Poster Presentation Melbourne Immunotherapy Network Winter Retreat 2018

Manipulation of recipient NK cells using Ruxolitinib to target the IL-15 signaling pathway improves allo-HSCT outcomes. (#44)

Kelei Du 1 2 3 4 , Joanne Davis 1 2 , Yuhao Jiao 2 3 4 , Rachel Koldej 1 2 , Nick Huntington 3 5 , David Ritchie 1 2 6
  1. ACRF Translational Research Laboratory, The Royal Melbourne Hospital, Melbourne, VIC, Australia
  2. Department of Medicine, University of Melbourne, Melbourne, Melbourne, VIC, Australia
  3. Molecular Immunology Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
  4. School of Medicine, Tsinghua University, Beijing, China
  5. Department of Medical Biology, University of Melbourne, Melbourne, Melbourne, VIC, Australia
  6. Clinical Oncology and Haematology, The Royal Melbourne Hospital, Melbourne, VIC, Australia

Background:Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for haematological malignancies due to its graft-versus-leukemia (GVL) effect. However myeloablative conditioning before allo-HSCT is toxic and promotes graft-versus-host disease (GVHD), the major complication post-transplantation. Natural Killer (NK) cells are the major residual recipient cell population after reduced intensity conditioning (RIC) which is less toxic to recipient organs than myeloablative irradiation. The survival and function of NK cells are dependent on the cytokine IL-15 and the downstream JAK1&2 signaling pathways. We hypothesized reducing survival of recipient NK cells via blocking the IL-15 signaling pathway, in combination with RIC, will promote donor cell engraftment and mitigate GVHD.

Methods:MHC-mismatched allo-HSCT: Donor BM and T cells from BALB/c (H2Kd+) mice were injected into irradiated wild-type (WT) C57BL/6 (H2Kb+) recipients and IL-15 knock out (KO) NK-cell deficient recipients. Before allo-HSCT, WT recipients were also pre-treated on days -2 and -1 by oral gavage with 180 mg/kg Ruxolitinib or vehicle. Mice were monitored for GVHD and donor cell engraftment.

Results:NK cell frequency in WT recipients was significantly decreased after treatment with the JAK1/2 inhibitor Ruxolitinib. The Ruxolitinib treated recipients conditioned with 800 rads RIC irradiation achieved complete donor cell engraftment at day 14 post-allo-HSCT, with similar kinetics as untreated mice given a myeloablative irradiation dose (1200 rads). In contrast, the vehicle-treated recipients irradiated with 800 rads rejected the donor graft. The impact of inhibiting recipient NK cell survival on the onset of GVHD is currently being investigated. The RIC-conditioned IL-15KO recipients exhibited enhanced engraftment compared to WT recipients with myeloablative conditioning very early post-transplantation, but they experienced severe body weight loss and hyperacute GVHD.

Conclusion:Pharmacological inhibition of recipient NK cells via the JAK1/2 inhibitor Ruxolitinib allowed donor cell engraftment in RIC treated WT recipients and showed improved outcomes compared with IL-15 genetically depleted recipients.