Tuesday, August 19, 2025 8/19/2025

Persistent STAT5 signaling in polyfunctional CD4 T cells and its application in adoptive T cell therapy

Award Number: R01CA264983
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Persistent STAT5 signaling in polyfunctional CD4 T cells and its application in adoptive T cell therapy - Project summary/abstract Recent advances in adoptive T-cell therapy (ACT), especially CD19-targeting chimeric antigen receptor (CAR) T-cell therapy (CD19CART), have highlighted the potential of immunotherapy to achieve durable and curative patient outcomes. However, even for the well-developed CD19CART, many patients have failed to respond to the treatment or succumbed to late relapse. Moreover, so far ACT in general has not been effective in treating most solid tumors. The major barriers to effective ACT include deficiencies in donor T cell expansion, persistence and tumor- infiltration, as well as loss of T-cell effector function - a process termed exhaustion. There is increasing demand for novel strategies that can overcome these barriers to improve the efficacy of ACT. The presence of CD4 T cells with a polyfunctional phenotype, characterized by concomitant production of multiple inflammatory cytokines, has been associated with favorable therapeutic outcomes in preclinical models and cancer patients. However, how to generate polyfunctional CD4 (pfCD4) T cells suitable for ACT remains elusive. We previously reported that CD4 T cells exposed to interleukin 7 (IL7) during antigenic stimulation can acquire polyfunctionality in a STAT5-dependent manner. Our recent work demonstrated that ectopic expression of a constitutively active form of STAT5 (CASTAT5) in CD4 T cells induces genome- wide transcriptional and epigenetic remodeling in tumor-specific CD4 T cells, endowing these cells polyfunctionality, exhaustion-resistance and tumor-infiltrating capability. Importantly, CASTAT5 can markedly improve the expansion and persistence of CD19CAR T cells, resulting in high cure rate in mice with advanced lymphoma. These new findings form the basis of our central hypothesis that CASTAT5-induced epigenetic remodeling endows CD4 T cells polyfunctionality and exhaustion-resistance, and these features equip CD4 T cells with superior helper activities to orchestrate potent antitumor immune responses. This cross-disciplinary multi- PI project will employ our well-characterized ACT model systems in conjunction with cutting-edge epigenomics and single cell RNA sequencing technologies to advance our understanding of the ontogeny, heterogeneity, regulatory circuitry and mechanism of action of pfCD4 T cells. Specifically, we will investigate how persistent STAT5 signaling induces and maintains pfCD4 T cells (Aim 1), how CASTAT5-induced pfCD4 T cells potentiate ACT (Aim 2), and the potential utility of CASTAT5 in human CD19CAR T cells (Aim 3). Successful completion of this project will establish CASTAT5 as a clinically applicable strategy to overcome the barriers impeding effective ACT including CAR T cell therapy.


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 = $522,742 )
2025	2025	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Biology Research	000	5	6/16/2025	NON-COMPETING CONTINUATION	$522,742
														Subtotal = $522,742

Issue Date FY: 2024 ( Subtotal = $496,606 )
2024	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Biology Research	000	4	6/28/2024	NON-COMPETING CONTINUATION	$496,606
														Subtotal = $496,606

Issue Date FY: 2023 ( Subtotal = $512,286 )
2023	2023	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Biology Research	000	3	7/20/2023	NON-COMPETING CONTINUATION	$512,286
														Subtotal = $512,286

Issue Date FY: 2022 ( Subtotal = $512,286 )
2022	2022	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Biology Research	000	2	7/13/2022	NON-COMPETING CONTINUATION	$512,286
														Subtotal = $512,286

Issue Date FY: 2021 ( Subtotal = $528,183 )
2021	2021	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Biology Research	000	1	6/30/2021	NEW	$528,183
														Subtotal = $528,183

Grand Total All Awards = $2,572,103

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Persistent STAT5 signaling in polyfunctional CD4 T cells and its application in adoptive T cell therapy

Award Number: R01CA264983

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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