Sunday, May 18, 2025
5/18/2025
Focused Ultrasound and CAR T Cells for Pediatric Brain Malignancies - Project Abstract Pediatric brain tumors represent a notoriously difficult, yet delicate, class of cancers with an urgent need for safer, more effective treatment options. Medulloblastoma (MB), the most common malignant brain cancer in children, is classified by four major subtypes; its molecular heterogeneity underscores the largely ineffective nature of current treatment options, which often harbor debilitating side effects and risk of chronic cognitive impairments. As such, there is a critical need for safer, selectively targeted approaches that can improve treatment efficacy while minimizing adverse effects. Adoptive cellular therapies have seen profound success as a treatment strategy in specific blood cancers, but their success in solid tumors – in particular, those resident in the brain – has been limited. Unique challenges for cellular therapy in MBs is multifactorial and includes: (1) the suppressive tumor microenvironment consisting of immunosuppressive signaling and dense stromal barriers; (2) limited local cellular infiltration and persistence; (3) heterogeneous antigen expression and antigen escape; and (4) high systemic toxicities. Direct intracranial administration of cellular therapies has displayed marginal success in overcoming these limitations but remains an unfavorable option due to its highly invasive nature. This underscores a critical and urgent need for novel, targeted approaches that can improve treatment efficacy for MB while minimizing adverse effects. Magnetic resonance imaging-guided focused ultrasound (MRgFUS), a burgeoning transcranial intervention strategy, represents a unique and promising approach for potentiating adoptive cellular therapy delivery to MB in a non-invasive, non-ionizing manner. Our group and others have shown that MRgFUS, in combination with microbubbles, drives mechanical effects that can be tuned to yield blood brain/tumor barrier opening for augmented therapeutic delivery, as well as controlled modulation of sterile inflammatory signatures, in primary or secondary brain tumors. We posit that the sono-immumomodulatory bioeffects of FUS, alongside its capacity to promote targeted delivery of cell products and/or allied immune-adjuvants, will enable more robust, less toxic MB therapy. In an effort to tackle on of the most aggressive subtypes of MB, characterized by accelerated growth and frequent metastasis, this proposal takes specific aim at group 3 (G3) MB, leveraging unique mouse models of G3 MB that faithfully recapitulate human disease and bringing them together with MRgFUS for the first time. The proposed grant will interrogate the capacity of spatially tunable MRgFUS interventions to potentiate adoptive cellular immunotherapy (B7-H3-targeted CAR T cells) in immunocompetent preclinical models of G3 MB - leveraging cutting-edge tools such as serial immunoPET imaging, multispectral flow cytometry, and digital spatial profiling to inform this process. Given the clinical relevance of the proposed models and interventions, as well as the translational expertise and history across investigating sites, we expect that findings from this proposal would be ripe for rapid clinical translation and extension to other pediatric brain tumor settings.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).