T Cells are a major component of the formidable immune system that the body keeps at the ready to respond to the first sign of infection or disease. T cells detect if cells have been infected with a virus; upon detection, they trigger these cells’ ablation and destroy the virus.
Unfortunately, the T cells do not detect cancer cells, as these cells use various tricks to fool the immune system into believing that they are normal healthy cells. Thus, they hide in plain sight, and the T cells cannot seek and destroy them. A new study has found a possible solution to this problem.
Engineering non-immune cells to seek and destroy
Recently, researchers have engineered a new kind of T cell that can combat tumors. Scientists have modified these new immune cells to include additional functions so that they can effectively seek and destroy cancer cells. The problem is that therapies involving these cells can have significant side effects, and the production of these synthetic T cells is technically challenging, making it a time-consuming and expensive process.
A team of researchers at ETH led by Professor Martin Fussenegger has found an innovative solution to this issue. In a new study, the team has demonstrated a simplified approach to creating customized immune cells for fighting cancer. The research team built human renal cells and (adipose) stem cells that included three additional components, which made them into customized cells that mimic T cells.
The first component that the team added to these synthetic T cells consisted of molecular antennae that extended well beyond the cell membrane. The second component consisted of antibodies with specific docking sites embedded in the cell membrane; these sense cancer cells due to their unique surface structures and bind to them. The third component was a gene network that generates a molecule complex. This complex includes a “warhead” that pierces the cancer cell membrane, this is linked to a converter molecule that activates and deploys an anti-cancer substance into the cancer cell.
The precursor of the anti-cancer substance has to be added to the system externally; the cancer cells absorb this substance, and the converter molecule changes the substance from a dormant to an activated state. The result is the cancer cell explodes like a grenade and showers the surrounding area with the anti-cancer substance, causing nearby tumor cells in the area of effect to also be destroyed. This “bystander effect” increases the effectiveness of the synthetic T cells, making them even more potent in dealing with cancer.
Using a new kind of mechanical trigger
The researchers created a new mechanism that triggers the signal cascade that leads to the destruction of the cancer cell. As the synthetic T cell approaches the target cancer cell, the antennae proteins buckle; this causes the antennae anchor deep inside the cell to lose contact with a molecular switch that it was keeping in an “OFF” state. The loss of contact by the anchor moves the switch to an “ON” state, and the signal cascade begins. This initiates production of the molecule complex, and thus the “warhead” is primed and the payload is ready to be delivered to the target.
These new synthetic T cells have advantages over current cancer therapies. Chemotherapy floods the body with active substances in order to kill as many cancer cells as possible in a wide and crude manner, only a few synthetic T cells would be needed in comparison, and these can be delivered locally in a targeted manner. The synthetic T cells operate independently of the body’s immune system, which can continue to function normally, thus reducing the risk of side effects.
Finally, the synthetic T cells have a modular design, allowing their range of functions to be potentially expanded. For example, the cells could be given different kinds of docking sites, allowing them to bind to other kinds of cancer cells. The study here saw the researchers using docking sites for only one specific type of mammalian cancer cell, but this can be easily expanded to include other cancers that cannot be fought using regular T cell therapies.
The researchers have only tested the system in cell cultures in vitro, so it is unclear if and how these new synthetic T cells will function in the human body. The new system is a long way from being used in cancer treatment, but the possibilities are considerable if the system can be made to work.
 Kojima R, Scheller L, Fussenegger M. (2017) Nonimmune cells equipped with T-cell-receptor like signaling for cancer cell ablation. Nature Chemical Biology DOI: 10.1038/nchembio.2498