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Targeting tumor and T cell DNA methylomes to improve CAR T cell therapies for diffuse midline glioma

Award Number: U01CA281823
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/07/2023
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Targeting tumor and T cell DNA methylomes to improve CAR T cell therapies for diffuse midline glioma - SUMMARY/ABSTRACT While improvements in immune therapies have revolutionized treatments in some cancers, pediatric brain tumors are especially resistant to current immunotherapy treatments, including immune check point inhibitors. This may be because many pediatric brain tumors have been characterized as “immune cold”, with little to no immune cell infiltration. Chimeric antigen receptor (CAR) T cell therapies have shown promise against fatal brain tumors such as diffuse midline glioma (DMG) in early clinical studies. However, in early studies, patients inevitably succumb to this fatal disease. This raises important questions about mechanisms of CAR T cell resistance and devising strategies to improve and prolong CAR T cell function. Targeting epigenetic programs has been identified as one strategy to overcome deficient immune responses in solid tumors through both tumor cell intrinsic and tumor microenvironment mechanisms. We have shown in DMG that inhibition of DNA methylation activates innate immune pathways that may stimulate immune cell recruitment and activity (Krug et al., Cancer Cell, 2019). Our data in CAR T cells deficient for a DNA methyl transferase (DNMT3A) displays reduced exhaustion and enhanced anti-tumor activity against multiple tumor models, including brain tumors (Prinzing et al., Science Translational Medicine, 2021). We hypothesize that combinatorial approaches that target distinct DMG and CAR T cell DNA methylomes represents a rational strategy to enhance CAR T cell therapy. We propose to test this in two specific aims: AIM1: Determine how tumor DNA demethylation in DMG impacts CAR T cell recruitment and function. We will test the hypothesis that inhibition of DNA methylation induced endogenous retroviral activation will enhance CART cell activation and persistence. AIM2: Determine if CAR T cell effector function is improved by DNA methylation inhibition in DMG. We will test the hypothesis that inhibition of DNA methylation in CAR T cells is a phenotype that translates to DMG, by preventing T cell exhaustion and improving long-term effector function.


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 = $786,304 )
2026	2026	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	4	8/12/2026	NON-COMPETING CONTINUATION	$786,304
														Subtotal = $786,304

Issue Date FY: 2025 ( Subtotal = $498,337 )
2025	2025	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	3	9/5/2025	NON-COMPETING CONTINUATION	$498,337
														Subtotal = $498,337

Issue Date FY: 2024 ( Subtotal = $746,809 )
2024	2024	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	2	9/4/2024	NON-COMPETING CONTINUATION	$746,809
														Subtotal = $746,809

Issue Date FY: 2023 ( Subtotal = $807,680 )
2023	2023	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	1	9/7/2023	NEW	$807,680
														Subtotal = $807,680

Grand Total All Awards = $2,839,130

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Targeting tumor and T cell DNA methylomes to improve CAR T cell therapies for diffuse midline glioma

Award Number: U01CA281823

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/07/2023

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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