JCI Insight (Nov 2021)

Peritransplant glucocorticoids redistribute donor T cells to the bone marrow and prevent relapse after haploidentical SCT

  • Takayuki Inoue,
  • Motoko Koyama,
  • Katsuji Kaida,
  • Kazuhiro Ikegame,
  • Kathleen S. Ensbey,
  • Luke Samson,
  • Shuichiro Takahashi,
  • Ping Zhang,
  • Simone A. Minnie,
  • Satoshi Maruyama,
  • Shinichi Ishii,
  • Takashi Daimon,
  • Takahiro Fukuda,
  • Hirohisa Nakamae,
  • Takahide Ara,
  • Yumiko Maruyama,
  • Ken Ishiyama,
  • Tatsuo Ichinohe,
  • Yoshiko Atsuta,
  • Bruce R. Blazar,
  • Scott N. Furlan,
  • Hiroyasu Ogawa,
  • Geoffrey R. Hill

Journal volume & issue
Vol. 6, no. 22

Abstract

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Patients with acute leukemia who are unable to achieve complete remission prior to allogeneic hematopoietic stem cell transplantation (SCT) have dismal outcomes, with relapse rates well in excess of 60%. Haplo-identical SCT (haplo-SCT) may allow enhanced graft-versus-leukemia (GVL) effects by virtue of HLA class I/II donor-host disparities, but it typically requires intensive immunosuppression with posttransplant cyclophosphamide (PT-Cy) to prevent lethal graft-versus-host disease (GVHD). Here, we demonstrate in preclinical models that glucocorticoid administration from days –1 to +5 inhibits alloantigen presentation by professional recipient antigen presenting cells in the gastrointestinal tract and prevents donor T cell priming and subsequent expansion therein. In contrast, direct glucocorticoid signaling of donor T cells promotes chemokine and integrin signatures permissive of preferential circulation and migration into the BM, promoting donor T cell residency. This results in significant reductions in GVHD while promoting potent GVL effects; relapse in recipients receiving glucocorticoids, vehicle, or PT-Cy was 12%, 56%, and 100%, respectively. Intriguingly, patients with acute myeloid leukemia not in remission who received unmanipulated haplo-SCT and peritransplant glucocorticoids also had an unexpectedly low relapse rate at 1 year (32%; 95% CI, 18%–47%) with high overall survival at 3 years (58%; 95% CI, 38%–74%). These data highlight a potentially simple and effective approach to prevent relapse in patients with otherwise incurable leukemia that could be studied in prospective randomized trials.

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