Prevention of acute GVHD disease using an orthogonal IL-2/IL-2Rbeta system to selectively expand regulatory T-cells in vivo. Blood Lopes Ramos, T., Bolivar-Wagers, S., Jin, S., Thangavelu, G., Simonetta, F., Lin, P., Hirai, T., Saha, A., Koehn, B. H., L Su, L., Picton, L. K., Baker, J., Lohmeyer, J. K., Riddle, M. J., Eide, C., Tolar, J., Panoskaltsis-Mortari, A., Wagner, J. E., Garcia, K. C., Negrin, R. S., Blazar, B. R. 2022

Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative option for patients with hematological disorders and bone marrow failure syndromes. Graft-versus-Host Disease (GVHD) remains a leading cause of morbidity post-transplant. Regulatory T cell (Treg) therapies are efficacious in ameliorating GVHD but limited by variable suppressive capacities and the need for a high therapeutic dose. Here, we sought to expand Treg in vivo by expressing an orthogonal IL-2Rbeta receptor (oIL2Rbeta) that would selectively interact with orthogonal IL-2 (oIL2) cytokine and not wildtype IL2. To test whether the orthogonal system would preferentially drive donor Treg expansion, we used a murine MHC-disparate GVHD model of lethally irradiated BALB/c mice given T-cell depleted bone marrow from C57BL/6 (B6) mice alone, or together with B6Foxp3+GFP+ Treg or oIL2Rbeta transduced Treg at low cell numbers that typically do not control GVHD with WT Treg. On day 2, B6 Tcons were injected to induce GVHD. Recipients were treated with PBS or oIL2 daily for 14 days, then 3 times weekly for an additional 14 days. Mice treated with oIL2Rbeta Treg and oIL2 compared to PBS had enhanced GVHD survival, in vivo selective expansion of Tregs, and greater suppression of Tcon expansion in secondary lymphoid organs, and intestines. Importantly, oIL2Rbeta Treg maintained graft-versus-tumor (GVT) responses in two distinct tumor models (A20, MLL-AF9). These data demonstrate a novel approach to enhance the efficacy of Treg cell therapy in allo-HSCT using an oIL2/oIL2Rbeta system that allows for selective in vivo expansion of Treg leading to GVHD protection and GVT maintenance.

View details for DOI 10.1182/blood.2022018440

View details for PubMedID 36564052