# Translating Novel Drug-Targetable Biomarkers to Treat Graft versus Host Disease

> **NIH NIH R01** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2021 · $323,667

## Abstract

PROJECT SUMMARY/ABSTRACT
Despite the high rates of acute graft versus host disease (aGVHD) (up to 50%) and their related
mortality/morbidity following allogeneic hematopoietic cell transplantation (allo-HCT), there remains a paucity
of therapies and biological correlative studies offered. Current therapies are limited to the nonspecific steroidal
targeting of effector cells. Our long-term goal is to identify and validate GVHD biomarkers with the potential for
risk stratification and therapeutic targeting. In the previous cycle, we discovered that: (1) soluble STimulation-2
(sST2), the interleukin-33 (IL-33) decoy receptor, as a biomarker for risk of therapy-resistant GVHD and death
(N. Engl. J. Med, 2013); (2) Mechanistically, we have shown that during GVHD, sST2 was secreted earlier by
intestinal stromal cells and later by cytopathic intestinal T effector cells (Teffs) (Science Translational Medicine,
2015); (3) Furthermore, we have shown that sST2 sequesters IL-33, limiting its availability to T cells expressing
the transmembrane molecule form of ST2, mostly cytoprotective regulatory T cells (Tregs) (Science
Translational Medicine, 2015; Journal of Clinical Investigation Insights, 2019); (4) Through another proteomics
discovery comparing samples at 14 days post-transplantation in patients who develop gastrointestinal (GI)
GVHD vs not, we found a T-cell population expressing CD146 that is Th17 prone and ICOS (Inducible T-cell
COStimulator)-induced (Journal of Clinical Investigation Insights, 2016). Our new hypotheses address gaps
remaining and will be tested with three specific aims: 1) Elucidate the cellular and molecular mechanisms of
anti-ST2 neutralizing antibody mediated regulation of inflammation; 2) Implement a prospective multicenter
study to determine ST2 threshold as a prognostic biomarker of aGVHD for enabling a biomarker-based
preemptive trial; and 3) Inhibit the ICOS/ICOSL pathway with a dual ICOS/CD28 antagonist to prevent and
treat aGVHD. The proposed research is significant because the impact of these studies will be 1) to risk stratify
patients before initiating GVHD treatment, and 2) to develop entirely novel therapeutic strategies while
simultaneously providing novel biological insights into a fatal condition, GVHD.

## Key facts

- **NIH application ID:** 10225589
- **Project number:** 5R01CA168814-07
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Sophie Paczesny
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $323,667
- **Award type:** 5
- **Project period:** 2013-05-03 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10225589

## Citation

> US National Institutes of Health, RePORTER application 10225589, Translating Novel Drug-Targetable Biomarkers to Treat Graft versus Host Disease (5R01CA168814-07). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10225589. Licensed CC0.

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