BHS

Transplant committee

Activities

BHS Transplant committee

• Negotiation with INAMI/RIZIV on changes in HSC transplantation nomenclature

• Continuation of the Valcyte MNP

• Hiring of BHS CRA (Aurélie Ory) to work on the Transplant Committee clinical trials

• Application on behalf of the BHS transplant committee at action 29 of the new Cancer Plan 2012 “Wilms’ tumor (WT1) antigen-targeted dendritic cell vaccination to prevent relapse in patients older than 65 years with acute myeloid leukemia: a multicenter randomized phase II trial” (PI Z Berneman) : successful award of 1,500,000 Eur.

• Initiation of the Belgian Transplant Registry (BTR) in collaboration with the Cancer registry and EBMT

• Ongoing clinical trials

BHS Transplant committee : 2012

– TC02 : Infusion of mesenchymal stem cells as treatment for steroid

resistant grade II to IV acute GVHD or poor graft function: a multicenter

phase II study (01-2008)

– TC03 : Co-transplantation of mesenchymal stem cells and HLA-

mismatched allogeneic hematopoietic cells after nonmyeloablative

conditioning: a phase II randomized double-blind study (07-2010)

– TC04 : A pilot study to assess the feasibility of unrelated umbilical cord

blood transplantation with coinfusion of third-party mesenchymal stem

cells after myeloablative or nonmyeloablative conditioning in adult patients

with hematological malignancies (11-2010)

– TC05 : Randomized double-blind study of mesenchymal stem cells (MSC)

in patients undergoing matched unrelated allogeneic bone marrow or

peripheral blood stem cell transplantation -A European multicentre study

(08-2010)

BHS Clinical trials : MSC

– TC01 : Allogeneic hematopoietic cell transplantation with HLA-matched

donors : a phase II randomized study comparing 2 nonmyeloablative

conditionings (01-2008) – Closed in 02-2011.

– TC06 : Prevention and treatment of severe GVHD after allogeneic

hematopoietic stem cell transplantation, applied as consolidation

immunotherapy in patients with hematological malignancies. A prospective

randomized phase III trial (10-2010)

– TC07 : Allogeneic hematopoietic cell transplantation from HLA-matched

donors after reduced-intensity conditioning: a phase II randomized study

comparing 2 GVHD prophylaxis regimen (09-2011)

– TC08 : Busulfan dosage in allogeneic stem cell transplant recipients

receiving PO Busulfan containing conditioning regimens (11-2012)

BHS Clinical trials : others

– TC09 : Wilms’ tumor (WT1) antigen-targeted dendritic cell vaccination to

prevent relapse in patients older than 65 years with acute myeloid

leukemia: a multicenter randomized phase II trial.

– TC10 : Sequential administration of 5-azacytidine (AZA) and donor

lymphocyte infusion(DLI) for patients with acute myelogenous leukemia

(AML) and myelodysplastic syndrome (MDS) in relapse after allogeneic

stem cell transplantation.

– TC11 : A Phase II study to assess the safety and efficacy of

extracorporeal photopheresis using the Theraflex ECP™ procedure for

patients with steroid-refractory chronic GVHD

– TC12 : Inhibiteurs de JAK2 ruxolitinib avant allogreffe de cellules souches

hématopoïétiques pour les patients atteints de myélofibrose primitive ou

secondaire : étude prospective multicentrique de phase II (in collaboration

with french SFGM-TC).

BHS Clinical trials : in preparation

MSC

Sources & properties

STEM CELLS Bone marrow : HSC & MSC

MSC Characteristics & sources

Leblanc et al,

Nature Rev Immunol

12:383, 2012

Sources

• BM

• Adipose tissue

• CB : no !

• Cord matrix (Wharton jelly)

MSC Multiple functions

Hematopoietic

support

Normal

differentiation

Fat Cartilage

Bone

Plasticity Immunosuppression

Anti-inflammatory

MSC Immunosuppressive properties

Leblanc et al, Nature Rev Immunol 12:383, 2012

MSC Immunosuppressive properties

Stimulated PBMC Stimulated PBMC + MSC (10/1)0

5000

10000

15000

20000

CP

MTregs

Without MSC

With MSC (1 MSC/10 PBMC ratio)

MLR

MSC Immunosuppressive properties

Bartholomew, Exp Hematol 2002

In vivo :

MSC prolong graft survival

In vivo :

MSC treat aGVHD

Le Blanc et al, Lancet 371:1579, 2008

MSC : CLINICAL

Production

Freezing &

banking

Culture

(3-4 weeks)

Bone marrow

collection

(volunteer)

MSC Cell production

• Morphology

• Viability

• Phenotype

• Trilineage differentiation

• Immunosuppressive (MLR)

• Microbiology – Bacterial / fungal culture

– Mycoplasma PCR

– Endotoxin (limulus)

• Karyotype

→ Pre- & post- freezing / thawing

MSC Validation & quality controls

ALLOGENEIC MSC MSC bank

As of May 1, 2012

MSC : CLINICAL

Protocols

• Support HSC engraftment when – Low dose of HSC is injected (cord blood transplantation)

– High risk of rejection (minitransplant)

– Poor graft function

• Immunosuppressive anti-rejection : improved graft survival

anti-GVH : prevention and treatment

autoimmune diseases ?

