The secret in cancer cells that can make immunotherapy more effective

Scientists at the Cancer Research UK Scotland Institute have discovered that certain mutations can make cancers much more likely to respond to immunotherapy. By mimicking the effects of those changes, we could make breakthrough drugs work for many more people.

Flick a light switch on and you get light. That happens for two reasons. The switch works because it’s linked up to somewhere that generates electricity. You can flick it because every one of your cells has tiny power stations, or mitochondria, creating energy of their own.  

But cancer cells aren’t interested in helping us light up the dark. They focus all their energy on multiplying and growing in places they’re not welcome. That’s not easy, and means cancer cells often need to make energy differently. Around half of all cancers have mutations that change how mitochondria work.  

It’s a trick that tumours use to grow and survive in difficult circumstances, but it might just prove their undoing. Our scientists have found that these mitochondrial mutations make cancers much more likely to respond to immunotherapy treatment.

Understanding immunotherapy

Immunotherapy is one of the most exciting advances in cancer treatment we’ve ever seen, helping more people live with and beyond cancer for longer. It works by reminding our own immune systems how to respond to the disease.  

This might come as a surprise, but our bodies don’t normally need any help.

To first start growing, potential cancers need to find a way around the immune system. They rarely get a chance. Immune cells quickly clear up most changes that could put our bodies in danger. Sometimes, though, a rogue group of cells can trick the rest of the body and find a way to grow without being noticed. That’s when cancer really starts.

Whereas other treatments attack these camouflaged cancer cells directly, immunotherapies point them out to our immune system, giving it the instructions it needs to get back to work. 

But there are still issues. Currently, immunotherapies aren’t able to help everyone. This study builds on a previous paper that found that the drug nivolumab made a difference for just over 1 in 5 people with a form of advanced skin cancer called metastatic melanoma.  

Beating cancer means pushing that proportion higher. It turns out changes to mitochondrial DNA can more than double it.

Predicting who can benefit from immunotherapy

“There was really no precedent for this at all,” explains Gammage. “And it means you can look at mitochondrial DNA mutations to understand who will benefit from immunotherapy.” 

Today, immunotherapies like nivolumab are often given to people once it’s clear that traditional treatments aren’t working for them. That’s partially because response rates are low and it’s hard to predict who might benefit. Those calculations change when 1 in 5 gets closer to 1 in 2. 

“If you can predict early doors that someone has a good chance of responding to immunotherapy, you can save them years of chemo and radiotherapy,” Gammage continues. With changes to mitochondrial DNA such a common feature of cancer, that means there’s potential to spare many people the side effects of other treatments. 

The research team has found the same jump in response rate across multiple different immunotherapies. And they have a plan that could lift it up even higher. 

Making immunotherapy work for more cancers

In the last stage of their study, the researchers started working with a lab-made enzyme called cyto-LbNOX. Adding it to cells makes the immune system think that they have mutated mitochondria. In mice at least, that means cyto-LbNOX can be used to make all tumours more sensitive to immunotherapy.  

If the same thing holds true in humans, cyto-LbNOX could make immunotherapy effective for tumours that don’t currently respond. And, where immunotherapy is already working, adding cyto-LbNOX could make it work better. 

“There’s a lot of hurdles to jump to test this, but if cyto-LbNOX works in humans, we’ll basically have the capacity to make every tumour type sensitive to immunotherapy,” says Gammage. “That means we’re going to be able to treat, and possibly cure, a lot more people. That’s our big vision for the future.” 

You can’t have a vision without light; and for light, you need power. That’s where we come in. Cancer Research Horizons, Cancer Research UK’s innovation arm, is helping Gammage and his team patent their technologies for spotting and mimicking mitochondrial DNA mutations. From there, we’re going to help develop it into potential new treatments.

Tim