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Immunosuppressive human invariant natural killer T cells for prevention of graft-versus-host disease

Award Number: K08HL151809
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 05/01/2020
PERIOD OF PERFORMANCE END DATE: 04/30/2025

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Immunosuppressive human invariant natural killer T cells for prevention of graft-versus-host disease - PROJECT SUMMARY Allogeneic hematopoietic stem cell transplantation (HSCT) plays a vital role in treating high-risk hematologic malignancies and some non-malignant conditions. However, many patients undergoing HSCT develop acute graft-versus-host disease (GVHD), and current prevention strategies that globally immunosuppress or selectively deplete T cells are associated with higher risks of cancer relapse, delayed immune reconstitution, increased infections, and other toxicities. Identifying the best way to suppress donor T cells to prevent GVHD while not losing their beneficial functions remains a critically unmet need. The adoptive transfer of murine invariant natural killer T (iNKT) cells significantly reduces GVHD, and a number of human studies support a role for iNKT cells in GVHD suppression. Several immunophenotypically and functionally distinct iNKT subsets have been defined in mice, and only certain subsets have the capacity to suppress GVHD. Despite these advances in understanding murine iNKT cells, the heterogeneity of human iNKT cells remains largely unexplored, and the subset best suited to prevent GVHD is unknown. The overall goal of this proposal is to define human iNKT cell heterogeneity and to develop strategies for the targeted selection and generation of immunosuppressive iNKT cells. To achieve this goal, similar approaches to those used in mice, as well as novel techniques, will be used to define the phenotypic, molecular, and functional characteristics of human iNKT subsets to delineate an immunosuppressive population with the potential to prevent GVHD. In addition, a gene-engineering strategy will be employed to enhance immunosuppressive function. These experiments will contribute substantially by providing the scientific basis for the isolation of immunoregulatory iNKT cells which will enable the design of a future clinical trial of iNKT cell adoptive transfer for GVHD prevention. Importantly, this work is broadly applicable beyond control of GVHD, as understanding human iNKT heterogeneity will provide a framework for future studies of iNKT cells and iNKT-based therapies in other disease states, including autoimmunity, cancer, and infection. The proposed project is part of a comprehensive career development plan for the applicant to build upon her substantial prior research experience in cellular immunology and hematopoietic stem cell transplantation. In particular, she plans to acquire new skillsets including high throughput proteomic and transcriptomic analyses and genetic engineering of cells. This training will occur under the guidance of her primary mentor, Dr. Robert Negrin, and her research advisory committee, including Drs. Maria Grazia Roncarolo, Matthew Porteus, Samuel Strober, and Holden Maecker. Their guidance and expertise, combined with that of her collaborators Drs. Ken Weinberg, Kara Davis, Nima Aghaeepour, and Everett Meyer, will ensure that the applicant completes the proposed studies and acquires the expertise necessary to fulfill her career goal of becoming an independent physician scientist with a research program focusing on immune regulation of GVHD in HSCT.


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: 2025 ( Subtotal = -$1 )
2025	2024	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Blood Diseases and Resources Research	000	5	8/25/2025	NON-COMPETING CONTINUATION	-$1
														Subtotal = -$1

Issue Date FY: 2024 ( Subtotal = $166,536 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Blood Diseases and Resources Research	003	5	4/10/2024	NON-COMPETING CONTINUATION	$166,536
2024	2022	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Blood Diseases and Resources Research	001	3	3/5/2024	NON-COMPETING CONTINUATION	-$166,536
2024	2022	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Blood Diseases and Resources Research	002	4	3/5/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$167,244
2024	2021	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Blood Diseases and Resources Research	000	2	3/5/2024	NON-COMPETING CONTINUATION	-$708
														Subtotal = $166,536

Issue Date FY: 2023 ( Subtotal = $166,536 )
2023	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Blood Diseases and Resources Research	001	4	5/24/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$166,536
2023	2022	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Blood Diseases and Resources Research	000	3	5/23/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $166,536

Issue Date FY: 2022 ( Subtotal = $166,536 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Blood Diseases and Resources Research	000	3	4/20/2022	NON-COMPETING CONTINUATION	$166,536
														Subtotal = $166,536

Issue Date FY: 2021 ( Subtotal = $166,536 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Blood Diseases and Resources Research	001	2	5/12/2021	NON-COMPETING CONTINUATION	$166,536
2021	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Blood Diseases and Resources Research	000	1	10/26/2020	NEW	$0
														Subtotal = $166,536

Issue Date FY: 2020 ( Subtotal = $166,536 )
2020	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Blood Diseases and Resources Research	000	1	4/10/2020	NEW	$166,536
														Subtotal = $166,536

Grand Total All Awards = $832,679

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Immunosuppressive human invariant natural killer T cells for prevention of graft-versus-host disease

Award Number: K08HL151809

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 05/01/2020

PERIOD OF PERFORMANCE END DATE: 04/30/2025

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