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Novel focused ultrasound enhanced calreticulin-nanoparticle for immune primed melanoma immunotherapy

Award Number: R37CA239150
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/04/2019
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Novel focused ultrasound enhanced calreticulin-nanoparticle for immune primed melanoma immunotherapy - Summary Malignant melanoma in advanced stages is a highly lethal form of cancer, refractory to chemo- and radio-therapy, and the median survival is typically less than 4years. To improve response rates, antibodies that target CTL-4, PD1, and PDL1 has gained prominence, and can achieve a response rate of ~50% in metastatic cases. This is promising but a large proportion of patients still do not respond to immune therapies due to the absence of infiltrating T-cells, and presence of aberrant and suppresive signaling pathways that blunt the expression of checkpoint proteins (e.g. CD47, PDL1). To promote inflamed melanoma microenvironment, recent studies indicate that image-guided focused ultrasound (FUS) can i) mediate precise mechanical perturbation and elevation of tumor temperature to induce tumor antigen release and ii) upregulate calreticulin (CRT), a protein that is key to the activation of local and systemic anti-immunity. However, the exact mechanisms and how to translate this approach for clinical treatment of malignant melanoma is poorly understood. The goal of this project is to combine ultrasound guided FUS with novel CRT-NP, a liposome-plasmid nanoparticle agent that transfects melanoma cells to induce expression of CRT. Our in vitro and in vivo data in murine melanoma suggest that combined local treatment with CRT-NP/FUS (CFUS) enhances expression of CRT and modulates innate (CD47) and adaptive checkpoint proteins (PDL1); all of which significantly enhance the local and systemic immune priming and anti-tumor responses. Based on this premise, our central hypothesis is that CFUS targeted optimization of the CRT/CD47/PDL1 axis will provide powerful immune priming and generation of systemic immunity against malignant melanoma. To test our hypothesis, we will mechanistically dissect and understand CFUS-mediated immune priming in a B16 orthotopic and genetically-engineered mouse melanoma model (Aim 1 & 2) and translate this approach to clinical use in trials using client-owned dogs with spontaneous oral melanoma (Aims 3). Specifically, we will evaluate the impact of the CFUS treatment sequence, FUS exposures, and CRT-activation mechanisms in murine melanoma and translate this information to improve efficacy of checkpoint blockage in murine and canine tumor models. We expect that the successful optimization of local CFUS in this project will liberate tumors from their immune- suppressive state, achieve consistent and predictable clonal expansion of cytotoxic immune cells, and improve immunotherapy efficacy independent of cancer complexity. If successful, this method will provide a promising new avenue for treating melanoma and other types of solid tumor (e.g., breast, prostate) by significantly overcoming current immunotherapy barriers.


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 = $1,239,509 )
2025	2025	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Detection and Diagnosis Research	001	7	8/18/2025	EXTENSION WITH OR WITHOUT FUNDS	$1,239,509
2025	2023	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Detection and Diagnosis Research	002	6	9/24/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2025	2023	OKLAHOMA STATE UNIVERSITY	401 WHITEHURST HALL	STILLWATER	OK	74078	PAYNE	USA	Cancer Detection and Diagnosis Research	000	5	2/19/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,239,509

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Detection and Diagnosis Research	001	6	4/9/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$286,470
2024	2023	OKLAHOMA STATE UNIVERSITY	401 WHITEHURST HALL	STILLWATER	OK	74078	PAYNE	USA	Cancer Detection and Diagnosis Research	000	5	4/9/2024	NON-COMPETING CONTINUATION	-$286,470
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $358,518 )
2023	2023	OKLAHOMA STATE UNIVERSITY	401 WHITEHURST HALL	STILLWATER	OK	74078	PAYNE	USA	Cancer Detection and Diagnosis Research	000	5	5/24/2023	NON-COMPETING CONTINUATION	$358,518
														Subtotal = $358,518

Issue Date FY: 2022 ( Subtotal = $345,260 )
2022	2022	OKLAHOMA STATE UNIVERSITY	401 WHITEHURST HALL	STILLWATER	OK	74078	PAYNE	USA	Cancer Detection and Diagnosis Research	000	4	5/25/2022	NON-COMPETING CONTINUATION	$345,260
														Subtotal = $345,260

Issue Date FY: 2021 ( Subtotal = $329,555 )
2021	2021	OKLAHOMA STATE UNIVERSITY	401 WHITEHURST HALL	STILLWATER	OK	74078	PAYNE	USA	Cancer Detection and Diagnosis Research	000	3	6/18/2021	NON-COMPETING CONTINUATION	$329,555
														Subtotal = $329,555

Issue Date FY: 2020 ( Subtotal = $315,862 )
2020	2020	OKLAHOMA STATE UNIVERSITY	401 WHITEHURST HALL	STILLWATER	OK	74078	PAYNE	USA	Cancer Detection and Diagnosis Research	000	2	6/1/2020	NON-COMPETING CONTINUATION	$315,862
														Subtotal = $315,862

Issue Date FY: 2019 ( Subtotal = $299,472 )
2019	2019	OKLAHOMA STATE UNIVERSITY	401 WHITEHURST HALL	STILLWATER	OK	74078	PAYNE	USA	Cancer Detection and Diagnosis Research	000	1	6/4/2019	NEW	$299,472
2019	2019	OKLAHOMA STATE UNIVERSITY	401 WHITEHURST HALL	STILLWATER	OK	74078	PAYNE	USA	Cancer Detection and Diagnosis Research	001	1	6/28/2019	NEW	$0
														Subtotal = $299,472

Grand Total All Awards = $2,888,176

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Novel focused ultrasound enhanced calreticulin-nanoparticle for immune primed melanoma immunotherapy

Award Number: R37CA239150

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/04/2019

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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