T lymphocytes engineered with chimeric antigen receptors (CARs) have shown remarkable
success in the treatment of leukemias. Conventional CARs seek to recapitulate TCR and
costimulatory signals through fusion of T cell signaling elements into a single receptor. The
robust anti-tumor activity of CAR T cells is often accompanied by debilitating toxicities due to
excessive T cell activation and cytokine production following infusion. Our lab has generated a
novel chimeric receptor termed T cell antigen coupler (TAC), which is designed to engage native T cell signaling domains for cellular activation. In a murine xenograft model, we previously found that TAC T cells mediated rapid tumour regression in the absence of toxicities. Comparatively, CAR T cells elicited significant lethal toxicities to the mice due to reactivity against an unspecific antigen that resulted in excessive proliferation and cytokine production in vivo. Here, we report that TAC and CAR T cells have fundamentally different biology, both at rest, and during activation. TAC T cells were more sensitive to the context of stimulation compared to CAR T cells. Whereas TAC T cells can discriminate between antigen bound to a bead, or antigen present on a cell, CAR T cells do not make the same distinction and responds equally well to both. Compared to several different CAR constructs, TAC T cells are less prone to tonic signaling and T cell differentiation in the absence of antigen. These findings support that TAC T cells may pose a safety benefit as a cancer immunotherapy, due to its distinct biology from CAR T cells that enables them to require more stringent contexts for activation. / Thesis / Master of Science (MSc) / Cytotoxic T cells are also known as “resident killer” cells of the immune system, as they can
seek and eliminate diseased or infected tissue, including cancer cells. However, cancer cells can evade elimination by T cells over time. Genetic engineering of T cells allows us to re-arm T cells against cancer cells. T cells isolated from a patient are genetically modified to recognize cancer cells specifically. So far, these modified T cells have been successful against several leukemias. However, the side effects of this treatment can be substantial and life-threatening, due to the massive reaction of the T cells against the cancer cells following infusion. We explore the biology of two different types of engineered T cells to better understand the interaction between T cell and tumour cell. Our results aim towards mitigating the side effects of T cell treatment, while investigating how we can improve its effectiveness for the future.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/23313 |
| Date | January 2018 |
| Creators | Lau, Vivian Wing Chong |
| Contributors | Bramson, Jonathan, Biochemistry and Biomedical Sciences |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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