Project 463213

T cells patrol the body using their T cell receptors (TCR) to seek out cells which display evidence of intracellular pathogens or cancers. In order to focus their attention on specific cancer antigens, T cells can be engineered to express a synthetic recognition receptor (Chimeric Antigen Receptor (CAR)). While CAR technology has been shown to be extremely powerful clinically, many patients with lymphoma either do not respond, or relapse, and thus there remains a great deal of room for innovation. Once a T cell expresses a CAR, it can still receive signals through its T cell receptor (TCR), and therefore has dual specificity. Our previous work elucidated how viruses can expand subsets of CAR T cells by providing TCR antigen as well as accessory cues like co-stimulation and cytokines. One important correlate of poor clinical response is limited CAR T expansion and we have seen that this dual specificity can provide a very strong proliferative and functional advantage to CAR T cells. To expand on these findings, the goal of the proposed research is to better understand how the CAR and the TCR cooperate to direct T cell activity and persistence. We will use oncolytic viruses as well as lipid nanoparticle formulated mRNA vaccines to stimulate CAR T cells that also have TCR specificity to viral proteins. Successful completion of this research will enable us to rationally design next generation combination immunotherapies for patients in Canada.