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Dual targeting of tumoral microenvironment and tumoral cells by blocking the IL-33/ST2 pathway

Award Number: U01CA232491
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/14/2018
PERIOD OF PERFORMANCE END DATE: 06/30/2024

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Dual targeting of tumoral microenvironment and tumoral cells by blocking the IL-33/ST2 pathway - PROJECT SUMMARY/ABSTRACT: A fundamental gap exists in our knowledge of the immunologic tumoral microenvironment during the development of acute myeloid leukemia (AML) and other deadly childhood cancers. Bridging of this gap could lead to novel immunotherapies. Our long-term goals are to develop novel immunotherapies for leukemia and pediatric solid tumors. Our objective in this application is to investigate the role of Foxp3+ regulatory T cells (Tregs) expressing Stimulation-2 (ST2), the IL-33 receptor in the microenvironment as well as ST2 on tumoral cells. Our central hypothesis is that we can target the tumoral microenvironment and tumoral cells by blocking the IL-33/ST2 pathway with neutralizing and bispecific antibodies that we will develop. This hypothesis was formed based on our unpublished preliminary data showing that: First, nonmalignant mice deficient in T-bet have elevated numbers of BM-infiltrating ST2+ Tregs compared to wild-type (WT) mice (45% vs 25%, respectively), suggesting reciprocal roles of ST2/IL33 and T- bet/interferon-γ (IFN-γ) in Tregs from the BM niche. Second, we observed 10-fold more Tregs expressing significantly more activation markers in the BM niche of AML-bearing mice than in the nonmalignant niche. Third, MLL-AF9 AML cell proliferation was significantly lower in mice receiving donor syngeneic ST2 knock-out (ST2-/-) T cells than in mice receiving donor syngeneic WT T cells (2% vs 17%, respectively). ST2 blockade also decreased Treg activation (i.e., KLRG1) and increased type 1 signaling in CD8+ T cells as well as decreased their exhaustion, suggesting restoration of an antitumoral response in ST2-/- mice. The rationale for this study is that once we are able to understand the biology of the immunological microenvironment in the malignant niche, we can propose personalized treatment plans to block the tolerogenic pathways. Similarly, understanding the biology responsible for the overexpression of ST2/IL-33 on the tumoral cell, will help target this pathway. This hypothesis will be tested with three specific aims: 1) Explore ST2 and IL-33 expression on tumoral cells and in the tumoral microenvironment from liquid and solid childhood cancers in human and mice; 2) Examine whether ST2/IL-33 blockade can impact tumor immunity in the malignant BM niche and solid tumor microenvironment as a proof-of-principle of a novel antitumoral immunotherapy; and 3) Optimizing anti-ST2 neutralizing antibodies against murine and human targets for translational purpose. This approach is innovative because, to our knowledge, the function of ST2+ Tregs in the malignant microenvironment, remains virtually unexplored. It will also provide biological insights into the nature of ST2+ Tregs and ST2+ tumoral cells in the microenvironment and determine whether their blockade can restore antitumoral activity and decrease tumoral proliferation via a dual mechanism. The proposed research is significant because novel antitumoral immunotherapies that are more targeted and less toxic than classical chemotherapy/irradiation regimens are needed.


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 = -$35,701 )
2025	2018	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	2	11/6/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$35,701
														Subtotal = -$35,701

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2018	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	2	6/19/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2018	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	001	2	12/22/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$12,016
2022	2018	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	003	2	4/20/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$38,822
2022	2018	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	1	12/22/2021	NEW	$12,016
2022	2018	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	004	2	6/10/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2022	2018	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	002	1	4/20/2022	NEW	-$38,822
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2018	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	1	10/29/2020	NEW	-$12,016
2021	2018	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	001	2	10/29/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$12,016
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $153,053 )
2020	2020	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	003	2	9/24/2020	SUPPLEMENT FOR EXPANSION	$0
2020	2020	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	002	2	9/10/2020	SUPPLEMENT FOR EXPANSION	$153,053
2020	2018	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	1	8/6/2020	NEW	-$2,940,474
2020	2018	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	001	2	8/6/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$2,940,474
														Subtotal = $153,053

Issue Date FY: 2018 ( Subtotal = $4,129,375 )
2018	2018	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	1	9/14/2018	NEW	$4,129,375
														Subtotal = $4,129,375

Grand Total All Awards = $4,246,727

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Dual targeting of tumoral microenvironment and tumoral cells by blocking the IL-33/ST2 pathway

Award Number: U01CA232491

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/14/2018

PERIOD OF PERFORMANCE END DATE: 06/30/2024

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