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Improving the platelet-mediated immune checkpoint inhibitor delivery for treating triple-negative breast cancer

Award Number: R01CA288851
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/10/2025
PERIOD OF PERFORMANCE END DATE: 12/31/2029

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Improving the platelet-mediated immune checkpoint inhibitor delivery for treating triple-negative breast cancer - Project Summary Despite the great success of immune checkpoint inhibitors in treating a subset of cancer patients by blocking PD1/PDL1 pathway, the treatment outcomes in triple-negative breast cancer (TNBC) remain dismal partially due to the immunosuppressive microenvironment and impaired T cell infiltration in the TNBC. We recently developed a platelet-mediated immune checkpoint inhibitor delivery system (designated P-aPDL1) that could efficiently target the post-surgical tumor site and bioresponsively release aPDL1 in the format of platelet-derived microparticles upon the activation of platelets at the tumor site. We have demonstrated the enhanced treatment efficacy against post-surgical B16F10 melanoma and 4T1 TNBC tumor recurrence, while treatment outcomes on the intact non-immunogenic 4T1 TNBC without pre-treatment with surgery remain to be improved. In this proposal, we intend to develop multi-faceted strategies to enhance the treatment efficacy of P-aPDL1 against TNBC through (1) increasing the tumor-selective P-aPDL1 accumulation by triggering a local thrombus formation at the TNBC site; and (2) modulating the immunosuppressive tumor microenvironment through depleting tumor- associated macrophages (TAMs). Specifically, in AIM 1, we will apply a truncated tissue factor-RGD (tTF-RGD) peritumorally or systemically to trigger the local thrombus formation in the tumor tissue and attract the accumulation of P-aPDL1. Both 4T1 TNBC primary and metastatic tumors will be used to evaluate the treatment efficacy. In AIM 2, we will intratumorally inject TAMs-depleting nanoparticles (PLX-NP) to modulate the immunosuppressive microenvironment to facilitate the infiltration of effector T cells to synergize with P-aPDL1 for enhanced treatment efficacy against TNBC. In AIM 3, the combination treatment strategies identified in AIM 1-2 will be evaluated on a fully validated patient-derived xenograft (PDX) TNBC humanized mouse model. This proposal will develop a suite of new combination immunotherapy strategies to increase the anti-tumor efficacy against TNBC and provide significant insights into advancing the current immunotherapeutics for treating other non-immunogenic tumors in the clinic.


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 = $575,212 )
2026	2026	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cancer Treatment Research	000	2	1/9/2026	NON-COMPETING CONTINUATION	$575,212
														Subtotal = $575,212

Issue Date FY: 2025 ( Subtotal = $619,764 )
2025	2025	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cancer Treatment Research	000	1	12/31/2024	NEW	$619,764
														Subtotal = $619,764

Grand Total All Awards = $1,194,976

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Improving the platelet-mediated immune checkpoint inhibitor delivery for treating triple-negative breast cancer

Award Number: R01CA288851

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/10/2025

PERIOD OF PERFORMANCE END DATE: 12/31/2029

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