Despite considerable improvements in the variety and effectiveness of therapeutic agents in recent years, advanced metastatic cancers remain largely incurable. Therefore, the development of novel therapeutic agents is needed. Chimeric Antigen Receptor-modified T cells (CAR-T) have shown tremendous success in haematological malignancies. However, the outcome of CAR-T cells in patients with solid tumours remains poor. Clinical trials conducted with CAR-T cells targeting solid tumours suggest that CAR-T cells can traffic to tumours and respond to antigen, but fail to expand, persist and mediate objective responses. Thus, a key question remaining is: How can we improve the activity of CAR-T cell responses in solid tumours? In order to answer this question, we need to understand the mechanisms and obstacles preventing effective CAR-T cell activity in solid tumours.
In solid tumours, infused engineered T cells need to undertake a long journey to reach the tumour, survive in a rough tumour microenvironment capable of inactivating their effector functions, and be fit enough to eliminate the whole tumour mass. But what is the main mechanism behind this lack of potency and persistence? The premise of our studies is that CAR-T cells become dysfunctional once they reach the tumour, similarly to what occurs with the natural tumour-specific T cells that fail to control tumour growth, and that this dysfunction is in part due to chronic antigen-exposure. The general aim of this project is to enhance the persistence and function of CAR-T cells in solid tumours by overcoming T-cell dysfunction. Our general goal is divided in the following aims: (1) Elucidate the T-cell intrinsic mechanisms by which CAR-T cells become unresponsive to solid tumours, (2) Design new approaches to enable infused T cells to effectively function and persist within the tumour microenvironment. My ultimate goal is to develop a technology to be used in clinical trials, giving a new opportunity to patients that have incurable cancer.
