

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Brunstein C G et al. Blood 2011;118:282-288

HAPLO VS UCB (CTN PARALLEL TRIALS)Hematooietic Recovery Outcome

Age <70 (med 58 UCB, 48 Haplo)AL in CR Chemosens Agg Lymphoma Foll Lymphoma >2 chemo

3

Time

100 40

% D

onor

Chi

mer

ism

Cord Blood Graft

Haplo- identical GraftCD34-Selected

Fernandez, Exp Hematology 31, 535, 2003Magro et al, Haematologica 91, 540, 2006, Liu et al, Blood 118, 6438, 2011

CliniMACS® Plus Cell Separation System

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Melphalan (140 mg/m2)

Tacrolimus

Fludarabine* (30mg/m2/day)

Flu-Mel

-7 -6 -5 -4 -3 -2 -1 0 Day

d –2-d 180

*Thymo 1.5 mg/kg

FLUDARABINE MELPHALAN ATG

d 0-d 28/60Mycophenolate

( )

TBI 2Gray (X X)

• Decrease ATG dose for patients over 50• Decrease MMF• TBI for selected patients

CHIMERISM

UNFRACTIONATED CD3

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PATIENT COURSE• 66 YO WM

• Refractory AML

• ANC d10, Plt d 30

• D50: Unfrac: 100% UCB

• D50: CD3: 100% UCB

Pt 7 Counts

0123456789

10

-10 190 390 590

Days after Transplant

WB

C/A

LC

0

20

40

60

80

100

120

140

160

180

P t 7 U n f r a c t i o n a t e d c h i me r i s m

0

20

40

60

80

100

D a y s a f t e r t r a n s p l a n t

WBC

• 65 YO WM• Transformed Follicular• ANC d10, Plt d14• D50: CD33 100% Haplo• D50: CD3 66% Haplo,

33% UCB

PLT

• 36 YO BF

• Hx Cadaveric Kidney Tx, CRF

• T- MDS

• ANC d10, Plt d42

• D50: CD33 100% UCB

• D50: CD3 100% UCB

WBC

PLT

HAPLOCORD VS DOUBLE UCB CASES REPORTED TO CIBMTR

Haplo Cord Double UCB P

N 98 737

Age 54 48 0.01

% Minority 34 24 0.001

Advanced Disease 44% 23% <0.0001

Year of Tx

2007-2009 18% 50% <0.0001

2010-2013 82% 50%

Presented by: Koen van Besien, MD

Control Selection – (Propensity Score Matching)Match 1 Case with up to four controls matched for: age, gender, race, disease type, disease stage pre-transplant, KPS and years within 2 years

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CASE CONTROL:HAPLOCORD VS DUCB MATCHED COHORTHaplo Cord DUCB P

N 98 340

Median Age 54 52 0.57

Median Weight 80 (41-136) 78 (40-155) 0.32

% male 61 59 0.63

% Minority 34 33 0.89

% AML 55 56 0.96

% Advanced Disease 44 34 0.08

KPS < 80 20 20 0.98

Year of Tx 0.33

2007-2009 18% 23%

2010-2013 82% 77%

Follow up of survivors (median)

14 mo 22 mo 0.19


ENGRAFTMENT OUTCOMES

Haplo Cord DUCB P

Neutrophil

d30 91% 72% <0.0001

d60 96% 86% 0.0001

Platelets

d30 54% 6% <0.0001

d60 78% 54% <0.0001

Presented by: Koen van Besien, MD, PhD

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NEUTROPHIL AND PLATELET ENGRAFTMENT

Presented by: Koen van Besien, MD, PhD

HAPLOCORD VS DOUBLE UCB MATCHED COHORTHaplo Cord Double UCB P

Conditioning Intensity <0.001

RIC or NMA Conditioning 100% 55%

GVHD prophylaxis

CNI+ MMF 100% 89% < 0.001

ATG 100% 24% < 0.001

Total Nucleated Cell Doses (x10^7/kg) Median (range)

1.93 (0.78-20) 4.1 (0.03-21) < 0.001

Degree of Mismatch* < 0.001

None (6/6) 10% 2% (4%)

One Mismatch (5/6) 65% 19% (30%)

Two Mismatches (4/6) 25% 41% (65%)

Three Mismatches (3/6) 0% 1% (2%)

Data not available 36%


Patients who are missing CB match or cell dose data are excluded from Computation

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EXAMPLESx Age Weight Comorb UCB

TNC/kgMatch Out of 8

ANC500

PLT 20 AGVHD CGVHD

Current Status

SC HL Ref 24 136 ADD 1.2 5 14 20 0 NO A&W 17 Mo



ANC500

PLT 20 AGVHD CGVHD

Current Status


CS Tr L SD

63 91 A fibSleepapnea

1.1 8 10 15 0 NO A&W10 Mo

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ANC500

PLT 20 AGVHD CGVHD

Current Status


CS Tr L SD


1.1 8 10 15 0 NO A&W10 Mo

DP AML PIF 66 96 DMArterialclot

1.2 7 9 13 0 NO A&W 12 Mo



ANC500

PLT 20 AGVHD CGVHD

Current Status


CS Tr L SD


1.1 8 10 15 0 NO A&W10 Mo

DP AML PIF 66 96 DMArterialclot

1.2 7 9 13 0 NO A&W 12 Mo

MS AML CR1 +PV +CLL

71 104 ProstatecaTIA Glaucoma

2.5 7 25 38 0 A&W 4 MO

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GVHD prophylaxis

CNI+ MMF 100% 89% < 0.001

ATG 100% 24% < 0.001


1.93 (0.78-20) 4.1 (0.03-21) < 0.001


None (6/6) 10% 2% (4%)

One Mismatch (5/6) 65% 19% (30%)

Two Mismatches (4/6) 25% 41% (65%)





RELATION BETWEEN MINIMAL UCB CELL DOSE AND HR HLA MATCH

0.7

2

0.8

6

0.9

4

0.6

8

0.8

2

0.9

3

0.5

2

0.7

0.8

8

0.3

2

0.5

0.7

8

0.2

0.3

0.6

2

AAFA KOREAN EURCAU

PROBABILITY OF 5/6 UCB UNIT

0.5

1

1.5

2

2.5

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GVHD prophylaxis

CNI+ MMF 100% 89% < 0.001

ATG 100% 24% < 0.001


1.93 (0.78-20) 4.1 (0.03-21) < 0.001


None (6/6) 10% 2% (4%)

One Mismatch (5/6) 65% 19% (30%)

Two Mismatches (4/6) 25% 41% (65%)





INCIDENCE OF ACUTE AND CHRONIC GVHD

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PFS AND OS HAPLO CORD VS CONTROL GROUP

CONCLUSION: HAPLO CORD TRANSPLANT• Reliable and fast Neutrophil and Platelet Recovery

• Ability to use smaller, better matched UCB grafts

• Low rates of acute and chronic GHVD without increases in relapse rates• Use of ATG?

• Better HLA matching?

• Excellent option for • Patients with limited UCB options

• Older patients

• Rapid hematopoietic Recovery

• Low rates of cGVHD

• Long term survival improved

Emerging Considerations for Cord Blood Transplantation · Flu 25 mg/m2 daily TBI 165 cGy twice...

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