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Modulation of Chimeric Antigen Receptor T Cells to Enhance Their Anti-Tumor Efficacy / Ruchi P Patel.
- Format:
- Book
- Thesis/Dissertation
- Author/Creator:
- Patel, Ruchi P., author.
- Language:
- English
- Subjects (All):
- Molecular biology.
- Cellular biology.
- Oncology.
- Therapy.
- Immunology.
- Cell and Molecular Biology--Penn dissertations.
- Penn dissertations--Cell and Molecular Biology.
- Local Subjects:
- Molecular biology.
- Cellular biology.
- Oncology.
- Therapy.
- Immunology.
- Cell and Molecular Biology--Penn dissertations.
- Penn dissertations--Cell and Molecular Biology.
- Physical Description:
- 1 online resource (147 pages)
- Contained In:
- Dissertations Abstracts International 85-12A.
- Place of Publication:
- [Philadelphia, Pennsylvania] : University of Pennsylvania, 2022.
- Ann Arbor : ProQuest Dissertations & Theses, 2024
- Language Note:
- English
- Summary:
- This study investigates mechanisms of resistance to CAR T therapy across diverse cancer models and explores innovative strategies to overcome these challenges. A key focus is directed towards the membrane protein CD5, known to be a negative regulator of T cell activation in normal T cells. While T cell dysfunction poses a formidable challenge for CAR T cells against all cancers, fratricide emerges as a specific hurdle in CAR T cell therapies targeting T cell malignancies. This underscores the pivotal role of CD5 as a dual-action regulator: by knocking it out, we can prevent CART-T cell fratricide and enhance T cell activation, as CD5 serves as a negative regulator of T cell activation in normal T cells. Experimental findings across multiple models, encompassing immunodeficient and immunocompetent settings, reveal that CD5 knockout enhances the efficacy of adoptive T cell therapies, including CART5, CART19, CARTmeso, CART-HER2, and TCR-GP100. Mechanistically, we identified notable upregulation of cytotoxicity-related genes in CD5 KO T cells compared to CD5+ T cells in vivo that were collected and subjected to single-cell RNA sequencing. As a result of these promising discoveries, our platform technology has introduced its initial product: a CD5 KO CART5 formulation that employs a unique dual-population approach. This innovative design allows for the integration of a CD5-negative, CAR-negative population, offering the possibility of replenishing normal T cells in patients. These advancements pave the way for clinical translation, with the evaluation of a CD5 KO dual population product in a phase I clinical trial targeting CD5+ nodal T cell lymphomas, promising to revolutionize CAR T therapy outcomes.
- Notes:
- Source: Dissertations Abstracts International, Volume: 85-12, Section: A.
- Advisors: Ruella, Marco; Committee members: Maillard, Ivan P.; Burkhardt, Janis K.; Kambayashi, Taku; Fraietta, Joseph A.
- Department: Cell and Molecular Biology.
- Ph.D. University of Pennsylvania 2024.
- Local Notes:
- School code: 0175
- ISBN:
- 9798382830506
- Access Restriction:
- Restricted for use by site license.
- This item is not available from ProQuest Dissertations & Theses.
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