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NK cell therapy after transplantation

NK cell therapy after transplantation. Miltenyi Satellite Symposium 1.4.2012. T-cell Immune Surveillance. ER. Pr. T. T. Golgi. NK cell Immune S urveillance. ER. +. Pr. NK. NK. -. Golgi. Killer Cell Immunoglobulin-like Receptors.

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NK cell therapy after transplantation

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  1. NK cell therapy after transplantation Miltenyi Satellite Symposium 1.4.2012

  2. T-cell Immune Surveillance ER Pr T T Golgi

  3. NK cell Immune Surveillance ER + Pr NK NK - Golgi

  4. Killer Cell Immunoglobulin-like Receptors Inhibitory KIR allow NK cells to detect missing self (HLA).

  5. Missing self in stem cell transplantation + L - Donor Cw1/Cw2 Leukemia patient Cw1/Cw4 NK NK + L Donor Cw1/Cw2 Leukemia patient Cw1/Cw3

  6. KIR mismatching in haploidentical HSCT Stern, BMT, 2009

  7. How to increase NK cell number and function • Increasenumber of NK cells administeredwith graft • CD3/CD19 depletion vs. CD34 selection • Adoptivetransfer of NK cells • Ex vivo expanded versus in vivo expansion • Enhancementof NK cellproducedbythe graft • Blockingofinhibitoryreceptors

  8. NK DLI to consolidate engraftment • N=5 • Infusion of non-expanded NK cells after haplo-HSCT • Indication= mixed chimerism/relapse • Hints of effectiveness Passweg Leukemia 2004

  9. NK DLI to consolidate engraftment • N=3 • Infusion of IL-2-expanded (five-fold) NK cells after haplo-HSCT + IL-2 sc • Indication= pre-emptive • All patientsachieved CR, 1 relapse/2 TRM Koehl, BCMD 2004

  10. Preemptive NK DLI in high risk malignancies • N=14 • Infusion of NK cells derived from CD34+ PBSC (median 9*10e6/kg) • Indication= pre-emptive • Noacutetoxicity Yoon, BMT 2010

  11. Infusion of NK DLI for relapse after haplo-HSCT • Relapse after Haplo-HSCT despite KIR2DL1 ligand mismatch • Re-inductionwithMitoxantrone, Ara-C, Fludarabine • Infusion of purified NK cells followedby IL-2 s.c. daily Nguyen, Transfusion 2011

  12. What happened in the last 5-10 years? Shiftto NK therapywithoutpreceding transplant Establishment of GMP compatibleexpansionprotocols

  13. NK cell infusion after chemotherapy • N=19 • Infusion of CD3 depleted PBMC topatientswith high-risk AML, s.c. IL-2 • Engraftment of NK cells, requireslymphodepletion • Temporarycompleteremission in 5 patients Miller Blood 2005

  14. NK cell infusion after chemotherapy • Infusion of KIR ligand mismatched NK cells after Cy-Fluchemotherapy • 10 pediatricpatientswith AML in CR1 • Transient engraftment of donor NK cells, 100% PFS @ 2 years RubnitzJCO 2010

  15. Basel approach OKT3, IL-2, irradiatedautologousfeeder cells Siegler Cytotherapy 2010

  16. Expansion with modified K562 DenmanPlosOne 2012

  17. Studies currently running or recently terminated More than half of all studiesemploy NK cells in the transplant setting

  18. Conclusions • Preparationof NK cellproductstechnicallyfeasibleandsafeforpatients • Excitingdatacoming in recentyearsfrom non-transplant settings • Variouscompetingapproachestoproduceexpanded/activated NK cellproductscurrentlyunderevaluation • Manystudiescurrentlyevaluation NK celltherapyafter transplantation

  19. Thank you!

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