Enhancing car T cell therapy for DMG using mrgfus
Active Project Grant Awarded Last action
- Award ID
- F31NS149676
- Recipient
-
ST. Jude Children's Research Hospital Graduate School Of Biomedical Sciences, LLC UEI MN2LFZNE4HH3
- Awarding agency
-
National Institute of Neurological Disorders and Stroke
National Institutes of Health, Department of Health and Human Services
- Obligated
- $49,114
Award facts
- Assistance listing
- 93.853 Extramural Research Programs in the Neurosciences and Neurological Disorders
- Completion date 0% complete
- Place of performance
- Memphis, TN 38105, USA
Award details come from USAspending.gov.
Description
- Abstract
- The objective of this study is to evaluate the potential therapeutic benefit of combining magnetic resonance imaging-guided focused ultrasound (MRGFUS) with car T cell therapy to treat the pediatric brain tumor, diffuse midline glioma (DMG). The current lack of targeted therapies for DMG has led to an abysmal survival rate for the disease. Car T cell therapy is one of the few therapies that has been shown to extend survival in DMG patients, albeit inconsistently. This has led to a large effort to improve car T cell therapy for DMG via modification of the T cells or combination therapy. MRGFUS is a technique that has been gaining traction in the brain tumor space, as IT can be used to safely and temporarily permeabilize the blood-brain barrier (BBB). This can increase permeation of circulating therapies that are not BBB-penetrant, such as car T cells. Further, MRGFUS has been shown to induce proinflammatory responses in targeted tissue, which may alleviate some of the immunosuppressive effects of the DMG tumor immune microenvironment (TIME). To date, the combination of MRGFUS and car T cell therapy has yet to be studied in the context of DMG. In this project, I will investigate the impact of this combination on survival in both patient-derived xenograft (PDX) and immunocompetent models of DMG, while also measuring tumor infiltration and persistence of the car T cells. Additionally, I plan to utilize single-cell RNA-sequencing to determine the cell type-specific contributions to inflammatory signatures observed with MRGFUS. I hypothesize that combining MRGFUS and car T cell therapy will extend survival as compared to either treatment alone, which will correlate with improved tumor infiltration and persistence of the car T cells. Further, I hypothesize that the tumor-associated macrophage population in DMG will shift to a more pro- inflammatory state upon treatment with MRGFUS and car T cells. I have demonstrated in preliminary studies that the MRGFUS platform that will be utilized for the proposed studies is capable of spatially distinct BBB opening. Additionally, I have demonstrated that MRGFUS does increase the amount of systemically administered car T cells trafficking to the brain in a TIME-dependent manner. Aim 1 will focus on measuring car T cell infiltration and persistence in PDX and syngeneic models of DMG treated with MRGFUS and car T cell therapy, then determining if these changes correlate with a change in survival. Aim 2 will investigate the MRGFUS-induced changes in inflammation on a single-cell level, while also using the transcriptomic data collected to inform other promising combination therapies with MRGFUS and car T cell therapy. Overall, these studies will investigate the therapeutic potential of the combination of car T cell therapy MRGFUS, while also deepening the field's understanding of the effects of this combination on the DMG TIME. This project will be conducted at ST. Jude children's research hospital, an NCI-designated comprehensive cancer center. The study and training plan proposed herein were carefully designed to train me in foundational and advanced techniques critical to the field of cancer immunotherapy and to further develop my writing, presenting, and mentoring skills.
Quick answers
Who received award F31NS149676?
F31NS149676 was awarded to ST. Jude Children's Research Hospital Graduate School Of Biomedical Sciences, LLC by National Institute of Neurological Disorders and Stroke (National Institutes of Health) on January 1, 2027.
How much is award F31NS149676 worth?
$49,114 has been obligated on F31NS149676.
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