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Epigenetic Profiling of circulating cell-free DNA for the Monitoring of Graft-Versus-Host Disease after Hematopoietic Cell Transplantation

Award Number: R01AI146165
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Epigenetic Profiling of circulating cell-free DNA for the Monitoring of Graft-Versus-Host Disease after Hematopoietic Cell Transplantation - Allogeneic Hematopoietic Cell Transplantation (HCT) is a widely used therapy for a variety of malignant and nonmalignant hematologic diseases. More than 8,500 patients, receive HCT transplants in the US each year. Yet, up to 50% of patients suffer complications due to graft-versus-host disease (GVHD) in the first year after HCT. GVHD occurs when donor immune cells attack the patient’s own tissues. GVHD can occur anywhere, with the skin, gut and liver most frequently affected. GVHD remains one of the major barriers to a more widespread application of allogeneic HCT. Early diagnosis of aGVHD is critical to inform treatment decisions and prevent serious organ injury and death. Unfortunately, few informative diagnostic approaches are available. In current clinical practice, diagnosis of aGVHD relies almost entirely on the presence of clinical symptoms and requires confirmation via invasive biopsy procedures, such as skin biopsy, colonoscopy, upper endoscopy or liver biopsy. HCT patients urgently need a better alternative. The goal of this proposal is to develop and apply a blood test to detect acute GVHD (aGVHD) and to predict long-term HCT outcomes. This test employs genome-wide profiling of methylation marks comprised within circulating cell-free DNA (cfDNA) in blood to trace their tissues-of-origin, and to quantify tissue-specific injury after HCT. This concept is supported by significant pilot data. We will perform a retrospective study of the utility of cfDNA to stratify HCT recipients with single organ aGVHD (Aim 1), and a prospective study of the utility of cfDNA to detect the early onset of GVHD and to predict HCT risk (Aim 2). Together these aims explore the highly innovative concept that a measurement of the tissues-of- origin of cfDNA in plasma enables to i) detect aGVHD, ii) quantify the severity of aGVHD and determine its organ involvement, iii) predict post-HCT mortality, and iv) predict the outcome of aGVHD treatments. This proposal directly addresses an urgent, unmet medical need: the early and noninvasive diagnosis of aGVHD after HCT. These studies are therefore highly translational. A highly informative, noninvasive monitoring tool may inform new treatment modalities and transplant strategies. Recognizing the limitations of universal prophylactic therapy against aGVHD, cfDNA assays could find future use in guiding pre-emptive treatment strategies, thereby reducing the need for prolonged immunosuppressive therapy after transplant. Furthermore, earlier detection of aGVHD could lead to shorter durations of therapeutic immunosuppression and improved patient outcomes.


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: 2024 ( Subtotal = $650,319 )
2024	2024	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	000	5	12/11/2023	NON-COMPETING CONTINUATION	$585,288
2024	2024	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	001	5	5/20/2024	NON-COMPETING CONTINUATION	$65,031
														Subtotal = $650,319

Issue Date FY: 2023 ( Subtotal = $653,663 )
2023	2023	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	000	4	12/14/2022	NON-COMPETING CONTINUATION	$653,663
														Subtotal = $653,663

Issue Date FY: 2022 ( Subtotal = $656,855 )
2022	2022	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	000	3	12/2/2021	NON-COMPETING CONTINUATION	$656,855
														Subtotal = $656,855

Issue Date FY: 2021 ( Subtotal = $733,701 )
2021	2021	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	000	2	1/13/2021	NON-COMPETING CONTINUATION	$733,701
														Subtotal = $733,701

Issue Date FY: 2020 ( Subtotal = $752,613 )
2020	2020	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	000	1	1/13/2020	NEW	$752,613
														Subtotal = $752,613

Grand Total All Awards = $3,447,151

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Epigenetic Profiling of circulating cell-free DNA for the Monitoring of Graft-Versus-Host Disease after Hematopoietic Cell Transplantation

Award Number: R01AI146165

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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