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KIR HLA-Ligand
2DL1 Cw2/4/5/6
2DL2/3 Cw1/3/7/8
3DL1 Bw4
3DL2 A3/11
Killer Cell Immunoglobulin-like Receptors
Inhibitory KIR allow NK cells to detect missing self (HLA).
Missing self in stem cell transplantation
KIR HLA-Ligand
2DL1 Cw2/4/5/6
2DL2/3 Cw1/3/7/8
3DL1 Bw4
3DL2 A3/11
NK+-L
Leukemia patientCw1/Cw4
DonorCw1/Cw2
+L
Leukemia patientCw1/Cw3
DonorCw1/Cw2
How to increase NK cell number and function
Increase number of NK cells administered with graft CD3/CD19 depletion vs. CD34 selection
Adoptive transfer of NK cells Ex vivo expanded versus in vivo expansion
Enhancement of NK cell produced by the graft Blocking of inhibitory receptors
Passweg Leukemia 2004
NK DLI to consolidate engraftment
• N=5• Infusion of non-expanded NK cells after haplo-HSCT• Indication= mixed chimerism/relapse• Hints of effectiveness
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 patients achieved CR, 1 relapse/2 TRM
Koehl, BCMD 2004
Preemptive NK DLI in high risk malignancies
• N=14• Infusion of NK cells derived from CD34+ PBSC (median 9*10e6/kg)• Indication= pre-emptive• No acute toxicity
Yoon, BMT 2010
Infusion of NK DLI for relapse after haplo-HSCT
• Relapse after Haplo-HSCT despite KIR2DL1 ligand mismatch
• Re-induction with Mitoxantrone, Ara-C, Fludarabine
• Infusion of purified NK cells followed by IL-2 s.c. daily
Nguyen, Transfusion 2011
What happened in the last 5-10 years?
Shift to NK therapy without preceding transplant
Establishment of GMP compatible expansion protocols
NK cell infusion after chemotherapy
Miller Blood 2005
• N=19• Infusion of CD3 depleted PBMC to patients with high-risk AML, s.c. IL-2• Engraftment of NK cells, requires lymphodepletion• Temporary complete remission in 5 patients
NK cell infusion after chemotherapy
• Infusion of KIR ligand mismatched NK cells after Cy-Flu chemotherapy• 10 pediatric patients with AML in CR1• Transient engraftment of donor NK cells, 100% PFS @ 2 years
Rubnitz JCO 2010
Studies currently running or recently terminated
More than half of all studies employ NK cells in the transplant setting
Conclusions
• Preparation of NK cell products technically feasible and safe for patients
• Exciting data coming in recent years from non-transplant settings
• Various competing approaches to produce expanded/activated NK cell products currently under evaluation
• Many studies currently evaluation NK cell therapy after transplantation