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DC Field | Value | Language |
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dc.contributor.advisor | Bramson, Jonathan | - |
dc.contributor.author | Bezverbnaya, Ksenia | - |
dc.date.accessioned | 2021-09-30T14:32:31Z | - |
dc.date.available | 2021-09-30T14:32:31Z | - |
dc.date.issued | 2021 | - |
dc.identifier.uri | http://hdl.handle.net/11375/26937 | - |
dc.description.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. | en_US |
dc.language.iso | en | en_US |
dc.subject | Engineered T cells | en_US |
dc.subject | BCMA | en_US |
dc.subject | Multiple Myeloma | en_US |
dc.subject | Immunotherapy | en_US |
dc.title | Development of BCMA-specific engineered T cells targeting multiple myeloma | en_US |
dc.title.alternative | Engineered T cells for multiple myeloma | en_US |
dc.type | Thesis | en_US |
dc.contributor.department | Medical Sciences | en_US |
dc.description.degreetype | Thesis | en_US |
dc.description.degree | Doctor of Science (PhD) | en_US |
dc.description.layabstract | Multiple myeloma is an incurable blood cancer that has a remarkable ability to develop resistance to different types of chemotherapy. In recent years, treatments redirecting immune cells against tumors have shown impressive clinical responses against different types of chemotherapy-resistant blood cancers, including multiple myeloma. Our lab has developed a new technology for redirecting T cells against tumors, called T cell antigen coupler (TAC) receptor. This thesis describes optimization of a fully human TAC receptor specific for a target on the surface of myeloma cells, known as BCMA. Durable remissions induced by TAC-engineered T cells in a preclinical mouse model of myeloma in the absence of toxicity warrant further testing of this therapeutic in a clinical trial. | en_US |
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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