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.
