First clinical results with αβ+ T-cell depleted haploidentical stem cells in children
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Transcript of First clinical results with αβ+ T-cell depleted haploidentical stem cells in children
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First clinical results with αβ+ T-cell depleted
haploidentical stem cells in children
Children’s University Hospital, Tübingen, Germany
P Lang, T Feuchtinger , HM Teltschik, P Schlegel, M Schumm,
P Schwarze, M Pfeiffer, K Schilbach, R Handgretinger
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Haploidentical donors :T cell depletion mandatory
1. CD34+ Selection„pure stem cells“
2. CD3/19 DepletionStem cells + effectors (NK cells)
3. TCRαβ/CD19 DepletionStem cells + effectors (NK cells + γδT cells)
4.
Antigen-
specific
T cells
+
+
1995
2011
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The anti-leukemic activity of gamma/delta T-cells
Otto M. et al: Human γδT cells from G-CSF mobilized donors retain strong tumoricidal activity and produce immunostimulatory cytokines after clinical scale isolation. J Immunotherapy 2005: 28: 73
Godder et al., Long term disease-free survival in acute leukemic patients recovering with increased γδT cells after partially mismatched related donor bone marrow transplantation. BMT 2007; 39,751-757.
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magnet magnetwaste( T cells)
1. biotin-anti- mAb2. microbeads with anti-biotin mAb
graftT-cells
CD34+ and CD34- progenitors
NK cells
dendritic cells
Strategy for depletion of + T-cellsChaleff S. et al.: A large scale method for the selective Depletion of / T-lymphocytes from PBSC
for allogeneic Transplantation. Cytotherapy, 2007
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TCR depletion: Efficacy of procedure
n = 9 Before After Log Depletion
Percent TCR
29.2 ± 6.4 0.0015 ± 0.0008
absolute TCR +
1.4 ± 0.52x1010
0,38 ± 0.22x106
4.6 ± 0.3
absolute CD3+
1.4 ± 0.44x1010
3.5 ± 1.8x108
1.6 ± 0.2
absolute CD19+
2.7 ± 1.4x109
5.3 ± 5.8x106
3.9 ± 0.6
100 101 102 103 104
TCR AB FITC-A
100
101
102
103
104
TC
R G
D P
E-A
1.7 0.1
4553
scatterSC 3-3-04_001.fcs
100 101 102 103 104
CD14 APC-Cy7-A
0
200
400
600
800
1000
SS
C-A
cd14 negSC 3-3-04_005.fcs
100 101 102 103 104
TCR AB FITC-A
100
101
102
103
104
TC
R G
D P
E-A
7.1 0.01
0.0393
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n=49
Comparative analysis of the efficacy of T-cell depletion CD34+ selection vs CD3- vs TcR-depletion
4.6 log
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Graft composition after TCR /CD19 depletion (n=24 patients)
CD34+x106/kg
CD3+x106/kg
CD19+x103/kg
CD56+x106/kg
CD14+x106/kg
aßTcR+x103/kg
TcR+x106/kg
min 5 4.6 46 35 351 1.6 5
max 38 41.8 528 192.2 811 46.4 30
median 12 13.6 110 107.4 618 18.9 11
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Patients (pediatric, n=24)
Diagnosis n=
ALL 12
AML/MDS/JMML 7
Nonmalignant 4
Solid tumors 1
Disease status n=
CR2-CR6 8 (35%)
NR/active disease 11 (48%)
2nd/3rd SCT 16 (70%)
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ATG-F (15 mg/kg)1mg 4 mg 5 mg 5 mg
-12 11 10 9 8 7 6 5 4 3 +12 1 0
Fludarabin (mg/m²) or Clofarabin40mg 40mg 40mg 40mg
Thiotepa (mg/kg)10mg
Melphalan (mg/m²)70mg 70mg
TCR/CD19 depleted cells
days from transplantation
Conditioning regimen (2) n=12
steroids
MMF, if >25.000 residual abT cells
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TCR /CD19 Depletion: Engraftment
ANC>500/ l andindependence from platelet substitution
0 10 20 30 40 50 600
102030405060708090
100
ANC>500 (median: 10days)
independence from platelets (median: 11 days)
days from trp.
%
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TCR/CD19 Depletion: residual T-cells do not cause GvHD
(22/24 patients without pharmacological immune suppression)
acute GvHD grade n= %
no GvHD 5 21
°1 12 50
°2 3 12
°3 3 12
°4 1 4
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TCR/CD19 Depletion: Outcome
Alive: 17 out of 24 patients (70%)
Median Follow up: 0.5 (0.06-1.4) years
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Comparison of CD3+ recovery: CD3/19 vs TCR/CD19 Depletion
0
50
100
150
200
250
300
350
400
0 7 14 21 30 60 90 120 150 180
cell
coun
t/µl
days post transplant
TcRab depletion CD3+
CD3/19 depletion CD3+
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Comparison of CD3+ recovery at day +30
p<0.0001
CD3/19 n = 45 TcRab n = 19
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Comparison of CD3+ recovery: CD3/19 vs TCR/CD19 Depletion
p<0.01
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T cell recovery after TCR Depletion
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T cell recovery after TCR Depletion
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• TCR-Depletion results in grafts with high numbers of effector cells (T cells, NK cells)
• Robust engraftment
• Profound depletion of T cells: prevents GvHD in HLA mismatched trp
• Immune recovery seems to be signifcantly faster than after other graft manipulation procedures
Conclusions
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University Children´s Hospital Tübingen:
Tobias Feuchtinger Heiko-Manuel TeltschikMichael SchummPatrick SchlegelMatthias PfeifferPhilip SchwarzeMartin EbingerKarin Schilbach
Rupert Handgretinger