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TLR7/8 agonist design and delivery for effective anticancer immune response

Award Number: R01CA260825
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/08/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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TLR7/8 agonist design and delivery for effective anticancer immune response - Agonists of toll like receptors (TLRs) are promising anticancer vaccine adjuvants because of their ability to induce proinflammatory cytokines necessary to generate a robust immune response. However, currently available TLR agonists suffer from a number of limitations including self-regulatory immunosuppression and unfavorable local pharmacokinetics resulting in poor availability within dendritic cells. Further, current TLR agonist-based anticancer vaccines generate a robust cytotoxic CD8 T cell response but not CD4 Th 1 helper T cell response, which is critical for inducing effective, long-term antitumor immunity. We will address these important challenges through a synergistic combination of drug discovery and drug delivery efforts. Our team has developed a suite of highly substituted imidazoquinolines, which activate TLR7 and/or 8 and induce significantly higher levels of cytokines compared to imiquimod, an FDA approved TLR7 agonist. Our studies show the balance between proinflammatory and immunosuppressive cytokines can be tuned through structural modifications. Encapsulation of these novel agonists in acidic pH responsive nanoparticles (NPs) resulted in robust activation of CD4 and COB T cells as well as natural killer (NK) cells, leading to a stronger anticancer immune response than free agonist or that encapsulated in non-pH responsive NPs. Importantly, intradermal delivery of NP vaccine using a hollow microneedle platform led to an enhanced Th1 immune response, which is essential for effective induction of long-term antitumor immunity. We will build on these exciting findings and further optimize the new agonists for efficient encapsulation in pH responsive NPs, tune the NP properties for improved targeting of dendritic cells following delivery via hollow microneedles, and investigate potentiation of NK cell-mediated antibody-mediated cellular cytotoxicity. The Specific Aims of this revised R01 grant application include: Aim 1: Design and synthesize TLR7/8 agonists that are optimized for NP encapsulation Aim 2: Optimize pH responsive NP formulation for hollow microneedle-assisted ID delivery Aim 3: Determine anticancer efficacy of NP vaccine following hollow microneedle-assisted ID delivery We expect our studies will identify new design principles and delivery strategies for TLR agonists that overcome the limitations of current anticancer vaccines and further advance the field of cancer immunotherapy.


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 = $314,801 )
2026	2026	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cancer Treatment Research	000	6	1/8/2026	NON-COMPETING CONTINUATION	$314,801
														Subtotal = $314,801

Issue Date FY: 2025 ( Subtotal = $349,778 )
2025	2025	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cancer Treatment Research	002	5	6/3/2025	NON-COMPETING CONTINUATION	$34,977
2025	2025	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cancer Treatment Research	000	5	1/17/2025	NON-COMPETING CONTINUATION	$314,801
2025	2025	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cancer Treatment Research	001	5	2/14/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $349,778

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Cancer Treatment Research	001	4	2/9/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$352,574
2024	2023	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1805 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Cancer Treatment Research	000	3	2/9/2024	NON-COMPETING CONTINUATION	-$352,574
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $352,575 )
2023	2023	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Cancer Treatment Research	000	3	5/31/2023	NON-COMPETING CONTINUATION	$352,575
														Subtotal = $352,575

Issue Date FY: 2022 ( Subtotal = $352,261 )
2022	2022	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Cancer Treatment Research	000	2	6/13/2022	NON-COMPETING CONTINUATION	$352,261
														Subtotal = $352,261

Issue Date FY: 2021 ( Subtotal = $374,075 )
2021	2021	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Cancer Treatment Research	000	1	6/8/2021	NEW	$374,075
														Subtotal = $374,075

Grand Total All Awards = $1,743,490

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TLR7/8 agonist design and delivery for effective anticancer immune response

Award Number: R01CA260825

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/08/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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