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Microbiome manipulation through oral live biotherapeutic product (LBP) for the treatment of gut acute graft-versus-host disease (GVHD)

Award Number: R34HL184529
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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Microbiome manipulation through oral live biotherapeutic product (LBP) for the treatment of gut acute graft-versus-host disease (GVHD) - PROJECT SUMMARY/ABSTRACT Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative treatment for a variety of malignant and non-malignant conditions but is often associated with a clinical complication known as graft-versus-host disease (GVHD), a major driver of mortality. Current treatment approaches are primarily immunosuppressive therapies that can dampen the intended activity of the transplanted immune cells against the tumor and cause delayed immune reconstitution and infections. Gastrointestinal (GI) microbiota, the highest microbial colonization in the body, has long been understood to contribute to the pathophysiology of GVHD. Indeed, patients undergoing allo- HCT are subject to dramatic immunological and microbiota perturbations that develop pre-HCT and continue during transplant. When GVHD occurs, the GI tract is frequently involved, and patients often succumb to GVHD. The only FDA-approved treatment for steroid-refractory (SR) acute GVHD (aGVHD) is the Janus kinase 1/2 inhibitor ruxolitinib. However, partial improvement and short duration of response are commonly present. New approaches to treat GVHD are urgently needed. We hypothesize that modulating the composition and function of the GI microbiome has the potential to treat GI aGVHD without causing deleterious immunosuppression. In 2 studies of fecal microbiota transplantation (FMT) in allo-HCT, our group reported that an FMT intervention is a safe way to restore microbiota diversity. However, FMT has batch-to-batch variability depending on specific donors and carries the risks of transmission of infectious organisms or antibiotic-resistance genes. Here, we propose an entirely novel approach: a rationally designed oral live biotherapeutic product (LBP) that delivers a defined composition of pure bacterial strains, which offers advantages of predictable and reproducible pharmacology and would be immediately scalable to future studies. In this proposal, we will conduct a pilot study using an adaptive design in an investigator-initiated trial for the treatment of SR GI aGVHD, led by PI, Doris Ponce, MD. Our group has shown in a recent large multicenter study that microbiome restoration early post-HCT is safe and associated with significant lower risk of bloodstream infections. In addition, innovative preclinical models of microbiome dysbiosis serve as the basis for the study, and the LBP product was developed by co- investigator, Eric Pamer, MD, at the University of Chicago in collaboration with Memorial Sloan Kettering Cancer Center. Project objectives: To evaluate microbiome manipulation in SR lower GI aGVHD. We will pursue 3 specific aims that will evaluate enrollment and accrual ability, treatment adherence, as well as LBP-engraftment and microbiome signatures of functional reconstitution. Expected outcome: Results will provide appropriate recruitment methods, adherence, and the ideal composition of an LBP-directed treatment. Impact: To inform future design of microbiome-directed trials not only in bone marrow transplant but also for other conditions in which GI injury occurs, such as chemotherapy and/or radiation-induced toxicity, and non-malignant inflammatory GI conditions. The proposed project outlines an entirely novel framework for targeting the GI microbiome in HCT.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $281,722 )
2026	2026	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cardiovascular Diseases Research	000	1	7/8/2026	NEW	$281,722
														Subtotal = $281,722

Grand Total All Awards = $281,722

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Microbiome manipulation through oral live biotherapeutic product (LBP) for the treatment of gut acute graft-versus-host disease (GVHD)

Award Number: R34HL184529

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/15/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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