Lung cancer discovery points to a better way to personalise immunotherapy

Treatments that harness the power of the immune system against cancer are an exciting area that’s seen an explosion of interest and developments in recent years.

A number of these immunotherapy drugs have now been approved in the UK for several different cancers. And trials are underway that could open them up to even more cancer types in the future.

Those that are already approved have had impressive results in some people with advanced disease. But there’s an issue. The drugs don’t work for everyone.

What is it about the immune systems and tumours of those who do respond well to the treatments that separates them from those who don’t? That’s a question Professor Christian Ottensmeier, a Cancer Research UK-funded immunotherapy expert at the University of Southampton, and Professor Pandurangan Vijayanand, from the University of Southampton and the La Jolla Institute for Allergy and Immunology in the US, set out to discover.

“The biggest aspect of this study was to attempt to figure out why some patients benefit from immunotherapy and others don’t,” says Ottensmeier.

“We were curious to see whether we could map out what key immune cells that are protective against tumours look like in patients with early disease.”

Their work, published in the journal Nature Immunology, points towards a special type of ‘killer’ white blood cell, or T cell, which seems to be playing a crucial protective role inside certain tumours. On top of this, the scientists believe they may have identified a new way to predict which patients might benefit from certain immunotherapies, and those who likely won’t.

More than a numbers game

For the study, the researchers homed in on a specific type of ‘killer’ white blood cell called a CD8 T cell. These are critical tumour-fighting cells, says Ottensmeier, and there’s a relationship between the number of them inside a patient’s tumour and how well they do.

“If there are lots, the patient tends to do better,” he explains. “What we didn’t understand was whether certain features of these cells are important for a good immune response.”

To find this out, the researchers picked out CD8 T cells from the tumours of 36 patients with lung cancer and 41 patients with head and neck cancer, and looked at the genetic make-up of these cells.

This showed that the characteristics of those specialised cells could vary widely from patient to patient. In particular, they found that the cells produced a range of different molecules that indicate whether they’re doing their cancer-fighting job or not. On top of this, they found differences in the levels of molecules that are either already targeted by immunotherapy drugs, like the immune-dampening ‘checkpoint’ molecule PD-1, or are being investigated as potential targets.

What we didn’t understand was whether certain features of these cells are important for a good immune response

– Prof Ottensmeier

“This will allow us to grade the T cells in patients’ tumours for their anti-cancer properties, creating a spectrum where patients have lots of ‘good’ T cells at one end, and those who have T cells that aren’t very active at the other,” says Ottensmeier.

“It also helps us begin to unravel why some patients benefit from PD-1 blocking immunotherapies. If the T cells in the tumour aren’t being dampened by this molecule in the first place, then they won’t respond to drugs that target PD-1.”

Another crucial finding was that it wasn’t just the number of CD8 T cells in the tumour that seemed to be important in generating a good immune response. It was the type too.

Lung cancer patients who had a lot of CD8 T cells inside their tumours also tended to have lots of a particular type of these cells known as a ‘tissue-resident’ T cell. These cells, Ottensmeier says, hang around in tissues rather than travelling around the body.

“For example if you get a cut, these cells are in the skin, ready to rumble and protect you from an infection,” he explains.

When the researchers looked at what these cells were doing more closely, they seemed to be producing lots of tumour-fighting molecules. And when the team took this discovery further by trawling through data from nearly 700 lung cancer patients, who were monitored between 2007 and 2016, those whose tumours had particularly high numbers of these cells survived longer on the whole. If a patient’s tumour had lots of CD8 T cells overall, but not many of this particular type, they didn’t see the same effect, highlighting the potential importance of these cells.

Unlocking the power

Finding ways to match patients to the best treatment for them is the goal of personalised medicine. And these findings could lead to a new way to do that for those receiving these immunotherapy drugs. Ottensmeier’s hope is that this immune cell profiling could be carried out during tests to diagnose cancer, potentially helping doctors to make decisions on which drugs to give to patients sooner. This could also identify patients who likely won’t respond to immunotherapies and therefore should be given different treatment options, sparing them from drugs that likely won’t work.

Already other studies are underway to explore this possibility of tailoring immunotherapies to the right patients. Just last week, a clinical trial published in the New England Journal of Medicine found that lung cancer patients whose tumours had many genetic mistakes and made lots of a particular immune molecule – PD-1’s molecular partner PD-L1 – may benefit from being given immunotherapy up front. Currently in the UK, immunotherapy for lung cancer patients is only available to NHS patients after they’ve been treated with chemotherapy.

It may also turn out that as scientists dig deeper, more ways to refine and improve immunotherapy than those already being investigated could be revealed. For example a recent study suggested that levels of another partner of PD-1, called PD-L2, could also indicate which patients might benefit from certain immunotherapy drugs, although this possibility has so far only been looked at in head and neck cancers.

Immune cells hold the key to the control of a patient’s cancer

– Prof Ottensmeier

So it seems there’s still much to learn about which immune cells and molecules are important in generating a good response against tumours, something Ottensmeier is pursuing right now.

Although it’s early days, his team is already beginning to take these findings into experimental studies in the clinic, looking at whether existing immunotherapies can stimulate these tissue-resident T cells. And it may well be that their discoveries could help patients beyond the two cancers looked at in this study.

“Immune cells hold the key to the control of a patient’s cancer,” said Ottensmeier.

“So I think we’ll move towards treating patients according to their tumour’s immune landscape, rather than where it is in the body.”

Justine