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http://hdl.handle.net/11375/26925
Title: | Identifying Biologically Active Compounds to Provide T Cell Costimulation for Cancer Immunotherapy |
Authors: | Bacchiocchi, Kaylyn |
Advisor: | Bramson, Jonathan |
Department: | Biochemistry and Biomedical Sciences |
Publication Date: | 2021 |
Abstract: | Adoptive cell therapy (ACT) is a powerful cancer immunotherapy platform, where T lymphocytes are collected from cancer patients, expanded ex vivo, and infused back into the patient as a cellular drug. Genetic modification with chimeric receptors redirects T cell tumour-specificity. While ACT is a clinical success in many cancers, it is dependent on T cell proliferation following infusion, where robust expansion is a predictor of a positive outcome. Costimulation is the activation of a class of receptors which provide maximal stimulatory signals to T cells, resulting in an enhancement of proliferation, survival, and memory. Costimulatory receptor signaling occurs in cooperation with the T cell receptor, and is provided by several receptor families that converge on costimulatory signaling pathways. Chimeric receptors can be modified with costimulatory domains however, the non-canonical signaling can lead to overstimulation and serious toxicity in the clinic. We hypothesize that pharmacological costimulation can be used to boost T cell proliferation, where drug administration and dosage is controlled and the drug can cease to be administered should toxicities manifest. Small molecule costimulation may prove to be a useful approach to boost the efficacy of ACT as a cancer therapy. The objective of my research project is to screen and characterize for small molecules that enhance T cell proliferation. Specifically, I will investigate the ability small molecule drugs to enhance T cell expansion following antigen-specific stimulation of T cells engineered with T cell antigen coupler (TAC) receptors. Methods: I identified candidate small molecules with costimulatory effects on TAC T cells using two strategies. First, I generated a database of small molecules that were predicted to interact with costimulation pathways based on connectivity mapping, provided by the Broad Institute, using the transcriptomes of TAC T cells activated in the presence or absence of costimulation. As a second screening strategy, I developed a bioluminescent reporter system that was used for high throughput screening of small molecules libraries available at the Centre for Microbial and Chemical Biology. Following the identification of several hits, these compounds were tested in vitro for their modification to TAC T cell proliferation and function. Results: We have identified several chemical classes of compounds which contributed to a robust increase in TAC T cell proliferation in the absence of costimulation, and have evaluated the top three drugs in vitro by proliferation and RNA sequencing assays. Ferutinin, and protein kinase C activating compounds mezerein and phorbol 12,13-dibutyrate, were found to robustly increase TAC T cell proliferation. The significance of this project is to identify costimulatory small molecules to enhance the efficacy of T cell cancer therapy, and yield novel insight into the chemical space that modulates costimulation. |
URI: | http://hdl.handle.net/11375/26925 |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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Bacchiocchi_Kaylyn_G_2021:08_Masters.pdf | 5.22 MB | Adobe PDF | View/Open |
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