Faculty, Staff and Student Publications

Publication Date

7-22-2025

Journal

Blood Advances

DOI

10.1182/bloodadvances.2025016170

PMID

40311075

PMCID

PMC12274834

PubMedCentral® Posted Date

5-5-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Belumosudil (KD025), an oral, selective, Rho-associated, coiled-coil-containing protein kinase 2 (ROCK2) inhibitor, is approved for third-line treatment of chronic graft-versus-host disease (cGVHD). Previous studies demonstrated that ROCK2 inhibition reduces blood interleukin-17 (IL-17) activity and promotes regulatory T-cell (Treg cell) recovery. However, these studies did not evaluate immune responses within cGVHD-affected tissues. This study assessed tissue-level immune dynamics in 20 patients with oral cGVHD from the phase 2 ROCKstar trial, before and after 6 months of belumosudil treatment, focusing on key effector sites (oral mucosa [OM], minor salivary glands [MSGs], and skin) and the peripheral blood. After belumosudil treatment, reduction in collagen was observed in OM in parallel with decreased IL-17+ cell frequency in both OM (n = 14 pairs) and MSG (n = 11 pairs). IL-17 was primarily produced by non-T cells in the oral tissues. Immune cell frequencies in the OM decreased after treatment, whereas CD4 Treg cells increased in both the MSG and blood. Per overall or mouth-specific clinical response criteria, responders to belumosudil exhibited a reduction in collagen type I and IL-17 in the OM. Additionally, salivary transforming growth factor β1 (TGF-β1), a critical driver of fibrosis, decreased significantly, with a strong correlation observed between TGF-β1 and IL-17 levels. These findings illustrate the tissue-level response to belumosudil therapy and suggest that there is a reduction in tissue fibrosis and inflammation, thereby highlighting the therapeutic impact of ROCK2 inhibition in mitigating cGVHD. The ROCKstar study was registered at www.ClinicalTrials.gov as #NCT03640481.

Keywords

Adult, Aged, Female, Humans, Male, Middle Aged, Chronic Disease, Fibrosis, Graft vs Host Disease, Inflammation, Interleukin-17, Mouth Mucosa, Protein Kinase Inhibitors, rho-Associated Kinases

Published Open-Access

yes

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