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Targeting myeloid suppression to enhance anti-tumor immunity in breast cancer

Award Number: R01CA283169
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/21/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Targeting myeloid suppression to enhance anti-tumor immunity in breast cancer - Project Summary Myeloid immune suppression, driven by macrophages and monocytes, is a known mechanism of intrinsic resistance to immune checkpoint inhibition (ICI), which has provided significant and durable responses in patients with advanced cancers, but not in most breast cancer patients. Our laboratory has been instrumental in demonstrating that targeting myeloid immunosuppression via decreasing the function of immature myeloid derived suppressor cells (MDSCs) is a novel and important strategy to sensitize the tumor microenvironment (TME) and improve the response to ICIs in breast cancer. We published two preclinical studies demonstrating that entinostat, a class I histone deacetylase inhibitor, decreased MDSC suppression of T cells; furthermore, combining entinostat with the ICIs nivolumab and ipilimumab improved survival in murine models of breast cancer. This provided a strong rationale for our Phase I clinical trial (NCI-9844) where we determined the recommended phase 2 dose (RP2D) for this treatment, given to patients with advanced solid tumors, including 10/33 with breast cancer, as a two-week pre-treatment with entinostat, followed by the combination of entinostat + nivolumab + ipilimumab. Furthermore, an overall response rate (ORR) of 30% was observed in an expansion cohort of 20 patients with advanced breast cancer, who received the RP2D. Nevertheless, we have yet to understand how entinostat decreases myeloid suppression to achieve TME sensitization that leads to this striking response to ICIs. Preliminary data in preclinical models demonstrate that entinostat 1) decreases suppressive function of intra- tumoral MDSCs; 2) decreases the activation of the STAT3-NFkB-AP-1 signaling axis; and 3) alters the phenotype and/or infiltration within the TME of other myeloid cells, including tumor associated macrophages (TAMs), and dendritic cells (DCs). Preliminary evaluation of patient samples from our clinical trial confirms these findings. Thus, we hypothesize that entinostat decreases MDSC immunosuppression and shifts the phenotype and function of TAMs, and DCs to collectively sensitize the TME to promote an enhanced response to ICIs. The Specific Aims are: 1) to determine the effects of entinostat on the STAT3-NFB-AP-1 axis decreases MDSC-mediated T cell suppression; and 2) to determine the cellular basis of entinostat-induced sensitization of the TME and how it mediates the anti-tumor response to ICIs. Our unique bidirectional approach combining preclinical studies, e.g., mouse models and mathematical modeling, with hypothesis-driven correlative investigations in patients, and vice versa, strengthens our ability to uncover the molecular and TME mechanisms driving clinical responses. These studies will reveal if changes in myeloid suppression and/or tumor- immune dynamics inform response to therapy or survival, while identification of new biomarkers may improve patient stratification for future trials.


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 = $562,338 )
2026	2026	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Cancer Biology Research	000	4	6/19/2026	NON-COMPETING CONTINUATION	$562,338
														Subtotal = $562,338

Issue Date FY: 2025 ( Subtotal = $562,338 )
2025	2025	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Cancer Biology Research	000	3	6/30/2025	NON-COMPETING CONTINUATION	$562,338
														Subtotal = $562,338

Issue Date FY: 2024 ( Subtotal = $536,866 )
2024	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90089	LOS ANGELES	USA	Cancer Biology Research	000	2	6/20/2024	NON-COMPETING CONTINUATION	$536,866
														Subtotal = $536,866

Issue Date FY: 2023 ( Subtotal = $579,770 )
2023	2023	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Cancer Biology Research	000	1	7/21/2023	NEW	$579,770
														Subtotal = $579,770

Grand Total All Awards = $2,241,312

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Targeting myeloid suppression to enhance anti-tumor immunity in breast cancer

Award Number: R01CA283169

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/21/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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