R01NS115971

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.

Virginia Polytechnic Institute & State University

(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM, TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.853 - Extramural Research Programs in the Neurosciences and Neurological Disorders

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

Roanoke, Virginia 240164950 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 378% from $694,724 to $3,320,824.