Introduction: Allogeneic haematopoietic stem cell transplantation (alloSCT) cures cancer, but is associated with significant side effects such as graft versus host disease (GVHD) and infection. In order to improve patient outcomes, we need to reduce pre-transplant conditioning, promote donor cell engraftment and limit GVHD. Natural killer (NK) cells are important for controlling donor cell engraftment, and are reliant on BCL2 and JAK1/2 pathways for survival. We investigated if NK cells could be depleted from the immune system prior to alloSCT, using the clinically approved BCL2 inhibitor Venetoclax, and the JAK1/2 inhibitor Ruxolitinib.
Methods: We used mouse models of acute myeloid leukaemia (AML) to explore the ability of Venetoclax or Ruxolitinib to deplete NK cells in wild-type alloSCT recipients, immediately prior to transplant. AML-bearing mice were treated with drug for 2 days, then given a reduced dose of irradiation, and alloSCT from a MHC-mismatched donor. Mice were monitored for GVHD, donor cell engraftment, and anti-AML response.
Results: Pharmacological inhibition of BCL2 or JAK1/2 prior to alloSCT in mice with Venetoclax or Ruxolitinib respectively resulted in rapid depletion of recipient NK cells. A significant proportion (>80%) of alloSCT recipient mice pre-treated with either drug developed full donor cell engraftment after reduced intensity conditioning, did not develop GVHD, and retained potent anti-tumour effects against pre-established AML.
Conclusions: BCL2 and JAK1/2 inhibition in alloSCT recipients, in combination with reduced intensity conditioning was:
1) well-tolerated
2) associated with low rates of GVHD
3) resulted in long-term donor haematopoietic cell engraftment
4) retained anti-tumour responses in an AML mouse model
Therefore, repurposing clinically-approved drugs to inhibit recipient NK cells may represent a means by which to deliver alloSCT more safely.