# Bronchiolitis Obliterans: Discovery and Therapy

> **NIH NIH P01** · DANA-FARBER CANCER INST · 2024 · $636,798

## Abstract

Project Summary – Project 3
Bronchiolitis Obliterans Syndrome (BOS) is a progressive, irreversible, and often fatal lung disease that occurs
following allogeneic hematopoietic cell transplantation (HCT). BOS occurs in approximately 5-10% of HCT
survivors and is the pulmonary manifestation of chronic graft-vs.-host disease (cGVHD). Approximately 10-15%
of cGVHD patients develop BOS, and less than 15% of BOS patients survive 5 years. The primary immunologic
focus of attack in BOS is the small airway, leading to pathologic fibrosis. BOS has no cure, and treatment options
are limited. Little is known about the pathophysiology of BOS. Innovations in lung organoid culture and
immunogenomics offers a means to pinpoint the cellular and antigenic targets of BOS, and our murine model of
BOS has proven invaluable in identifying promising therapeutics for this disease. Given these advances, in this
Project, we hypothesize that we can reverse BOS with a promising pharmacologic agent that addresses
dysregulated immunity and reduces fibrosis while fundamentally improving our understanding of the
pathophysiology of BOS by using in vitro models to identify the cellular and antigenic targets of immunologic
attack in BOS.
We will test these hypotheses by performing a clinical trial of the novel agent, KD025, in subjects with BOS.
KD025 is a ROCK2 inhibitor whose mechanism of action was initially deciphered and tested by our group. This
agent has shown promising activity in cGVHD therapy and in idiopathic pulmonary fibrosis. A phase II trial will
determine the BOS response rate, measured by NIH cGVHD Response Criteria, in a cohort of subjects with new
onset and steroid-refractory BOS, following a 24-week course of KD025. In this trial we will also test whether
CT-scan based parametric response mapping can act an imaging biomarker in BOS.
Using samples from subjects being treated on the KD025 trial, we will establish an airway organoid (AO) platform
to study mechanisms and therapeutic avenues for BOS. Using AO, we will study cellular injury and cell-cell
interactions in BOS, and we will test whether AO can serve as treatment response indicators to therapeutic
drugs. The precise role of lung-infiltrating CD4+ T cells in the pathobiology of BOS is unknown; using cutting
edge immunogenomics, we will identify the antigenic determinants of immune attack in BOS and interrogate the
transcriptional programs in BOS using single-cell TCR sequencing and RNA-seq analysis.

## Key facts

- **NIH application ID:** 10914143
- **Project number:** 5P01HL158505-03
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Corey S Cutler
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $636,798
- **Award type:** 5
- **Project period:** 2022-09-15 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10914143

## Citation

> US National Institutes of Health, RePORTER application 10914143, Bronchiolitis Obliterans: Discovery and Therapy (5P01HL158505-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10914143. Licensed CC0.

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