Bendamustine with total body irradiation conditioning yields tolerant T-cells while preserving T-cell-dependent graft-versus-leukemia

Oncoimmunology. 2020 Apr 30;9(1):1758011. doi: 10.1080/2162402X.2020.1758011. eCollection 2020.

Abstract

Graft-versus-host disease (GvHD) remains a significant impediment to allogeneic hematopoietic cell transplantation (HCT) success, necessitating studies focused on alleviating GvHD, while preserving the graft-versus-leukemia (GvL) effect. Based on our previous studies showing bendamustine with total body irradiation (BEN-TBI) conditioning reduces GvHD compared to the current clinical standard of care cyclophosphamide (CY)-TBI in a murine MHC-mismatched bone marrow transplantation (BMT) model, this study aimed to evaluate the role and fate of donor T-cells following BEN-TBI conditioning. We demonstrate that BEN-TBI reduces GvHD compared to CY-TBI independently of T regulatory cells (Tregs). BEN-TBI conditioned mice have a smaller proportion and less activated donor T-cells, with lower CD47 expression, early post-transplant, but no sustained phenotypic differences in T-cells. In BEN-TBI conditioned mice, donor T-cells gain tolerance specific to host MHC antigens. Though these T-cells are tolerant to host antigens, we demonstrate that BEN-TBI preserves a T-cell-dependent GvL effect. These findings indicate that BEN-TBI conditioning reduces GvHD without compromising GvL, warranting its further investigation as a potentially safer and more efficacious clinical alternative to CY-TBI.

Keywords: BMT; GvHD; GvL; bendamustine; conditioning.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bendamustine Hydrochloride* / pharmacology
  • Female
  • Graft vs Host Disease
  • Graft vs Leukemia Effect*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • T-Lymphocytes* / drug effects
  • T-Lymphocytes* / immunology
  • T-Lymphocytes* / radiation effects
  • Transplantation Conditioning*
  • Whole-Body Irradiation*

Substances

  • Bendamustine Hydrochloride

Grants and funding

This work was supported by the Leukemia and Lymphoma Society Translational Research Program, Hyundai Hope on Wheels, Courtney’s Courage, and PANDA.