Our scientists reveal how we can rewire cancer cell death to help fight tumours

Professor Pascal Meier and his team recreated an ongoing clinical trial in mice to better understand how triple negative breast cancer responds to certain immunotherapy treatments.

The team, based at the Breast Cancer Now Toby Robins Research Centre at The Institute of Cancer Research, London, now hope their findings will help shape more effective immunotherapy combinations.

Their study showed that triggering a specific type of cell death, called necroptosis, can act like an alarm signal that wakes up the immune system and boost treatment response. Importantly, this alarm is strongest when not only the cancer cells die in this way, but also the nearby supporting cells around the tumour. This wider response helps send clearer danger signals to the immune system. The treatment worked best in tumours that already had immune cells nearby, ready to respond.

Immune checkpoint blockade (ICB) is a type of immunotherapy that is already used to treat thousands of people living with triple negative breast cancer. But sometimes, tumours can find ways to resist this type of treatment.  

One of the ways that the cancer cells can do this is by preventing cell death. In other words, by refusing to die. This not only allows them to keep growing, but can also help them stay hidden from the immune system. Normally, dying cells can send out “danger signals” that alert the body’s defences. By preventing this process, cancer cells become harder for the immune system to recognise and attack.

Breast cancer cells can die in several different ways. And depending on how they die, they can release molecules that turn the immune system on or off.    Professor Pascal Meier has spent over 20 years studying how these cell death pathways shape the immune response to cancer.

In 2022, he launched a Phase 1 clinical trial called ASTEROID with teams at The Institute of Cancer Research and the Royal Marsden Hospital. This trial is investigating tolinapant, a drug that stops breast cancer cells from preventing their own cell death, in combination with immunotherapy as a way to treat triple negative breast cancer.

The ASTEROID trial is ongoing , and it will tell us if the treatment combination is safe and if it might work. But, we still need to understand more about why it works and how we can continue to make treatments  more effective.

The researchers set up a model of the ASTEROID trial using mice with triple negative breast cancer.  The tumours in these mice were designed to closely resemble human breast cancers.

When given to the mice separately,  neither immunotherapy nor tolinapant were  able to stop tumour growth. But when combined, 45% of tumours responded. And when a third drug called emricasan was added, 71% of tumours responded.

Emricasan is a drug that prevents cells dying ‘quietly’, without causing inflammation or harming surrounding tissues. When used to treat triple negative breast cancer, it means that the cancer cells can only die in a way that sounds an alarm and alerts the immune system.

With the triple  drug combination, tumours in 47% of mice disappeared completely. And when they injected these mice with more cancer cells, no tumours formed. This suggests the immune system was able to recognise the cancer cells and destroy them before tumours had a chance to grow.

But, for this way of killing cancer cells to work as we want it to, the tumour needs to have immune cells both in and around it. This isn’t always the case, and some tumours don’t have many immune cells at all. We call these tumours ‘cold’.

The team showed that they could ‘heat up’ the cold tumours by tricking the immune system into thinking there was a viral infection in the tumour. To do this, they used a drug called a STING agonist  that sends out signals that cause immune cells to travel to and enter the tumour.

This helped their treatment combination work more effectively.  And in one mouse in each group tested, tumours disappeared completely and they remained tumour-free for more than 60 days.

The study builds on an ongoing clinical trial testing a similar treatment com­­­­bination. By modelling this trial in the lab, researchers were able to explore in detail how and why it works. And how it could be improved to help more people respond.

How cancer cells die matters. By forcing them to die in a way that alerts the immune system, we may be able to make treatments more effective and longer-lasting. And even help prevent the cancer from coming back.

While promising, this research is still at an early stage. Further clinical trials will be needed to confirm whether this approach is safe and effective for people living with breast cancer.

But that’s why we’re researching now. So no one dies of breast cancer in the future.