NK cell therapy after transplantation Miltenyi Satellite Symposium

T-cell Immune Surveillance Pr ER Golgi

NK cell Immune Surveillance Pr ER Golgi NK + -

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

Missing self in stem cell transplantation NK + - L L Leukemia patient Cw1/Cw4 Donor Cw1/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% 2 years Rubnitz JCO 2010

Basel approach Siegler Cytotherapy 2010 OKT3, 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!