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Adoptive T Lymphocyte Administration for Chronic Norovirus Treatment Following Hematopoietic Stem Cell Transplantation

Award Number: R01HL152161
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Hematopoietic stem cell transplantation (HSCT) is the treatment of choice for many patients with malignancies as well as other life-threatening conditions such as primary immunodeficiency disorders (PID). Chronic norovirus infection is a potential complication of HSCT, and can cause chronic diarrhea and wasting. There are currently no available therapies to treat norovirus. We have demonstrated that healthy individuals have T cell immunity against norovirus, and that viral epitopes in antigens NS6 and VP1 are well conserved across viral genotypes. The overarching goal of this proposal is the development of a novel treatment for chronic norovirus infection in patients undergoing HSCT. In our previous study, we demonstrated safety and potential efficacy of virus-specific T cells targeting CMV, EBV, and adenovirus as well as the feasibility of this approach. To restore immunity against norovirus we now propose to take blood from the healthy donors and expand and enrich the norovirus-specific T cells (NSTs) present in donors' blood, followed by extensive characterization of the function of NSTs. We will then give NSTs as treatment for chronic norovirus in patients who have undergone HSCT. If successful, this novel antiviral therapy could provide long-term protection against norovirus. Thus, we hypothesize that the infusion of NSTs will be safe and effective against norovirus infections in patients post HSCT, and will restore lasting immunity against norovirus. We further hypothesize that antiviral efficacy will correlate with expansion of T cells recognizing immunodominant viral epitopes, which will correspond to stable regions of the viral genome. Through this phase I IND study, we will address the following specific aims: 1) To determine the breadth of norovirus T cell epitopes and MHC restrictions, as well as their genetic stability in clinical viral isolates, 2) To study the safety and feasibility of administering ex vivo expanded T cells targeting norovirus as treatment of chronic infection in immunocompromised patients, and 3) To determine whether infusion of NSTs can enhance norovirus specific immunity in immune compromised hosts. Collectively, these aims will determine if NSTs may be a safe and effective treatment for chronic norovirus infection in patients post HSCT. Completion of this study could provide a novel antiviral therapy which could reduce virus- associated morbidity in HSCT, and will guide future cellular therapy and vaccine trials targeting enteric viruses.


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: 2023 ( Subtotal = $715,637 )
2023	2023	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Blood Diseases and Resources Research	000	4	5/30/2023	NON-COMPETING CONTINUATION	$715,637
														Subtotal = $715,637

Issue Date FY: 2022 ( Subtotal = $715,637 )
2022	2022	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Blood Diseases and Resources Research	001	3	5/13/2022	NON-COMPETING CONTINUATION	$715,637
2022	2021	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Blood Diseases and Resources Research	000	2	12/24/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $715,637

Issue Date FY: 2021 ( Subtotal = $722,458 )
2021	2021	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Blood Diseases and Resources Research	001	2	7/30/2021	NON-COMPETING CONTINUATION	$722,458
2021	2020	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Blood Diseases and Resources Research	000	1	10/22/2020	NEW	$0
														Subtotal = $722,458

Issue Date FY: 2020 ( Subtotal = $735,811 )
2020	2020	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Blood Diseases and Resources Research	000	1	4/23/2020	NEW	$735,811
2020	2020	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Blood Diseases and Resources Research	001	1	4/28/2020	NEW	$0
														Subtotal = $735,811

Grand Total All Awards = $2,889,543

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Adoptive T Lymphocyte Administration for Chronic Norovirus Treatment Following Hematopoietic Stem Cell Transplantation

Award Number: R01HL152161

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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