The question is not whether or not to deplete T-cells, but how to deplete which T-cells

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1 The question is not whether or not to deplete T-cells, but how to deplete which T-cells CD34+ positive selection Negative Depletion of: CD3/CD19 TcRαβ/CD19

2 T-cell depletion: positive selection versus negative depletion CD34+ positive selection CD3/19 depletion Gordon et al.: A large-scale method for T cell Depletion: towards graft engineering of mobilized peripheral Blood stem cells. Bone Marrow Transplant 2002; 30: Barfield et al.: A one-step large-scale Method for T-and B-cell depletion of Mobilized PBSC for allogeneic transplantation. Cytotherapy 2004; 6:1-6. Chaleff S. et al.: A large scale method for the selective Depletion of αβ+ T-lymphocytes from PBSC for allogeneic Transplantation. Cytotherapy 2007; 9:

3 CD34+ positive selection Aversa F et al.: Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype. New England J. Medicine 1998;339: BM + G-PBSC s: E-rosetting + CD34+selection (CellPro)

4 Tübingen Pilot Study (children) Perugia (adults) Handgretinger et al.; Bone Marrow Transplant. 2001; 27: Aversa et al., J Clin Oncol 2005; 23:

5 GvHD after myeloablative conditioning (TBI/Busulfan/ATG/OKT-3 based) no GvHD prophylaxis T-cells: /kg (range ) grade 0-I II III-IV 91% 7% 2% Ciritical threshold for T-cells: /kg (without GvHD prophylaxis)

6 Reconstitution of CD3+ T-cells after haploidentical With CD34+ positively selected stem cells % of patients with CD3>0.1x10/L 9 Cumulative Incidence >20x10 6 /kg <20x10 6 /kg days after transplantation lethal viral infections (ADV, CMV, HSV) lethal viral infections(onlyadv) years Handgretinger et al.; Bone Marrow Transplant. 2001; 27: CD34+

7 EFS after haploidentical transplantation in patients with AML with refractory disease or remission at time of Tx Ruggeri et al., BLOOD 2007; 110:

8 Risk of relapse in pediatric patients with ALL (n=19) after haploidentical transplantation of CD34+ stem cells from a NK alloreactive or NK nonalloreactive donor Journal of Immunology 172, , Probability of relapse Non-alloreactive alloreactive P= Days after transplantation

9 CD3/19-depleted haploidentical PBSC s Tuebingen Fludarabine (160 mg/m2) or Clofarabine (200 mg/m²) Thiotepa (10 mg/kg) Melphalan (140 mg/m2) OKT-3 Infusion of stem cells +10 Donor: G-CSF PBSC s MMF (if T-cells > /kg BW)

10 GvHD Prophylaxis MMF (1200mg/m 2 ) if residual T-cells > 25000/kg 500 Zellen x10 6 /µl Graft composition (/kg BW) 16.2x x x x x stem cells T-cells B-cells NK-cells Myeloid

11 Recovery of Platelets (>20 000/µl) 1.0 CD3/CD19 depleted: 9 days Proportion CD days Days from Transplantation percent Neutrophils all patients (with GCSF) median: day 11 (9-17) engraftment rate: 89.7% days from transplantation

12 Incidence of GvHD (grade 1-3) percent ; 36.7% 2; 23.5% 3, 4.4% 35.3% without GvHD days from transplantation

13 Comparison of TRM: Positive selection vs. CD3/19 depletion 100 Percent death CD3/19 depletion CD34+ selection p<0.05 Day 100 TRM: years from transplantation

14 EFS acute leukemias/mds (influence of remission status) Portion CR 1-3 Refractory disease Years from Trp

15 High succes of hematopoietic cell transplantation regardless of donor source in children with very high-risk leukemia. W.Leung et al., BLOOD, ahead of print May 25, (all T-cell depleted) Overall survival

16 Negative depletion strategy of αβ+ T-cells Chaleff S. et al.: A large scale method for the selective Depletion of αβ+ T-lymphocytes from PBSC for allogeneic Transplantation. Cytotherapy 2007; 9: Biotin-anti-αβ (BMA031) + anti-biotin mab magnet Graft magnet Waste CD34+ and CD34- progenitors NK cells Dendritic/myeloid cells γδ T-cells

17 Comparative analysis of the T-cell depletion efficacy of the different methods

18 TcRαβ/CD19- depleted haploidentical PBSC s Conditioning regimen Clofarabine Thiotepa Melphalan Anti-CD3 (OKT-3) -8-1 G-CSF Donor: G-CSF Infusion of stem cells No post-transplant immunosuppression

19 TCRαβ/CD19 Depletion: Graft composition (/kg BW) 500 Cells x10 6 /µl x x x x x CD34+stem cells TCRγδ TCRαβ NK-cells myeloid

20 TcRαβ/CD19 Depletion: Engraftment Engraftment rate Thrombo>20x10 3 /µl, n=11 ANC>500/ µl, n= days after SCT

21 TCR αβ/cd19 Depletion: residual γδ T-cells do not cause severe GvHD GvHD grade n= % no GvHD (only skin) (only skin)

22 Rather than inhibiting the effector cells by GvHD prophylaxis or GvhD therapy, we need to exploit their antileukemic potentials Cytokines Antibodies Antibody constructs

23 Which cytokines augment NK activity best against ALL blasts in patients post transplant 100 % specific lysis no IL2 with IL2 with IL :1 10:1 5:1 2.5:1 E:T

24 Use of low dose s.c. IL 2 in vivo after Haplo trp.: Temporal development of NK-cell activity against K percent specific lysis n=6 n=5 n=8 n=6 n=3 n=2 20:1 10:1 5:1 2.5: pre IL2 0-2 weeks 3-4weeks 5-8 weeks weeks >26 weeks time after start of IL2

25 ADCC 3 weeks after haplotx with TcRαβ/CD19-depleted stem cells against the Patient s own call- blasts. ADCC overrides KIR mediated inhibition P.Lang, Blood 15: 3982, Inhibititory signal - KIR HLA Fc receptor+ CD19 20 Activatory signal 0 = Killing % specific lysis no antibody Anti-CD19 antibody provided by Prof. Jung, Tübingen anti-cd19 anti-hla

26 Single-chain bispecific antibody MT103 (Micromet AG, Munich, Germany) Anti-CD3 Anti-CD19 Science 2008; 321:

27 Treatment of a patient with chemorefractory ALL relapse post Tx Handgretinger et al., Leukemia 2010 Prior MT103 After MT103 MT103 infusion

28 Conclusion: T-cell depletion prevents severe GvHD The immune recovery depends on the T-cell depletion method Omission of GvHD prophylaxis allows a platform on which further in vitro or in vivo manipulation of the graft (adoptive transfer of donor cells, in vivo IL-2, IL-15, antibodies, antibody contructs etc.) can be envisioned. Yes!

Is in vitro T-cell depletion necessary for Haploidentical TransplantationTitle of Presentation. Disclosure of Interest: Nothing to Disclose

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