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Breast Cancer Brain Metastasis Therapy by Focused Ultrasound-Guided Control of HER2 CAR T cells

Award Number: R01CA273878
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/08/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Breast Cancer Brain Metastasis Therapy by Focused Ultrasound-Guided Control of HER2 CAR T cells - Project Summary HER2-targeted therapies are promising treatment options for metastatic breast cancer and have improved the median overall survival. However, breast cancer brain metastasis (BCBM), which is observed in up to 50% of HER2-positive breast cancer patients, continues to be a clinical challenge with most patients surviving less than 2 years following CNS involvement. These dismal outcomes underscore the need for new and more effective treatments for BCBM. Chimeric Antigen Receptor (CAR) T cell therapy has led to durable responses in patients with certain types of blood cancers. However, the treatment of brain tumors, such as BCBM, involves a unique set of challenges, including limited infiltration of CAR T cells, heterogenous expression of target CAR antigens, and high systemic toxicity. Although direct intracranial administration of CAR T cells has resulted in anti-tumor responses in a few patients with relatively low systemic toxicity, BCBM is multifocal and requires repeat treatments, which pose significant challenges to effective delivery. Moreover, in recent clinical trials, heterogeneous antigen expression led to relapse from the outgrowth of antigen-negative tumor cells. Therefore, new strategies that can concurrently increase CAR T cell infiltration, combat tumor heterogeneity, and limit off target toxicity are necessary to address the critical and unmet need to treat BCBM. Recently advances in Magnetic Resonance guided Focused Ultrasound (MRgFUS) technology and CAR T cell engineering are uniquely suited to advance CAR T cell therapy for difficult-to-treat BCBM. Closed-loop control of MRgFUS enables spatially localized and noninvasive application of mild hyperthermia (41.5 ± 0.5 oC) in the brain across an intact skull that can transiently increase perfusion and vessel permeability in brain tumors. Preliminary studies indicate that FUS-induced hyperthermia also increases trafficking of CAR T cells to brain tumors. In complementary studies, engineered CAR T cells that respond to mild hyperthermia (40–42 oC) by producing a bi-specific T cell engager (BiTE) that targets CD3 and natural killer group 2 member D ligands (NKG2DL) has been shown to potentiate anti-tumor activity and mitigate antigen escape. By merging these synergistic advances in image-guided therapy and CAR T cell engineering, the proposal objective seeks to apply thermal targeting of brain tumors by MRgFUS to enhance therapeutic trafficking of CAR T cells and spatially control the intratumoral production of BiTEs to potentiate anti-tumor responses against BCBM. Preclinical studies will focus on HER2+ BCBM using both syngeneic and human HER2 (hHER2) transgenic mouse models. The proposed grant will refine, integrate, and test using clinically relevant models two exciting technologies that, if successful, can offer desperately needed new treatment strategies to patients with BCBM.


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 = $655,363 )
2026	2026	GEORGIA TECH RESEARCH CORP	926 DALNEY ST NW	ATLANTA	GA	30318	FULTON	USA	Cancer Detection and Diagnosis Research	000	4	5/18/2026	NON-COMPETING CONTINUATION	$655,363
														Subtotal = $655,363

Issue Date FY: 2025 ( Subtotal = $670,977 )
2025	2025	GEORGIA TECH RESEARCH CORP	926 DALNEY ST NW	ATLANTA	GA	30318	FULTON	USA	Cancer Detection and Diagnosis Research	000	3	5/12/2025	NON-COMPETING CONTINUATION	$670,977
														Subtotal = $670,977

Issue Date FY: 2024 ( Subtotal = $655,509 )
2024	2024	GEORGIA TECH RESEARCH CORP	926 DALNEY ST NW	ATLANTA	GA	30318	FULTON	USA	Cancer Detection and Diagnosis Research	000	2	6/7/2024	NON-COMPETING CONTINUATION	$655,509
														Subtotal = $655,509

Issue Date FY: 2023 ( Subtotal = $655,926 )
2023	2023	GEORGIA TECH RESEARCH CORPORATION	926 DALNEY ST NW	ATLANTA	GA	30332	FULTON	USA	Cancer Detection and Diagnosis Research	000	1	6/8/2023	NEW	$655,926
														Subtotal = $655,926

Grand Total All Awards = $2,637,775

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Breast Cancer Brain Metastasis Therapy by Focused Ultrasound-Guided Control of HER2 CAR T cells

Award Number: R01CA273878

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/08/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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