Leveraging the native TCR with mRNA vaccines to enhance CAR T cell therapy in solid tumours.

The white blood cells known as T cells actively patrol the body for signs of pathogens or cancers, and their behaviour can be redirected to specifically target cancers by engineering them to express a Chimeric Antigen Receptor (CAR). This personalized approach, known as CAR T cell therapy, has shown remarkable success in certain challenging blood cancers. However, CAR T cell effectiveness against solid tumours has been limited. To overcome the barriers to solid tumour treatment, we propose to combine CAR T cell therapy with an mRNA vaccine (as used in the COVID-19 vaccination campaign). Although CAR T cells have a new cancer-specific receptor, they retain their natural receptor (TCR) which the cell normally uses to recognize pathogens and other foreign material. Based on preliminary data from our laboratory, we predict that the vaccine will directly amplify the activity of CAR T cells through this receptor. We will systematically explore various vaccine design elements, including the formulation, the type of protein encoded in the vaccine and the delivery method to identify the most effective combination. Ultimately, we seek to better understand the variables that maximize combination therapy for translation to human use.