Transcript NK + - Congrex Switzerland

NK cell therapy after transplantation
Miltenyi Satellite Symposium
1.4.2012
T-cell Immune Surveillance
ER
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T
Golgi
NK cell Immune Surveillance
ER
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Pr
Golgi
NK
Killer Cell Immunoglobulin-like Receptors
KIR
HLA-Ligand
2DL1
Cw2/4/5/6
2DL2/3
Cw1/3/7/8
3DL1
Bw4
3DL2
A3/11
Inhibitory KIR allow NK cells to detect missing self (HLA).
Missing self in stem cell transplantation
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L
Leukemia patient
Cw1/Cw4
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Donor
Cw1/Cw2
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L
Leukemia patient
Cw1/Cw3
NK
NK
Donor
Cw1/Cw2
KIR
HLA-Ligand
2DL1
Cw2/4/5/6
2DL2/3
Cw1/3/7/8
3DL1
Bw4
3DL2
A3/11
KIR mismatching in haploidentical HSCT
Stern, BMT, 2009
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
NK DLI to consolidate engraftment
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N=5
Infusion of non-expanded NK cells after haplo-HSCT
Indication= mixed chimerism/relapse
Hints of effectiveness
Passweg Leukemia 2004
NK DLI to consolidate engraftment
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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
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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
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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
Miller Blood 2005
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
Basel approach
OKT3, IL-2, irradiated autologous feeder cells
Siegler Cytotherapy 2010
Expansion with modified K562
Denman Plos One 2012
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
Thank you!