# Novel Biologic Therapies for GVHD

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2022 · $1,171,119

## Abstract

Novel Biologic Therapies for GVHD
Abstract:
For patients with high-risk malignant and non-malignant hematologic diseases, hematopoietic stem cell transplant
(HCT) often represents the only option for cure. However, HCT is fraught with complications, leading to high rates of
toxicity and patient death. The principal cause of early non-relapse mortality is acute graft-versus-host disease
(AGVHD), with death from infection a close second. These two are interrelated, as intensifying global immune
suppression to control AGVHD increases infection risk. Moreover, augmented immunosuppression can also increase
the risk of malignant relapse. To move the field forward, we must develop targeted, evidence-based prevention and
treatment strategies, designed to specifically control alloreactivity while preserving anti-tumor and anti-viral protective
immunity. Perhaps the greatest need for these targeted therapeutics is in GI AGVHD, the leading cause of AGVHD-
related death. Two issues predominate, which significantly impede progress: (1) We do not adequately understand
the distinct mechanisms controlling GI T cell infiltration versus tissue residency or damage, which inhibits
development of specific therapies. (2) We do not understand the mechanisms driving steroid-refractory GI AGVHD,
significantly slowing treatment development for this most deadly type of AGVHD. The goal of this proposal is to
address these unmet needs, and thereby discover the next generation of therapeutics for GI AGVHD.
We will do so by completing the following three Specific Aims: (1): Prioritize and validate next-generation GI-targeted
therapeutics with a novel translational pipeline. We will test the hypothesis that a pipeline from patient/NHP-derived
therapeutic candidates → mouse → NHP AGVHD models can prioritize new AGVHD therapeutics. (2) Determine the
impact of Notch ligand blockade on the blood and GI immune landscape in NHP and transplant patients. We will test
the hypothesis that Notch ligand blockade with the anti-DLL4 mAb REGN421 protects against GI AGVHD, and that it
does so by inhibiting effector T cell infiltration into the GI tract. (3) Identify predictors of steroid responsive and
resistant GI AGVHD in patients. We will test the hypothesis that unifying mechanisms of steroid response and
resistance can be identified in patients by comprehensive linked immune studies of the blood and GI tract at AGVHD
diagnosis. By completing these aims, we will discern the mechanisms driving GI AGVHD, and thus fundamentally
advance our ability to care for patients undergoing HCT.

## Key facts

- **NIH application ID:** 10379469
- **Project number:** 5R01HL095791-12
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Leslie S Kean
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,171,119
- **Award type:** 5
- **Project period:** 2010-02-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10379469

## Citation

> US National Institutes of Health, RePORTER application 10379469, Novel Biologic Therapies for GVHD (5R01HL095791-12). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10379469. Licensed CC0.

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