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Mechanisms of immune evasion in T-cell acute lymphoblastic leukemia and its therapeutic implications

Award Number: R01CA249185
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/24/2021
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Mechanisms of immune evasion in T-cell acute lymphoblastic leukemia and its therapeutic implications - Project Summary T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic malignancy in children and young adults that frequently becomes treatment-refractory and relapses. Although cure rates have improved with intensified multi-agent chemotherapy, relapsed or treatment refractory disease remains very difficult to treat. Therefore, there is a great medical need for identifying novel vulnerabilities and therapeutic approaches. Targeting of the immunosuppressive tumor microenvironment has led to promising results in many solid tumors. Yet, comprehensive studies of the T-ALL microenvironment, which are necessary to characterize leukemia/immune cell interactions and identify therapeutic vulnerabilities, have not been performed. Using single cell sequencing technologies of T-ALL blasts and their microenvironmental cells, we have generated preliminary data suggesting a novel role of immune evasion in T-ALL with the potential to incorporate immunotherapy approaches into current treatment regimens to overcome T-cell exhaustion. This proposal seeks to define novel mechanisms of immune evasion in T-ALL and develop means for their therapeutic targeting. We will define mechanisms of CD8+ T-cell dysfunction by combining RNA-Seq, immune repertoire and protein analysis in single leukemia and microenvironmental cells in primary T-ALL patient samples and determine the necessary and sufficient exhaustion receptor/ligands through functional perturbation in in vitro and in vivo models of T-ALL (aim 1); We will study epigenetic and transcriptional mechanisms that regulate immune evasion in T-ALL and develop novel strategies to target T-cell dysfunction in pediatric leukemias by perturbing the epigenetic machinery (aim 2). Successful completion of this proposal is expected to uncover novel mechanisms of immune evasion in T- ALL and will lead to development of innovative therapeutic strategies for targeting T-cell exhaustion in the immune microenvironment in patients with high-risk T-ALL. The principles described in T-ALL will have a significant impact on a wide variety of malignancies.


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 = $294,347 )
2025	2025	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	004	6	7/11/2025	NON-COMPETING CONTINUATION	$352,270
2025	2024	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	003	5	5/8/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2025	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	4	3/17/2025	NON-COMPETING CONTINUATION	-$238,971
2025	2024	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	001	5	4/7/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$238,971
2025	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	002	4	4/7/2025	NON-COMPETING CONTINUATION	-$57,923
														Subtotal = $294,347

Issue Date FY: 2024 ( Subtotal = $385,461 )
2024	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	4	7/19/2024	NON-COMPETING CONTINUATION	$385,461
														Subtotal = $385,461

Issue Date FY: 2023 ( Subtotal = $397,633 )
2023	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	3	7/25/2023	NON-COMPETING CONTINUATION	$397,633
														Subtotal = $397,633

Issue Date FY: 2022 ( Subtotal = $405,748 )
2022	2022	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	2	7/19/2022	NON-COMPETING CONTINUATION	$405,748
														Subtotal = $405,748

Issue Date FY: 2021 ( Subtotal = $405,748 )
2021	2021	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	1	8/24/2021	NEW	$405,748
														Subtotal = $405,748

Grand Total All Awards = $1,888,937

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Mechanisms of immune evasion in T-cell acute lymphoblastic leukemia and its therapeutic implications

Award Number: R01CA249185

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/24/2021

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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