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http://hdl.handle.net/11375/26937
Title: | Development of BCMA-specific engineered T cells targeting multiple myeloma |
Other Titles: | Engineered T cells for multiple myeloma |
Authors: | Bezverbnaya, Ksenia |
Advisor: | Bramson, Jonathan |
Department: | Medical Sciences |
Keywords: | Engineered T cells;BCMA;Multiple Myeloma;Immunotherapy |
Publication Date: | 2021 |
Abstract: | Multiple myeloma is a plasma cell cancer that progressively evolves to an aggressive, multi-drug resistant disease, which presents an unmet clinical need. In clinical trials, myeloma shows susceptibility to novel immunotherapeutic agents, particularly those targeting B-cell maturation antigen (BCMA). Among different classes of immunotherapies, T cell-based approaches have progressed the most due to their ability to induce durable responses in patients with advanced drug-resistant blood cancers. Most T cell engineering strategies rely on the use of chimeric antigen receptors (CARs), which although effective, can cause serious life-threatening toxicities. We created a new synthetic receptor, T cell antigen coupler (TAC), which recruits the endogenous T cell receptor and allows T cells to autoregulate their activity. Our experience in solid tumor models has shown that TAC-T cells are similarly efficacious and significantly less toxic than CAR-T cells. This thesis describes our optimization of BCMA-specific TAC-T cells and analysis of different anti-BCMA antigen-binding domains. TAC receptor functions by engaging endogenous TCR-CD3 complex and redirecting it to the target of interest. In Chapter 3, we characterize optimization and humanization of the CD3-recruitment domain in the TAC scaffold and provide evidence that TAC-T cells are effective against multiple myeloma, irrespective of receptor surface levels. In Chapter 4, we describe selection of the human BCMA-binding domain and the creation of a fully humanized TAC receptor against BCMA. Chapters 5 and 6 describe how a BCMA-targeting antigen-binding domain that cross-reacts with an unknown antigen in mice augments in vivo efficacy of TAC- and CAR-T cells, respectively. The work described in Chapters 3 and 4 presents an optimized, fully human BCMA-TAC that is being moved into clinical testing. The work in Chapters 5 and 6 improves our understanding of how antigen-targeting domains in synthetic receptors influence the functionality of engineered T cells. |
URI: | http://hdl.handle.net/11375/26937 |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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Bezverbnaya_Ksenia_finalsubmission202108_PhD.pdf | 4.54 MB | Adobe PDF | View/Open |
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