Tuesday, July 1, 2025 7/1/2025

Dual action immunostimulatory nanoparticles for treatment of aggressive cancers

Award Number: R01CA278633
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/26/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2025

Group Awards By:

View Award Description

Dual action immunostimulatory nanoparticles for treatment of aggressive cancers - PROJECT SUMMARY: Cancer immunotherapy is based on the premise of immune-recognition and targeted killing of tumor cells, thus possesses the promising power to eradicate aggressive disease. Notably to date, immunotherapy with immune checkpoint inhibitors significantly prolongs the survival of patients. Unfortunately, recurrent and metastatic disease occurs to a significant portion of patients within 5 years largely due to resistance to the immune checkpoint inhibitor. This largely stems from the local immunosuppressive tumor microenvironment (TME), which is enriched with immunosuppressive myeloid cells. To reprogram the TME into a “hot” environment enriched with functional myeloid cells, we designed a dual action immunostimulatory nanoparticle (dual-NP) that triggers a highly potent activation of the dysfunctional tumor-resident myeloid cells. The premise of our strategy is based on three key components: (1) Our previous studies showed that V domain Immunoglobulin Suppressor of T cell Activation (VISTA) is a novel myeloid cell-intrinsic immune checkpoint protein, which controls antitumor immunity. We showed VISTA is highly expressed on immunosuppressive myeloid cells and blocking VISTA can synergize with TLR9 agonist to reprogram the immunosuppressive myeloid cells to boost antitumor immunity. (2) The dual-NP is co-loaded with a VISTA siRNA and the TLR9 agonist CpG. Upon intratumoral administration, the dual-NP ensures the simultaneous uptake of its synergistic cargoes by the same tumor-resident myeloid cells and proficient intracellular delivery of each cargo, thus achieving optimal effects to activate these cells. Our recent studies show that simultaneous silencing of the VISTA gene and stimulation of TLR9 leads to a synergistic T cell-mediated tumor clearance and curative responses with protective immunological memory against tumor recurrence. (3) We developed a simple and controllable method to generate ionizable lipid dual-NPs of different sizes (i.e., 30, 40 or 60 nm) with high degree of uniformity and consistency. Our studies show that small dual-NPs achieve widespread distribution and predominant uptake by myeloid cells throughout the tumor volume upon intratumoral administration. Innovation: To our knowledge, this is the first effort to combine advanced nanoparticle design, simultaneous delivery of siRNA and a TLR agonist, and silencing of a gene related to an immune checkpoint protein specific to myeloid cells. AIM 1: Optimize the design of the dual-NP and test the ex vivo and in vivo efficacy in reprograming tumorassociated myeloid cells. AIM 2: Evaluate the short and long-term safety profile of the dual-NP and characterize the mechanism of antitumor immune responses associated with dosage and frequency of dual-NP administration. AIM 3: Evaluate the therapeutic efficacy of the dual-NP as a monotherapy and in combination with standard immune checkpoint inhibitors in murine models of advanced melanoma and metastatic breast cancer.


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	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Treatment Research	001	2	5/9/2025	NON-COMPETING CONTINUATION	$0
2025	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Treatment Research	002	2	6/16/2025	SUPPLEMENT FOR EXPANSION	$0
2025	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Treatment Research	000	2	5/9/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $647,989 )
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Treatment Research	003	2	5/22/2024	SUPPLEMENT FOR EXPANSION	$77,121
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Treatment Research	002	2	5/21/2024	NON-COMPETING CONTINUATION	$570,868
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Treatment Research	001	1	4/16/2024	SUPPLEMENT FOR EXPANSION	-$81,180
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Treatment Research	000	1	3/1/2024	SUPPLEMENT FOR EXPANSION	$81,180
														Subtotal = $647,989

Issue Date FY: 2023 ( Subtotal = $600,913 )
2023	2023	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Cancer Treatment Research	000	1	6/26/2023	NEW	$600,913
														Subtotal = $600,913

Grand Total All Awards = $1,248,902

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Dual action immunostimulatory nanoparticles for treatment of aggressive cancers

Award Number: R01CA278633

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/26/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2025

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer