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http://hdl.handle.net/11375/22904
Title: | PRE-CLINICAL DEVELOPMENT OF SYNTHETIC RECEPTOR-ENGINEERED T LYMPHOCYTES FOR THE TREATMENT OF CANCER: NOVEL RECEPTORS AND UNDERSTANDING TOXICITY |
Authors: | Hammill, Joanne |
Advisor: | Bramson, Jonathan |
Department: | Medical Sciences |
Keywords: | Immunology;Immuno-oncology;Chimeric antigen receptor;CAR-T cells |
Publication Date: | 2018 |
Abstract: | Advances in our understanding of the molecular events leading to cancer have facilitated the development of next-generation targeted therapies. Among the most promising new approaches is immuno-oncology, where therapeutic agents engage the immune system to fight cancer. One exciting strategy therein is the adoptive transfer of ex vivo cultivated tumor-specific T lymphocytes into a cancer patient. Tumor-specific T cells can be produced by engineering a patient’s own T cells with synthetic receptors (e.g. chimeric antigen receptors (CARs)) designed to redirect T cell cytotoxicity against a tumor target. CAR-engineered T cells (CAR-T cells) were expected to be a non-toxic cellular therapy which would seek out and specifically eliminate disseminated tumors. The clinical experience supports the promise of CAR-T cell therapy (striking efficacy has been observed in the treatment of hematological malignancies), while highlighting areas for improvement; CAR-T cell use has been associated with a host of toxicities and robust clinical efficacy has yet to be replicated in solid tumors. This thesis uses pre-clinical models to describe previously unappreciated aspects of CAR-T cell-associated toxicity and novel synthetic receptor strategies, including: i. The capacity of NKG2D-based CAR-T cells to mediate toxicity. ii. The utility of designed ankyrin repeat proteins as CAR antigen-binding domains. iii. The discovery that variables intrinsic to human CAR-T cell products contribute to toxicity. iv. A novel synthetic receptor capable of redirecting T cell specificity against a tumor target – the T cell antigen coupler (TAC). Unlike equivalent CAR-T cells, TAC-T cells are capable of mediating efficacy against a solid tumor in the absence of toxicity. We anticipate that these results will contribute towards the development of next-generation synthetic receptor-engineered T cell products that can deliver upon the promise of safe, systemic cancer therapeutics. |
URI: | http://hdl.handle.net/11375/22904 |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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Hammill_Joanne_A_2018Feb_PhD.pdf | 26.5 MB | Adobe PDF | View/Open |
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