• Anti-inflammatory

Not immunogenic → universal “off-the-shelf” MSC donor ?

ALLOGENEIC MSC Cell therapy

ALLOGENEIC MSC BHS transplant clinical network

6 clinical trials

Thawing & infusion

Low-dose

conditioning

Co -

transplantation

Safety

D100 NRM

HSC TRANSPLANTATION & MSC Prevention of GVH/rejection : NMHCT (1)

Engraftment

GVHD

ULg

PBSC MSC

(n = 30) Mismatched

donor

Nakamae et al., BBMT 2010 Willems et al., Leukemia 2009

0 365 730 1095 14600

20

40

60

80

100

P=0.04

HLA-mismatched donors

HLA-matched URD

HLA-id sib

Days after HCT

Overa

ll s

urv

ival

(%)

HLA-MISMATCHED NMHCT

STUDY SCHEDULE

Tacro

MMF

2 Gy TBI MSC (> 1-2 x 106 /kg)

PBSC

Days -4 -3 -2 0 28 42 60 100 180 365

Flu 30mg/m2/d

Chimerism Analyses

1 Al 2 Al 1 Ag 1 Ag + 1 Al 2 Ag

0

2

4

6

8

10

12

# o

f p

ati

en

ts

HLA mismatching →

PRIMARY ENDPOINT Day 100 nonrelapse mortality < 35%

0 365 730 1095 14600.0

0.2

0.4

0.6

0.8

1.0

20%

6.5%

Days after HCT

% n

on

rela

pse m

ort

ali

ty

aGVHD (n=2), toxo (n=1), sepsis (n=1), stroke (n=1), CRF (n=1), cGVHD (n=1),

rejection & aspergillosis (n=1)

SURVIVAL

Baron et al, BBMT 2010

N = 20

Low-dose

conditioning

Co -

transplantation

OS

HSC TRANSPLANTATION & MSC Prevention of GVH/rejection : NMHCT (2)

Engraftment

GVHD

BHS

Mismatched

donor PBSC MSC

(n = 120)

R

Pla

ceb

o

High-dose

conditioning

Engraftment Co -

transplantation

AGVHD

CGVHD

HSC TRANSPLANTATION & MSC Prevention of GVH : UD HCT

EBMT + BHS

PBSC MSC

(n = 172)

R

Pla

ceb

o

High-dose

conditioning

Co -

transplantation

Safety

D100 TRM

HSC TRANSPLANTATION & MSC Prevention of GVH/rejection : CBT

Engraftment

GVHD

BHS

CB MSC

(n = 20)

Conditioning No GVHD

HSC TRANSPLANTATION & MSC Treatment of GVHD

HSC

GVHD

MSC

HSC

transplantation

BHS

n = 40

(2 dose levels)

• 20 patients, 17 evaluable – AGVHD : II (2) – III (7) – IV (8)

– Progression D3 (5), refractory D7 (4), no CR D14 (3), relapse during CS taper (5)

– Median time post-Tx 180 days

– Median time post-steroid initiation 25 days

• Results – 13 died

– 4 CR but 2 relapsed

HSC TRANSPLANTATION & MSC Treatment of GVHD

• Why so poor ? – MSC thawing : infuse within 1 H

– Late intervention : include earlier

– Dose : increase MSC dose

• What else ?? – IFN-γ in culture ?

– Sirolimus in patient ?

HSC TRANSPLANTATION & MSC Treatment of GVHD

Conditioning Poor engraftment

- Hematopoiesis HSC

transplantation

HSC TRANSPLANTATION & MSC Hematopoietic support : hematopoiesis

HSC MSC

Hematopoiesis

BHS

n = 40

RESPONSES

CR P

R

NR/P

D NE

0

2

4

6

8

10

# o

f p

ati

en

ts

-50 0 50 100 150 2000

5

10

15

Neutrophils

PlateletsHb

0

100

200

MSC

Days after MSC

Hb

(G

/dL

) &

Neu

tro

p (

x109/L

)

Pla

tele

ts

Survival from MSC

0 200 400 600 8000

20

40

60

80

100

Days after MSCs

Perc

en

t su

rviv

al

46%

N = 30

MSC : CLINICAL

Conclusion

MSC Translational human protocols