Description:
T cell therapeutics encompass a variety of modalities, including Chimeric antigen receptor (CAR)-Ts, engineered- Temperature Coefficient of Resistance (TCRs) and ‘off-the-shelf’ allo-therapies, and have become a central treatment modality for leukemias, lymphomas, and increasingly, for solid tumors. They have revolutionized the field of cancer treatment by providing a living drug, able to expand, seek out its target, and invade the tumor microenvironment, resulting in the ability to treat tumors which were historically impervious to conventional treatment regimens. However, T cell therapeutics also face multiple challenges, many of them intrinsic to the T cell biology that has been harnessed to create these drugs. Amongst the most common, and most significant in driving therapeutic dysfunction, is the entity known as ‘T cell exhaustion’, a complex molecular program in which normal T cells are restrained in order to avoid uncontrolled T cell expansion, cytotoxicity and cytokine release. This process occurs when chronic TCR signaling drives T cells towards a state of hyporesponsiveness, which, in the setting of T cells engineered to fight cancer, can result in loss of anti-tumor functionality.  This session will highlight state-of-the-art research on mechanisms controlling T cell exhaustion and focus on new strategies to harness and overcome exhaustion in order to engineer optimal T cell therapeutics.  

Dr. Andrea Schietenger will provide insights into CD8 T cell differentiation in the context of cancer and autoimmunity. She will discuss the molecular programs that drive tumor-reactive T cells into dysfunction/exhaustion and how T cells can be reprogrammed for cancer therapy, as well as novel insights into differentiation, function, and heterogeneity of autoimmune T cells.  

Dr. Evan Weber will give an overview of CAR T cell exhaustion biology, highlight recent advancements in overcoming CAR-T cell exhaustion, and propose a conceptual framework to help inform the next generation of anti-exhaustion strategies. He will discuss emerging evidence which suggests that exhaustion can manifest in CAR T cells through chronic CAR signaling, which is associated with poor response in patients. 

Dr. Giedre Krenciute will discuss strategies to overcome T cell exhaustion. She will describe how genetic disruption of Dnmt3a, an enzyme that regulates DNA methylation in human CAR T cells, preserves the cell’s developmental potential, proliferative capacity, and effector functions during chronic antigen exposure allowing for a long-lasting antitumor response.