Graduation Year
2023
Date of Submission
12-2022
Document Type
Open Access Senior Thesis
Degree Name
Bachelor of Arts
Department
Neuroscience
Second Department
W.M. Keck Science Department
Reader 1
Dr. Michael Barish
Reader 2
Dr. Melissa Coleman
Terms of Use & License Information
Rights Information
© 2022 Arianna Livi
Abstract
Chimeric Antigen Receptor T (CAR-T) cells have demonstrated anti-tumor activity against aggressive and invasive cancers such as glioblastoma (GBM); however, clinical response rates remain low in clinical trial studies. Tumor heterogeneity and tumor microenvironment conditions pose significant challenges for treatment of GBM, thus continuous optimization of CAR-T cell therapies and identification of novel, widely expressed, and highly specific GBM antigens are vital to better patient outcomes. A newly developed CAR-T cell construct incorporating chlorotoxin (CLTX) as the targeting domain exhibited broad GBM-targeting capabilities and elicited potent cytotoxic effects during preclinical studies and is currently being tested in a phase I clinical trial (NCT04214392) for recurrent GBM. Since much is still unknown about the binding mechanism and cytotoxic action of CLTX-CAR-T cells, characterization of the immunological synapse is important to be able to quantify and visualize structural, functional and signaling cascading components of CAR-T cell cytotoxicity. The purpose of this research project was to investigate the morphology of the immunological synapse between the novel CLTX-CAR-T cells and GBM tumor cells using key structural components such as receptor aggregation, actin accumulation, cytotoxic granule convergence and MTOC polarization to indicate effective cytotoxic activity and potentially predict clinical performance. Through confocal microscopy, visualization of the CLTX-CAR-T cell immunological synapse provided evidence of significant cytotoxic activity and matrix metaoproteinase-2 (MMP2) receptor localization at CLTX-CAR-T cells contact sites during tumor cell killing. These findings further our understanding of the CLTX-CAR-T cell binding complex and enhance the potential for optimizing the clinical efficacy of CLTX-CAR-T cells, thereby contributing to better treatment outcomes for patients with glioblastoma.
Recommended Citation
Livi, Arianna, "Visualization and Characterization of the Immunological Synapse Between Chlorotoxin Chimeric Antigen (CLTX-CAR) Redirected T Cells and Targeted Glioblastoma Tumors" (2023). CMC Senior Theses. 3114.
https://scholarship.claremont.edu/cmc_theses/3114
Included in
Cancer Biology Commons, Immunotherapy Commons, Medical Neurobiology Commons, Molecular and Cellular Neuroscience Commons, Oncology Commons
