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The impact of interstitial fluid flow on CAR T cell trafficking, distribution, and efficacy

Award Number: R01NS115971
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/15/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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The impact of interstitial fluid flow on CAR T cell trafficking, distribution, and efficacy - PROJECT SUMMARY Chimeric Antigen Receptor (CAR) T-cells are tumor-tropic cell-based therapies that are being investigated as a novel immunotherapy treatment for glioblastoma (GBM). Early clinical findings are highly encouraging, with established safety and demonstrated antitumor activity, and have shown complete regression in at least one patient. However, the effects of CAR T therapies are not uniform across GBM patients, and we have limited knowledge about what may predict efficacy prior to treatment. Identification of predictive biomarkers and approaches to optimize therapy could benefit patients and increase efficacy, yet much is still unknown in regards to their transport and delivery within solid tumors and resection cavities. In GBM, as the tumor grows, there is heightened interstitial fluid flow (IFF) from the tumor into the surrounding parenchyma through the extracellular matrix, interacting with invading cells and surrounding glia. Therapies that increase bulk fluid flow such as infusion of CAR T-cells will also increase IFF through the extracellular spaces of the brain. Thus, throughout tumor progression and during therapeutic intervention, the brain tissue is exposed to heightened IFF. IFF has been linked to altered cell invasion. In peripheral tissues, increased interstitial fluid flow due to injury or infection triggers trafficking of activated dendritic cells to draining lymph nodes, and is necessary to mount an appropriate immune response. These effects are poorly studied in the brain but are critical to understanding how T-cells move both during tumor growth and therapy. T-cells are particularly responsive to fluid shear stress, however, the role of IFF on T-cell motility is unknown. Non-invasive imaging of interstitial fluid flow via MRI in brain tumors could help clinicians predict patterns of T-cell localization during and after therapy. We therefore propose to combine MRI techniques to measure IFF with predictive modeling. Our goal is to characterize barriers to optimal CAR T-cell administration, and to identify imaging biomarkers for evaluation and prediction of clinical response to CAR T-cell therapies for glioblastoma. We hypothesize that the effectiveness of CAR T-cell therapy depends critically on fluid dynamics in the brain and in the tumor, which are patient-specific. This hypothesis leads us to the following specific aims: Specific Aim 1. Identify the impact of interstitial fluid flow on T-cell migration and efficacy in the brain tumor microenvironment. Specific Aim 2. Modulate clinically-relevant CAR T-cell delivery strategies that depend on IFF to increase therapeutic effect. Specific Aim 3. Build predictive mathematical models to study CAR T-cell trafficking and distribution within the tumor based on IFF and tissue structure. Impact and deliverables. The impact of this work is to advance our understanding of factors, which influence the efficacy of CAR T-cell therapy in the brain, with potential implications for other solid tumors. If successful, we will establish both readily implementable strategies to leverage IFF in CAR T-cell therapy and IFF as a potential biomarker of response to CAR T-cell therapy in brain tumors, which can be evaluated non-invasively prior to treatment, followed longitudinally in vivo, and easily incorporated into ongoing and future clinical trial designs.


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 = $0 )
2026	2025	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	3/6/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $652,200 )
2025	2025	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	8/5/2025	NON-COMPETING CONTINUATION	$65,219
2025	2025	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	3/25/2025	NON-COMPETING CONTINUATION	$586,981
														Subtotal = $652,200

Issue Date FY: 2024 ( Subtotal = $637,292 )
2024	2024	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	4/9/2024	NON-COMPETING CONTINUATION	$45,989
2024	2024	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	3/27/2024	NON-COMPETING CONTINUATION	$591,303
														Subtotal = $637,292

Issue Date FY: 2023 ( Subtotal = $664,834 )
2023	2023	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	4/20/2023	NON-COMPETING CONTINUATION	$664,834
														Subtotal = $664,834

Issue Date FY: 2022 ( Subtotal = $671,774 )
2022	2022	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	8/18/2022	NON-COMPETING CONTINUATION	$671,774
														Subtotal = $671,774

Issue Date FY: 2021 ( Subtotal = $694,724 )
2021	2021	VIRGINIA POLYTECHNIC INSTITUTE AND STATE UNIVERSITY	300 TURNER ST NW STE 4200	BLACKSBURG	VA	24061	MONTGOMERY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/11/2021	NEW	$694,724
														Subtotal = $694,724

Grand Total All Awards = $3,320,824

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The impact of interstitial fluid flow on CAR T cell trafficking, distribution, and efficacy

Award Number: R01NS115971

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/15/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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