We've made some impressive advances toward inducing the immune system to attack cancers. One of these techniques, using CAR-T cells, is amazing. CAR-T cells are made by inserting receptors that recognize cancerous cells into a leukemia patient’s own T cells. This induces those T cells to recognize the patient’s tumor as the threat that it is and destroy it.

But, that T cells mount such an effective immune response is their therapeutic weakness as well as their strength. Engineered immune cells like these can completely disrupt normal immune function, causing unpleasant conditions with names like macrophage activating syndrome, cytokine storms, and even neurotoxicity, all of which can be life-threatening. So a group of Swiss researchers has decided to engineer a killing system into non-immune cells to avoid all these side effects.

T cells target their tumor-killing immune response through cell-to-cell contact. This is a distinctive feature of how the T cell receptor works. It hangs out on the T cell's surface membrane, with some parts on the outside and some parts on the inside. When its external part contacts a particular feature on the surface of a cell, its intracellular part sends a signal through a cascade of molecules that eventually results in collection genes getting expressed. These genes include the ones needed to kill the target cell.

Non-immune cells don’t have this cell-contact sensing capability; receptors on their surfaces tend to be activated by soluble molecules floating around in the environment. But if non-immune cells could be granted a cell-contact sensing capability, they could be engineered with the tumor-targeting abilities of CAR-T cells but wouldn't generate the associated risks.

So some bioengineers in Basel put T-cell-like signaling into non-immune cells. They opted to modify a type of stem cell called mesenchymal stem cells, because these are known to have anti-tumor effects and have already been engineered to deliver drugs that kill cancer cells. In order to make these cells responsive to cell contact, the researchers had to import a whole signaling cascade of molecules from T cells.

This cascade includes a receptor that recognizes a protein found on the surface of a tumor cell, as well as an associated molecule that makes sure that the protein is attached to the right cell and doesn’t let any signals propagate unless it is. They also inserted the protein that receives the signal from the receptor and transmits it to another protein that is able to activate specific genes. In this case, five specific target genes were engineered into these mesenchymal stem cells. One of them encodes an enzyme that activates a latent anti-cancer drug.

As a result of all of this engineering, these stem cells should be able to convert the drug into its active form only when they are in contact with cancer cells. But that's a lot of engineered genes, and there's no guarantee that they'd all work in these cells. Yet amazingly, they did.

The researchers also showed that the system could be retargeted to other types of cells, so it can be expanded to other systems with other needs. The engineered cells were themselves killed by the very drug that they activated in order to kill the tumor cells they contacted; the authors call this “suicide-type behavior,” and it makes sure these cells don't stick around to cause problems after the tumor is gone. But the team suggests that this suicide function of the engineered cells could be circumvented by incorporating drug resistance into the suite of characteristics engineered into them.

Nature Chemical Biology, 2017. DOI: 10.1038/nchembio.2498 (About DOIs).