Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

One of the main issues with all pharmaceutical therapy is unwanted side effects. Not only are these adverse effects extremely unpleasant and even at times life threatening, but concerns over adverse outcomes often limit the utility of a given therapeutic. These adverse affects are typically caused by a combination of poor specificity and inappropriate distribution. Specificity is an issue when a drug acts not only on its target, but also at other sites. Distribution is an issue either when a harmful drug accumulates in sensitive regions of the body, for example the brain, or conversely when a beneficial drug cannot access an important region. The aim of this project is to develop a human T-cell based system that can deliver a therapeutic molecule to only the diseased tissue and cells. Cytotoxic T-cells are a part of the human immune system that kill tumor or virally infected cells. T-cells have three characteristics that make them suitable for this project: (i) they have T-cell receptors that are specific for a matching small molecule on a given cell surface, enabling very precise targeting; (ii) they have a unique secretion pathway that delivers molecules from the T-cell to the target cell, without letting any molecules diffuse to other, non-target cells; and (iii) they are known to distribute throughout the body, ensuring access to all necessary tissue. These properties are already exploited in the field of adoptive cell therapy. T-cells that have been extracted from a patient are given a specificity for a tumor or virally infected cell, replicated (both in a laboratory), and then re- administered to the same patient, whereupon they kill tumor or virally infected cells. I am engineering T-cells so that rather than only killing a cell, they may be used to deliver any type of molecule: one that may be either detrimental to the cell (if it needs to be eliminated, as in cancer) or therapeutic to the cell (if it needs to be healed, as in autoimmune disorders).