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Fractionated photoimmunotherapy to harness low-dose immunostimulation in ovarian cancer

Award Number: U01CA280849
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Fractionated photoimmunotherapy to harness low-dose immunostimulation in ovarian cancer - PROJECT SUMMARY The survival of advanced or recurrent epithelial ovarian cancer (EOC) remains dismal due in part to the complex tumor–immune microenvironment (TIME). The presence of tumor-infiltrating T cells correlates with improved patient outcome in advanced EOC, yet checkpoint inhibitor immunotherapy has generally shown poor efficacy against EOC in clinical trials. A major challenge is the low number of T cells compared to EOC cells in the tumor that establish an immune-suppressive TIME. Tumor-targeted, cell-activatable photoimmunotherapy (taPIT, a near infrared phototherapy) may provide an alternative treatment approach that selectively destroys EOC cells expressing cell-surface epidermal growth factor receptor (EGFR) while enhancing the preservation of tumor infiltrating immune cells salient to an adaptive immune response (e.g., local cytotoxic T cells and dendritic cells). While photoimmunotherapy is not new, this is the first exploration of taPIT dose fractionation to selective eradicate EOC while stimulating immune cells at lower doses and preferentially sparing immune cells at higher doses. Based on our rich preliminary data, we propose that mathematical modeling-informed taPIT serves as a new paradigm for combined cytotoxic therapy and immunotherapy in metastatic EOC. Our overall goal is a novel experimental, simulation- and image-guided approach for utilizing the local selectivity of taPIT to prime “cold” TIME’s for immune checkpoint inhibition. This proposal contributes an innovative physical sciences approach to cancer therapy integrating mathematical modeling with a 3D culture model of the TIME and in vivo imaging experiments in immunocompetent mouse models of EOC, including in silico immuno-oncology modeling to optimize TIME composition-specific therapy; fractionated taPIT dosimetry to reduce the EOC cell burden relative to effector T cells and dendritic cells within the TIME; and, in vivo multiplexed fluorescence microendoscopy to interrogate the TIME of metastatic EOC within the peritoneal cavity. The unique ability to image micronodular disease will enable parameterizing a mathematical model with pre-treatment conditions and dynamic in vivo responses to therapy as a basis for the quantitative design of custom-tailored therapies. Our aims are (1) to train an in silico model by correlating clinical pre-treatment EOC TIME compositions with pathological anti-PD1 response; (2) to derive optimal fractionated taPIT protocols that shift “cold” to anti-PD1-sensitive “hot” TIME in vitro, and (3) to prime the TIME for anti-PD1 therapy in vivo. The concepts introduced here will ultimately enable taPIT–anti-PD1 therapy dosimetry that synergistically stimulates both local and distal immune-enhancing effects to impact disease sites missed by near infrared light, in combination with frontline surgical tumor debulking and systemic chemotherapy. The approaches developed here are translatable to other tumor sites that can be treated with taPIT, including head and neck cancers, skin cancers, and lung cancers.


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 = $536,528 )
2025	2025	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	001	3	7/25/2025	NON-COMPETING CONTINUATION	$536,528
2025	2024	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	2	4/1/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $536,528

Issue Date FY: 2024 ( Subtotal = $490,448 )
2024	2024	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	2	6/27/2024	NON-COMPETING CONTINUATION	$490,448
														Subtotal = $490,448

Issue Date FY: 2023 ( Subtotal = $529,280 )
2023	2023	NORTHEASTERN UNIVERSITY	360 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Biology Research	000	1	6/23/2023	NEW	$529,280
														Subtotal = $529,280

Grand Total All Awards = $1,556,256

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Fractionated photoimmunotherapy to harness low-dose immunostimulation in ovarian cancer

Award Number: U01CA280849

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 07/01/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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