Oral Presentation Melbourne Immunotherapy Network Winter Retreat 2018

Targeting Natural Killer cells via BCL2 inhibition improves stem cell transplant outcomes (#14)

Joanne Davis 1 2 , Yuhao Jiao 3 4 5 , Kelei Du 1 2 4 , Rachel Koldej 1 2 , Nicholas Huntington 3 5 , Ritchie David 1 2 6
  1. Melbourne Health, Parkville, VIC, Australia
  2. Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia
  3. Molecular Immunology Division, Victoria, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
  4. School of Medicine, , Tsinghua University, Beijing, P. R. China
  5. Department of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia
  6. Clinical Haematology and Bone Marrow Transplantation Service, Department of Clinical Oncology and Haematology, The Royal Melbourne Hospital, Melbourne, VIC, Australia

Background: The outcome of allogeneic haematopoietic stem cell transplantation (alloHSCT) is a complex interaction between conditioning regimen intensity, recipient immunology and donor immunology. We must find means to lower conditioning toxicity, promote donor engraftment and limit graft-versus host disease (GVHD) in order to improve alloHSCT outcomes.

Methods: MHC-mismatched alloHSCT: Donor BM and T cells from BALB/c (H2Kd) mice were injected into irradiated WT C57BL/6 (H2Kb), or Bcl2fl/fl NK cell-deficient recipients. WT mice were treated on day -2 and -1 with 100 mg/kg Venetoclax (ABT-199) or vehicle, before alloHSCT. Mice were monitored for GVHD, and donor cell engraftment. MLL-AF9 acute myeloid leukaemia (AML) cells were injected on day 0 into WT recipients, and treated with 100 mg/kg Venetoclax or vehicle on days 8 and 9, before alloHSCT on day 10.

Results: NK cells are significantly more radio-resistant than CD8+ T or myeloid cells, at both myeloablative (1200 rad) and reduced intensity conditioning (RIC) radiation doses (800 rad). Genetic and pharmacological models of recipient NK cell suppression during alloHSCT with RIC promoted donor cell engraftment, reduced GVHD, and retained graft-versus leukaemia (GVL) effects. Bcl2fl/fl alloHSCT RIC recipients showed robust donor engraftment, and significantly reduced GVHD compared to WT recipients. Pharmacological inhibition of BCL2 in WT mice with Venetoclax resulted in rapid depletion of NK cells. A significant proportion of alloHSCT WT recipient mice pre-treated with Venetoclax developed full donor engraftment after RIC, with minimal GVHD, and retained potent GVL effects against pre-established AML.

Conclusions: BCL2 inhibition in WT alloHSCT recipients in combination with RIC was: 1) well-tolerated, 2) associated with low rates of GVHD and 3) resulted in long-term donor haematopoietic cell engraftment. Recipient NK cell inhibition may represent a means by which to deliver alloHSCT more safely.