Presenter Status
Fellow
Abstract Type
Research
Primary Mentor
Dr. Viveka Nand Yadav
Start Date
15-5-2024 12:15 PM
End Date
15-5-2024 12:30 PM
Presentation Type
Oral Presentation
Description
Background: Pediatric high-grade gliomas (pHGGs) are aggressive brain tumors responsible for significant childhood mortality. These tumors often carry mutations in the H3F3A gene, which encodes histone H3.3 proteins. However, current treatment options are limited, underscoring the need for innovative approaches. Chimeric antigen receptor (CAR) therapy, which was successful in treating certain childhood cancers, holds promise for pHGGs with H3G34R/V mutations. This study aims to assess the potential of anti-B7-H3 CAR T cell therapy in treating the challenging pHGG tumors.
Method and Results: Here, we examined the expression of B7-H3 in various pHGG cell lines, encompassing those with H3G34V/R and H3K27M mutations. Data revealed substantial B7-H3 expression, confirming its potential as a therapeutic target. We observed that, co-culturing B7H3 CAR T cells with KNS42 and SJ-HGG-X42 cells, led to noteworthy increases in the expression of markers associated with T cell activation (IL2, IL6, IF-γ, TNF-α) and immune responses involving cytolytic cells (Granzyme A, B, Perforin) in comparison to mock-treated cells. Furthermore, flow cytometry analysis indicated elevated levels of exhaustion markers (2B4, PD1, Tim3, Lag3) on B7-H3 CAR T cells when co-cultured with KNS42 and SJ-HGG-X42 cells, as opposed to mock-treated cells. We evaluated the capability of B7-H3 CAR T cells to eliminate KNS-42 cells through in vitro testing. Our results after 72 hours of co-culture revealed strong killing potential of B7-H3 CARs against B7-H3 positive KNS-42 cells, while minimal impact on B7H3-negative MDA MD 453 cells was observed. Lastly, we generated a novel immune-competent mouse model of pHGGs that enables exploration of CAR T cell activation and function within the immune suppressive tumor microenvironment.
Conclusion: B7-H3 emerges as a promising therapeutic target, and bi-specific CAR T cells display encouraging functionality within the context of pHGGs. This research contributes significantly to advancing our comprehension of pHGG biology and lays the foundation for potential therapeutic breakthroughs.
Future Directions: We will test human-specific anti-B7-H3 and anti-B7H3-anti-GD2 CAR T cells in vivo using our unique mouse model of pHGGs. The impact of CAR T cell function on the tumor microenvironment will be studied using Pediatric High-Grade Gliomas model.
Included in
Analytical, Diagnostic and Therapeutic Techniques and Equipment Commons, Higher Education and Teaching Commons, Medical Education Commons, Pediatrics Commons, Science and Mathematics Education Commons
Therapeutic Efficacy of B7-H3 CAR T Cell Therapy In Pediatric High-Grade Gliomas with H3G34R/V Mutation.
Background: Pediatric high-grade gliomas (pHGGs) are aggressive brain tumors responsible for significant childhood mortality. These tumors often carry mutations in the H3F3A gene, which encodes histone H3.3 proteins. However, current treatment options are limited, underscoring the need for innovative approaches. Chimeric antigen receptor (CAR) therapy, which was successful in treating certain childhood cancers, holds promise for pHGGs with H3G34R/V mutations. This study aims to assess the potential of anti-B7-H3 CAR T cell therapy in treating the challenging pHGG tumors.
Method and Results: Here, we examined the expression of B7-H3 in various pHGG cell lines, encompassing those with H3G34V/R and H3K27M mutations. Data revealed substantial B7-H3 expression, confirming its potential as a therapeutic target. We observed that, co-culturing B7H3 CAR T cells with KNS42 and SJ-HGG-X42 cells, led to noteworthy increases in the expression of markers associated with T cell activation (IL2, IL6, IF-γ, TNF-α) and immune responses involving cytolytic cells (Granzyme A, B, Perforin) in comparison to mock-treated cells. Furthermore, flow cytometry analysis indicated elevated levels of exhaustion markers (2B4, PD1, Tim3, Lag3) on B7-H3 CAR T cells when co-cultured with KNS42 and SJ-HGG-X42 cells, as opposed to mock-treated cells. We evaluated the capability of B7-H3 CAR T cells to eliminate KNS-42 cells through in vitro testing. Our results after 72 hours of co-culture revealed strong killing potential of B7-H3 CARs against B7-H3 positive KNS-42 cells, while minimal impact on B7H3-negative MDA MD 453 cells was observed. Lastly, we generated a novel immune-competent mouse model of pHGGs that enables exploration of CAR T cell activation and function within the immune suppressive tumor microenvironment.
Conclusion: B7-H3 emerges as a promising therapeutic target, and bi-specific CAR T cells display encouraging functionality within the context of pHGGs. This research contributes significantly to advancing our comprehension of pHGG biology and lays the foundation for potential therapeutic breakthroughs.
Future Directions: We will test human-specific anti-B7-H3 and anti-B7H3-anti-GD2 CAR T cells in vivo using our unique mouse model of pHGGs. The impact of CAR T cell function on the tumor microenvironment will be studied using Pediatric High-Grade Gliomas model.
