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Augmenting T cell trafficking and functionality through novel combinations of epigenetic agents and PD-1 blockade

Award Number: R01CA212169
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/28/2017
PERIOD OF PERFORMANCE END DATE: 07/31/2024

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Augmenting T cell trafficking and functionality through novel combinations of epigenetic agents and PD-1 blockade - Despite therapeutic advances over the last decades, the 5-year overall survival of lung cancer patients remains dismal. In an important breakthrough, recent studies have shown efficacy of immunotherapy in the treatment of lung cancer and other malignancies. PD-1 checkpoint blockade is an especially promising approach, yet response rates remain relatively low (~20% in lung cancer); thus, new approaches are needed to enhance efficacy. Notably, benefit from immunotherapy, including T cell checkpoint blockade, is often associated with elevated pre-treatment expression of immuno-stimulatory genes in tumors, especially T cell chemokines including CCL5, CXCL9 and CXCL10. We hypothesized that an unbiased screen to identify FDA-approved oncology agents with immuno-stimulatory properties would identify agents that augment the response to immunotherapy. In our cancer cell-based screens designed to identify small molecules that induce the expression of T cell chemokines, we found that only a single agent class, HDAC inhibitors (HDACi), induced expression of these chemokines in an array of mouse and human lung cancer cells. Focusing on the HDACi romidepsin, we found that this agent induced a strong anti-tumor response against KRAS mutant non-small cell lung cancer tumors in mice, and that this was entirely dependent on the presence of T cells. Importantly, romidepsin co-treatment markedly augmented the response to PD-1 blockade. These results support using HDACi in combination with PD-1 blockade as a new approach for the treatment of lung cancer patients. However, key in vivo mechanisms of action of HDACi and of synergy with anti-PD-1 need to be defined, especially the effect of these agents on tumor cells and tumor-infiltrating T cells. These studies will rigorously test the hypothesis that targeting HDACs provides a new strategy for generating a tumor microenvironment favorable for checkpoint blockade immunotherapy. Three Specific Aims will test this hypothesis. Aim 1: Defining in vivo mechanisms of chemokine expression and T cell trafficking in NSCLC tumors. Aim 2: Investigating stimulatory effects of HDACi on TIL function and synergism with PD- 1 blockade. Aim 3: Efficacy of novel combinatory strategies to augment PD-1 blockade response in KRAS/TP53 and KRAS/STK11 autochthonous lung tumor models.


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 = -$33,617 )
2025	2021	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Treatment Research	000	5	12/3/2024	NON-COMPETING CONTINUATION	-$33,617
														Subtotal = -$33,617

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2021	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Treatment Research	000	5	11/22/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $393,450 )
2021	2021	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Treatment Research	000	5	8/9/2021	NON-COMPETING CONTINUATION	$393,450
														Subtotal = $393,450

Issue Date FY: 2020 ( Subtotal = $393,450 )
2020	2020	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Treatment Research	000	4	7/31/2020	NON-COMPETING CONTINUATION	$393,450
														Subtotal = $393,450

Issue Date FY: 2019 ( Subtotal = $381,646 )
2019	2019	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Treatment Research	000	3	8/1/2019	NON-COMPETING CONTINUATION	$381,646
														Subtotal = $381,646

Issue Date FY: 2018 ( Subtotal = $393,450 )
2018	2018	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Treatment Research	000	2	7/24/2018	NON-COMPETING CONTINUATION	$393,450
														Subtotal = $393,450

Issue Date FY: 2017 ( Subtotal = $393,450 )
2017	2017	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Treatment Research	000	1	8/28/2017	NEW	$393,450
														Subtotal = $393,450

Grand Total All Awards = $1,921,829

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Augmenting T cell trafficking and functionality through novel combinations of epigenetic agents and PD-1 blockade

Award Number: R01CA212169

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/28/2017

PERIOD OF PERFORMANCE END DATE: 07/31/2024

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