How do CARs control T cell function or failure?
Chimeric antigen receptors are synthetic surface receptors that co-opt naturally-occurring components of the immune system to generate a receptor able to initiate potent T cell activity.
T cells from a patient can be engineered to express CARs targeting specific cancer antigens, turning these otherwise silent T cells into cancer killers. The greatest clinical experience to date using CAR T cells is in the treatment of B cell cancers, namely acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL). For many patients with these diseases, CAR T cells can result in complete eradication of disease within one month of infusion – a breakthrough in the development of novel cancer therapies.
Long-term follow up, however, has proven less exciting. Many patients do not have successful long-term outcomes after this therapy. These failures result from both a lack of any response at all after therapy, or relapse after an initial response.
Our laboratory is interested in how these synthetic molecules control T cell function, and under certain conditions lead to T cell failure. Using in vitro and in vivo models, as well as primary tissues from patients receiving CAR therapies, we investigate how CARs initiate and sustain effective T cell function, and how they alternatively promote the development of T cell dysfunction that leads to therapeutic failure.
Broadly, our questions are grounded in the fundamental areas of:
- Receptor protein biology: how does receptor structure influence function and how can we modify structure to change function?
- T cell lineage commitment: what are the signals that instruct T cells to change identity and how can we influence this process?
- Cellular engineering: what are the chromatin, gene, transcript and protein targets that can be regulated to improve anti-cancer activity of cell therapies? What are the approaches that will be most effective to control circuitry in human T cells?
We aim to develop strategies to overcome dysfunctional CAR-driven T cell circuitry and engineer enhanced T cell therapies for patients with cancer.