NK cell therapy after transplantation

Miltenyi Satellite Symposium1.4.2012

T-cell Immune Surveillance

Pr

ER

GolgiT

NK cell Immune Surveillance

Pr

ER

Golgi

NK+

-

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

Stern, BMT, 2009

KIR mismatching in haploidentical HSCT

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

Basel approach

Siegler Cytotherapy 2010OKT3, IL-2, irradiated autologous feeder cells

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!