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Harnessing TLR4 Signaling Pathways in CAR Dendritic Cells to Overcome Tumor Immune Tolerance

Award Number: R21CA313766
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/13/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Harnessing TLR4 Signaling Pathways in CAR Dendritic Cells to Overcome Tumor Immune Tolerance - Solid tumors may evade immune destruction due to T-cell or dendritic cell (DC) dysfunction, and current immunotherapies face limitations in solid tumors. This project addresses these challenges by leveraging our myeloid chimeric antigen receptor (CAR) expertise to mechanistically characterize a novel DC-based immunotherapy: αB7H3-TLR4 CAR-DCs. These engineered DCs express a B7H3-specific CAR fused to the intracellular signaling domain of Toll-like receptor 4 (TLR4). Preliminary data demonstrate that αB7H3-TLR4 CAR-DCs efficiently capture tumor antigens from tumor cells expressing the tumor associated antigen B7H3, potently upregulate costimulatory molecules, and robustly cross-prime naïve tumor-specific CD8⁺ T cells, leading to complete tumor rejection and durable immune memory in a heterogenous B7H3-expressing sarcoma model. This project will dissect the distinct roles of MyD88 and TRIF signaling pathways downstream of TLR4 in these CAR-DCs. Aim 1 will define the role of MyD88 in acute T-cell priming and effector differentiation, while Aim 2 will define the role of TRIF in long-term memory and recall responses. By elucidating these mechanisms, we will provide a roadmap for rationally designing DC-based therapies that maximize both immediate tumor control and durable immune protection, ultimately leading to more effective treatments for a wide range of solid tumors.


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 = $399,829 )
2026	2026	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	000	1	5/14/2026	NEW	$399,829
														Subtotal = $399,829

Grand Total All Awards = $399,829

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Harnessing TLR4 Signaling Pathways in CAR Dendritic Cells to Overcome Tumor Immune Tolerance

Award Number: R21CA313766

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/13/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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