Abstract
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.
| Original language | English (US) |
|---|---|
| Article number | e153551 |
| Journal | JCI Insight |
| Volume | 6 |
| Issue number | 22 |
| DOIs | |
| State | Published - Nov 22 2021 |
Bibliographical note
Funding Information:consulted for Generon Corporation, NapaJen Pharma, Neoleukin Therapeutics, and iTeos Therapeutics and receives research funding from Compass Therapeutics, Syndax Pharmaceuticals, Applied Molecular Transport, and iTeos Pharmaceuticals. BRB receives remuneration as an advisor to Magenta Therapeutics and BlueRock Therapeutics and research funding from BlueRock Therapeutics and Rheos Medicines; he and is a cofounder of Tmunity Therapeutics.
Funding Information:
This work was supported in part by the Grant-in-Aid for Scientific Research (C) (MEXT/JSPS KAK-ENHI grant no. JP 16K09882) from Japan Society for the Promotion of Science and also in part by the MEXT-Supported Program for the Strategic Research Foundation at Private Universities from the Ministry of Education, Culture, Sports, Science and Technology, Japan. We thank Ryoko Ishimoto for her help with the data management and Kimiko Yamamoto for excellent laboratory support. We also thank all physicians, nurses, pharmacists, and support personnel for their care of the patients in this study.
Funding Information:
GRH and MK are supported by NIH R01 HL148164. Experimental histopathology at Fred Hutchinson Cancer Research Center was supported by NIH P30 CA015704. Scientific Computing Infrastructure at Fred Hutchinson Cancer Research Center was supported by ORIP grant S10OD028685. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Publisher Copyright:
Copyright: © 2021, Inoue et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
