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First clinical results with αβ+ T-cell depleted haploidentical stem cells in children

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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First clinical results with αβ+ T-cell depleted haploidentical stem cells in children

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  1. 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

  2. Haploidentical donors :T cell depletion mandatory 1995 • CD34+ Selection • „pure stem cells“ • 2. CD3/19 Depletion • Stem cells + effectors (NK cells) 4. Antigen- specific T cells + 3. TCRαβ/CD19 Depletion Stem cells + effectors (NK cells + γδT cells) + 2011

  3. The anti-leukemic activity of gamma/delta T-cells 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. 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

  4. 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 1. biotin-anti-mAb 2. microbeads with anti-biotin mAb waste ( T cells) magnet magnet graft T-cells CD34+ and CD34- progenitors NK cells dendritic cells

  5. TCR depletion: Efficacy of procedure

  6. Comparative analysis of the efficacy of T-cell depletion CD34+ selection vs CD3- vs TcR-depletion 4.6 log n=49

  7. Graft composition after TCR /CD19 depletion(n=24 patients)

  8. Patients (pediatric, n=24)

  9. -12 11 10 9 8 7 6 5 4 3 2 1 0 +1 Conditioning regimen (2) n=12 ATG-F (15 mg/kg) 1mg 4 mg 5 mg 5 mg Fludarabin (mg/m²) or Clofarabin TCR/CD19 depletedcells 40mg 40mg 40mg 40mg Thiotepa (mg/kg) 10mg Melphalan (mg/m²) 70mg 70mg steroids days from transplantation MMF, if >25.000 residual abT cells

  10. TCR /CD19 Depletion: Engraftment

  11. TCR/CD19 Depletion: residual T-cells do not cause GvHD(22/24 patients without pharmacological immune suppression)

  12. TCR/CD19 Depletion: Outcome • Alive: 17 out of 24 patients (70%) • Median Follow up: 0.5 (0.06-1.4) years

  13. Comparison of CD3+ recovery: CD3/19 vs TCR/CD19 Depletion

  14. Comparison of CD3+ recovery at day +30 p<0.0001 CD3/19 n = 45 TcRab n = 19

  15. Comparison of CD3+ recovery: CD3/19 vs TCR/CD19 Depletion p<0.01

  16. T cell recovery after TCR Depletion

  17. T cell recovery after TCR Depletion

  18. Conclusions • TCR-Depletion results in grafts with high numbers of effector cells (T cells, NK cells) • Robust engraftment • Profound depletion of T cells: preventsGvHD in HLA mismatched trp • Immune recovery seems to be signifcantly faster than after other graft manipulation procedures

  19. University Children´s Hospital Tübingen: Tobias Feuchtinger Heiko-Manuel Teltschik Michael Schumm Patrick Schlegel Matthias Pfeiffer Philip Schwarze Martin Ebinger Karin Schilbach Rupert Handgretinger

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