Activating the immune system in the therapeutic treatment of cancer is rapidly growing and has demonstrated tremendous success. One such method is engineering T cells with chimeric antigen receptors (CARs) to specifically direct them in targeting tumours, however this has been associated with several toxicities that may be linked to the synthetic nature of the CAR. To address this, our laboratory created the T Cell Antigen Coupler (TAC), an alternative receptor that redirects T cells in a more natural TCR-dependent fashion.
The TAC consists of three components: the antigen-binding domain that recognizes a tumour antigen, a TCR-recruitment domain that co-opts the native CD3-TCR complex and a CD4 co-receptor domain. The TAC displays unique biology, specifically in the increased antitumor infiltration and clearance of solid malignancies without any of the observed host toxicities seen with CARs.
The functionality of the TAC was shown to be dependent on both the antigen binding and TCR-recruitment domains, however the co-receptor domain remains relatively uninvestigated despite evidence in the literature indicating its importance in endogenous T cell activation. This thesis seeks to better understand the biology of the TAC receptor by investigating the contributions of co-receptor domain.
In Chapter 3, we replaced the CD4 co-receptor domain with CD8 variants and showed that the TAC retains functionality.
In Chapter 4, we removed the cytosolic domain of the TAC in its entirety (creating a “tailless TAC”) and observed increased in vivo efficacy.
In Chapter 5, we evaluated the tailless TAC in different cancer models and consistently observed increased in vivo efficacy compared to the full length TAC.
These results demonstrate an increase in the in vivo functionality of the TAC receptor when the cytoplasmic tail is removed, giving us further insights into the mechanisms behind the unique biology of the TAC receptor. / Thesis / Doctor of Philosophy (PhD) / Cancer is the leading cause of death in Canada, and it is expected that 2 in 5 Canadians will develop some form of cancer in their lifetime. The immune system presents an intriguing alternative method to treat tumours since immune cells such as T cells can circulate through the body and seek and destroy harmful cells, including tumours. Here, we focus on the T cell Antigen Coupler (TAC), a genetically engineered receptor that our laboratory originally designed that directs T cells to recognize and destroy specific cancer cells. This thesis looks at the inner workings of the receptor, specifically a part called the inner tail, and how this feature contributes to how the TAC works. Our results show that removing the tail increases the T cell’s ability to safely clear different tumours in living organisms, bringing us a step closer in designing new and safe treatments for cancer patients.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/25402 |
| Date | January 2020 |
| Creators | MWAWASI, KEN |
| Contributors | BRAMSON, JONATHAN, Medical Sciences (Molecular Virology and Immunology Program) |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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