Short term ex vivo graft conditioning with venetoclax, fluticasone propionate, and IL-2 reduces graft versus host disease in mouse allogeneic hematopoietic cell transplantation

Abstract

Hematopoietic cell transplantation is a curative therapy for certain hematologic malignancies but is limited in use due to post-transplant complications such as graft-versus-host disease (GVHD), wherein donor cells mount an immune response against host tissues. GVHD is a major cause of post-transplant mortality, inspiring the development of prophylactic strategies to reduce GVHD severity. However, these involve administration of cytotoxic or immunosuppressive compounds into patients, increasing adverse side effects. To address this issue, we have developed a strategy to reduce GVHD through ex vivo graft conditioning. Previously we demonstrated that pretreatment of mouse grafts with a single compound, fluticasone propionate, dramatically reduced GVHD symptoms after allogeneic transplantation. Here, we condition grafts in a combination of fluticasone propionate, venetoclax, and IL-2 for 6 hours ex vivo prior to transplantation. We demonstrate that the preconditioning process increases the frequency of tolerogenic regulatory T cells pre- and post-transplant. Recipient mice receiving conditioned cells display reduced GVHD severity and increased overall survival in both fully mismatched and haploidentical models. This study highlights an alternative strategy to GVHD prophylaxis which reduces reliance on the administration of toxic compounds.