Designed T cells expressing both cars and TCRs can better distinguish between cancer and healthy tissue

The researchers have developed an innovative double receptor T-cell therapy that promises safer and more effective cancer treatments. This study, published in Cell, shows that Engineering T cells express both chimeric antigen receptors (CARs) and T-cell receptors (TCRs), improve their ability to distinguish between cancerous and healthy tissues.

Treatments that involve the use of the body’s immune system to combat cancer have in recent years led to significant improvements in patient survival, particularly using a method called CAR T-cell therapy. This treatment involves extracting the patient’s own T cells and modifying them in the lab to express a special receptor called chimeric antigen receptors (CARs), which recognize tumor proteins. These are then reperfused into the patient, where they can be found and destroyed.

However, CAR T cells show great promise in treating hematological cancers, but they struggle to effectively target solid tumors. CARs cannot easily distinguish tumor cells from healthy cells of the same target protein. This is a major problem when treating solid tumors. Healthy tissue surrounding solid cancers is often important for survival, but they express proteins similar to the tumor itself.

In contrast, natural T cells containing T cell receptors (TCRs) allow them to better distinguish between tumor cells and healthy cells. However, TCR-based therapies often have limited efficacy against tumors.

Researchers at the Kennedy Institute at Oxford University have collaborated with the National Cancer Institute (NCI) and the University of Montreal to combine these approaches to overcome these limitations.

Sooraj Achar, a NIH/Oxford graduate student at the Kennedy Institute, and Dr. Taisuke Condo, a postdoctoral researcher at NCI, worked together to create cells that express both TCR and vehicle. They characterized the response to hundreds of ligand combinations using both a high-throughput immunotron robotic platform and an animal model. Surprisingly, the data they collected suggest that weak TCR signals inhibited car activity.

François Brussa, a graduate student at the University of Montreal, developed a mathematical model of interreceptor crosstalk mediated by covalent inhibitory signaling molecules to explain this unexpected phenomenon. Further experiments conducted further at the Kennedy Institute using high-resolution microscopy confirmed the proximity between the two receptors during joint stimulation, which helped validate this model.

The researchers then combined these insights to develop a new car T system called the Antagonistic Enhanced Brake System (AEBS) Car T Cell. This works by adding TCR to Car-T cells weakly stimulated (and thus inhibited) by proteins in healthy tissues and “brakes” unwanted CAR T-cell activity against these critical cells. However, when the same TCR recognizes mutant versions of these proteins in cancer cells, it “accelerates” CAR T-cell activity against the tumor.

This approach allows AEBS Car T cells to reduce aggression towards healthy cells while increasing their efficacy against tumors.

“By improving the ability of these engineered T cells to distinguish between cancerous and healthy cells, our research paves the way for better outcomes of immunotherapy,” said Dr. Gregoire Altan-Bonnet, deputy chief of NCI’s Institute of Integrated Cancer Immunology.

Professor Michael Dustin, professor of molecular immunology at the Kennedy Trust at the Kennedy Institute, said, “Future work at the Kennedy Institute will focus on increasing the amount of crosstalk between receptors through the analysis of AEBS CAR T-cell immunological synapses, allowing for the generation of safer and more effective forms of cancer immunotherapy.