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Development of a Novel Immunotherapy Platform for Triple-Negative Breast Cancer

Award Number: R21CA256321
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/06/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2024

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Development of a Novel Immunotherapy Platform for Triple-Negative Breast Cancer - Triple-negative breast cancer (TNBC) accounts for 15-20% of all breast cancer diagnoses, is the most aggressive form of the disease, and has the poorest clinical outcome. Chemotherapy is the mainstay treatment for these patients despite significant treatment-related toxicities and short-term clinical responses. Therefore, the need for more effective and better tolerated treatment modalities for TNBC is warranted. Immune checkpoint blockade (ICB) is an immunotherapy-based approach that can reinvigorate durable immunity in advanced cancers such as melanoma and lung. In the case of other cancer types, such as breast cancer, the FDA approved the first immunotherapy for TNBC in March 2019. This regimen consists of α-PD-L1 antibody (Tecentriq) plus Abraxane (Nab-paclitaxel) as a frontline therapy for patients with unresectable locally advanced or metastatic PD-L1+ TNBC. Unfortunately, overall response rates remain relatively low and survival outcomes are extended for only a few months due in large part to expansion of immunosuppressive polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) that potently suppress antitumor immunity. Thus, developing strategies to reduce PMN-MDSC activity may improve response rates to α-PD-L1/Abraxane in TNBC. One approach to lessen myeloid-based mechanisms of immune suppression is by modulating signaling pathways that govern immune suppression to those that promote stimulation in a concept known as reprogramming. Toll-like receptor (TLR) 5 signaling can both mitigate MDSC activity and stimulate antitumor immunity against multiple pre-clinical tumor models, including PD-L1+ TNBC. Thus, we posit that TLR5 agonists are a novel class of agents that can mediate myeloid reprogramming with potential in vivo therapeutic efficacy in PD-L1+ TNBC. To this end, we engineered and pharmacologically optimized entolimod, a derivative of the natural TLR5 agonist Salmonella flagellin. Importantly, three Phase I safety trials cumulatively involving nearly 200 subjects showed that systemically administered entolimod is safe. Our recent work showed that entolimod suppresses metastatic PD-L1+ TNBC by stimulating durable CD8+ T cell immunity. Here, we show that entolimod-driven PMN-MDSC reprogramming governs the anti-metastatic activity of entolimod in PD-L1+ TNBC. These findings provided the rationale for our additional studies showing that combining entolimod with α-PD-L1/Paclitaxel triggers regression of early-stage mouse PD-L1+ TNBC and induces durable immunity. However, whether entolimod enhances the antitumor activity of α-PD-L1/Abraxane in locally advanced and the neoadjuvant and/or adjuvant setting of metastatic PD- L1+ TNBC, for which this therapy is FDA approved, remains unknown, as well as whether entolimod alters the PMN-MDSC response as part of its mechanism of action. To test our central hypothesis, we propose two aims: (1) to determine the most effective TNBC treatment platform and disease setting by which entolimod bolsters the efficacy of α-PD-L1/Abraxane; and (2) to elucidate the contribution of PMN-MDSCs to the mechanism by which entolimod promotes the antitumor efficacy of α-PD-L1/Abraxane in TNBC.


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 = $0 )
2025	2022	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Cancer Treatment Research	000	2	10/29/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $192,653 )
2022	2022	HEALTH RESEARCH, INC.	ELM AND CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Cancer Treatment Research	000	2	6/22/2022	NON-COMPETING CONTINUATION	$192,653
														Subtotal = $192,653

Issue Date FY: 2021 ( Subtotal = $235,901 )
2021	2021	HEALTH RESEARCH, INC.	ELM AND CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Cancer Treatment Research	000	1	8/6/2021	NEW	$235,901
														Subtotal = $235,901

Grand Total All Awards = $428,554

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Development of a Novel Immunotherapy Platform for Triple-Negative Breast Cancer

Award Number: R21CA256321

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/06/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2024

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