Session: 701. Experimental Transplantation: Basic Biology, Pre-Clinical Models: Poster I
Hematology Disease Topics & Pathways:
Diseases, Non-Biological, Therapies, Biological Processes, Clinically relevant, inflammation
- a) To develop a refined model of pre-clinical GvHD where NOG animals transgenic for human IL-15 (hIL-15 NOG) are able to support long-term engraftment of T-cells as well as NK cells.
- b) To characterize the role of JAK1/2 inhibition on steroid refractory GvHD in the hIL-15 NOG model.
Materials and Methods: Xenogeneic GvHD was induced in hIL-15 NOG receiving 3 different doses of human PBMCs, as well as in control NOG animals. Engraftment was weekly assessed by flow cytometry. Ruxolitinib, prednisolone or vehicle was orally administered twice daily. Efficacy was assessed by GvHD symptom scores, cachexia, and histological analysis of end organ damage.
Results: hIL-15 NOG animals develop a rapid onset, highly aggressive, form of GvHD after adoptive transfer of 5x106 PBMC, including a significant engraftment of NK, NK-T and T-cells. Significant PBMC infiltration and inflammation was found in GI tract, lung, liver, skin, eyes and pancreas. Ruxolitinib treatment, but not prednisolone, ameliorated GvHD severity scores with concomitant reduction of GI tract infiltration and tissue damage. Overall GvHD mice survival was significantly improved with JAK1/2 inhibition. Therapeutic ruxolitinib treatment initiated after steroid failure significantly inhibited the chronic-progressive disease and reduced tissue markers of inflammation and fibrosis.
Conclusion: hIL-15 NOG animals develop a rapid onset, highly reproducible, form of GvHD after PBMC transfer, with successful engraftment of NK, NK-T and T-cells. Ruxolitinib, a potent and selective JAK1/2 inhibitor, significantly ameliorated GvHD scores, reduced tissue-inflammation and improved survival. Ruxolitinib was also able to improve clinical parameters in mice unresponsive to prednisolone treatment, underscoring the relevance of the new model. Ruxolitinib has demonstrated statistically significant improvement in in patients with steroid-refractory GvHD (REACH3, NCT03112603).
Disclosures: Huarte: Incyte corporation: Current Employment. Peel: Incyte corporation: Current Employment. Dube: Taconic: Current Employment. Stephens: Incyte: Current Employment. Stewart: Incyte: Current Employment. Long: Incyte: Current Employment. Czerniak: Incyte: Current Employment. Oliver: Incyte: Current Employment. Smith: Incyte corporation: Current Employment.
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