ROCK2, a critical regulator of immune modulation and fibrosis has emerged as a therapeutic target in chronic graft-versus-host disease

Alexandra Zanin-Zhorov, Bruce R. Blazar

Research output: Contribution to journalReview articlepeer-review

Abstract

Chronic graft-versus-host disease (cGVHD) is an immune-mediated disorder characterized by chronic inflammation and fibrosis. Rho-associated coiled-coil–containing protein kinases (ROCKs) are key coordinators of tissue response to injury, regulating multiple functions, such as gene expression and cell migration, proliferation and survival. Relevant to cGVHD and autoimmunity, only the ROCK2 isoform drives a pro-inflammatory type 17 helper T (Th17) cell response. Moreover, ROCK2 inhibition shifts the Th17/regulatory T (Treg) cell balance toward Treg cells and restores immune homeostasis in animal models of autoimmunity and cGVHD. Furthermore, the selective inhibition of ROCK2 by belumosudil reduces fibrosis by downregulating both transforming growth factor-β signaling and profibrotic gene expression, thereby impeding the creation of focal adhesions. Consistent with its anti-inflammatory and antifibrotic activities, belumosudil has demonstrated efficacy in clinical studies, resulting in an overall response rate of >70% in patients with cGVHD who failed 2 to 5 prior lines of systemic therapy. In summary, selective ROCK2 inhibition has emerged as a promising novel therapeutic approach for treating cGVHD and other immunologic diseases with unique mechanisms of action, targeting both immune imbalance and detrimental fibrotic responses.

Original languageEnglish (US)
Article number108823
JournalClinical Immunology
Volume230
DOIs
StatePublished - Sep 2021

Bibliographical note

Funding Information:
Bruce Blazar receives remuneration as an advisor to Magenta Therapeutics and BlueRock Therapeutics and receives research funding from BlueRock Therapeutics , Rheos Medicines, Equilibre Biopharmaceuticals, Carisma Therapeutics, Inc. , Children's Cancer Research Fund and Kids First Fund . He is a cofounder of Tmunity Therapeutics and serves as a member of a steering committee for Kadmon Corporation (and was previously a paid consultant for Kadmon but has not received any consulting compensation of any kind in the past year). He is also an ad hoc consultant to Incyte Corporation.

Funding Information:
This work was supported by Kadmon Corporation, LLC, who funded medical writing assistance provided by RevHealth, and the National Institutes of Health (grants P01 CA142106 , P01 AI056299 and R01 HL147324 ).

Funding Information:
The authors thank all the patients, caregivers, health care professionals, investigators and Kadmon employees who were and are involved in the clinical studies of belumosudil. This work was supported by Kadmon Corporation, LLC, who funded medical writing assistance provided by RevHealth, and the National Institutes of Health (grants P01 CA142106, P01 AI056299 and R01 HL147324). Bruce Blazar receives remuneration as an advisor to Magenta Therapeutics and BlueRock Therapeutics and receives research funding from BlueRock Therapeutics, Rheos Medicines, Equilibre Biopharmaceuticals, Carisma Therapeutics, Inc., Children's Cancer Research Fund and Kids First Fund. He is a cofounder of Tmunity Therapeutics and serves as a member of a steering committee for Kadmon Corporation (and was previously a paid consultant for Kadmon but has not received any consulting compensation of any kind in the past year). He is also an ad hoc consultant to Incyte Corporation. Alexandra Zanin-Zhorov was a full-time employee of Kadmon Corporation, LLC from January 2012 to December 14, 2020. She is now Senior Vice President, Translational Medicine at Equilibre Biopharmaceuticals. Bruce Blazar and Alexandra Zanin-Zhorov shared senior authorship on the paper published in Blood, 2016, which demonstrated, for the first time, the therapeutic potential of selective ROCK2 inhibition with KD025 in chronic GVHD. Furthermore, they have co-authored several papers to define the molecular and cellular mechanisms of how targeting ROCK2 modulates the immune response by simultaneously downregulating the pro-inflammatory and upregulating the regulatory arms of the immune system published in PNAS, 2014 and Sci Signal, 2016, and a review in Small GTPases, 2016. Bruce Blazar has also co-authored papers for the phase 2a study (KD025-208) published in the Journal of Clinical Oncology, 2021 (also co-authored by Alexandra Zanin-Zhorov), and the pivotal phase 2 study (KD025-213, ROCKstar) published in Blood, 2021. Bruce Blazar serves on the KD025 Chronic GVHD Steering Committee and participated in the submission of KD025 for FDA approval.

Publisher Copyright:
© 2021 The Author(s)

Keywords

  • Autoimmunity
  • Belumosudil
  • Chronic graft-versus-host disease
  • Fibrosis
  • Immunomodulation
  • ROCK2

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

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