CAR T Cell Therapy Signaling (CAR T 301)

If you’ve read the previous articles I’ve written on CAR T cell therapy (CAR T 101 and CAR T 201), you’ll be amazed at its sophistication (genetic engineering!) and simplicity (using nature’s own immune system!).

But of course, there is a lot more to it, and we are still discovering more complexities and challenges with fighting cancer. The story we’ve learned so far has many layers – let’s go one deeper…

We’ve used the analogy of a lock and a key to talk about how a modified T-cell can work out which cells to target when fighting cancer. What happens when the lock meets the key though, and how complicated is this lock anyway?

Stimulation

It’s all very well that the lock combines with the key – ie the CAR T-cell binds with the cancer cell – but the T-cell needs stimulation in order for the cancer cell to be eliminated. Sort of like telling the key to turn in the lock. They do this through the use of ‘stimulatory domains’ – areas on the binding mechanism (the lock/key combo) that send signals back and forth between the cells. The main one has the fancy name of CD3ζ (that squiggle is a ‘Zeta’, a Greek letter). This CD3ζ part of the mechanism sends signals back and forth between the cells (‘Who are you?’ ‘I’m a cancer cell’).

The main signal – The cancer cell suicide signal

The primary function of the CAR T-cell is to kill the cancer cell, and the main way this is done is by the CAR T-cell sending the ‘suicide signal’ to the cell. All cells have a gene that, when triggered, causes the cell to self-destruct. Its technically called ‘apoptosis’ and is happening in us all the time. Each day, over 50 billion of our cells are ‘self-destructing’ in this way when they are old, past their use-by date, or when told to by the immune system. One of the hallmarks of cancer can be that this natural self-destruction system is not working properly.

So adding the signal to the CAR T-cell, which triggers apoptosis, is the mechanism the engineered cell uses to destroy cancer. However, cancer can be tricky…

The brake and the accelerator

Since CAR T-cell therapy was pioneered, scientists have realized that cell signaling is more sophisticated than first imagined, and that they can create multiple signaling areas between the cells, called ‘co-stimulatory domains.’ These signals do more than just ask the cell what it is. They can be engineered to communicate about how the cell should operate, and to overcome its resistance to messages. The clinical trial I was on used a 2nd generation CAR T-cell, with an extra co-stimulatory domain, but we are now seeing trials with 3rd and even 4th generation CAR T-cells (somewhat pleasingly called ‘TRUCKS’, or ‘Armoured CARs’ due to their extra signaling properties).

These extra domains are trying to overcome some of the other clever/devious properties that cancer has; some cancer cells can develop the ability to send messages that suppress the T-cell’s operation. They can block the ‘accelerator and brake’ functions of the cell’s response (ways cells can signal to speed up or slow down cell growth). There is growing understanding of these mechanisms, and the ways that CAR T-cells can be designed to bypass cancer cells’ confusing signals.

Increasing our understanding of cell signaling

The other impact of this increasing level of understanding of the cell signaling and the new co-stimulatory domains, is that that we should see fewer side effects. The new engineered cells are more precise and targeted, and so less likely to attack healthy, non-cancerous cells.

Clearly, we have come a long way in our understanding of how cancer works, but there is still a lot to learn and discover. I hope you can see through this series of articles why CAR T-cell therapy (and immune therapy in general) is such an exciting breakthrough and a whole new way to fight cancer.

Read Part 1 and Part 2 of David's series about how CAR T-cell therapy works.