T cells are important fighters against disease. Credit: NIAID/NIH (public domain), via Wikimedia Commons
Some of the most exciting new cancer treatments are those that take a patient’s own immune cells and turn them against their cancer.
Collectively called ‘adoptive cell therapies’, these treatments have had dramatic results in patients with certain forms of cancer, notably lymphomas and leukaemias. But they don’t work in everyone.
One of the reasons why is that many patient’s cancers develop the ability to switch off immune cells that are trying to attack them.
Using drugs that block cancer cells from doing this has been another promising avenue for treatment. Known as checkpoint inhibitors, these drugs when given on their own have already shown impressive responses in patients with a variety of cancers, including melanoma and lung cancers.
Importantly though, these drugs affect all of a patient’s immune cells, not just the ones that target cancer – and this can lead to serious side effects. It’s not uncommon for patients to have to stop taking them as a result.
But what if you could have the best of both worlds – a cell-based therapy that was resistant to a tumour’s attempts to switch it off?
A team of our scientists, led by Dr Sergio Quezada and Professor Karl Peggs, at the University College London Cancer Institute, are trying to do just that, by engineering immune cells and potentially avoiding the need to combine cell therapies with checkpoint drugs.
Their discovery centres on specialised gene editing technology to precisely alter the DNA inside cells. Applying this to immune cells, the team has been able to make immune cells completely resistant to tumour cell’s ability to switch them off, dramatically improving their ability to kill cancer cells, at least in mice.
Its early days, but the team’s findings – published in the journal Cancer Research – could form an important part of the increasingly ingenious ways that scientists are turning the immune system on cancer.
So what are these ‘off switches’ and how did they remove them?
Flipping the switch back on
The immune ‘switch’ that checkpoint drugs aim to flip is a molecule found on the surface of immune cells known as Programmed-cell death protein-1, or PD-1 for short.
PD-1 was discovered in the early 1990s by Japanese scientists, and ever since researchers have been trying to understand how it controls the way the immune cells react to tumours. Once it was understood that PD-1 could be hijacked by cancer cells to escape the immune system in the early 2000s the race was on to see if blocking this signal could help immune cells fight cancer more effectively.
In 2015, results from late stage clinical trials using drugs that target PD-1 were published and showed considerable promise in lung and melanoma patients.
But there was a catch. In a lung cancer trial, only around 20 per cent of patients responded well to treatment targeting PD-1.
Another trial, this time in melanoma patients, used a combination of drugs to target the brakes on immune cells. This time the number of patients responding was much higher, but so too were the side effects.
So how to increase the number of patient’s responding to this promising type of treatment without the side effects?
The team wanted to see whether they could get around this problem by only disrupting PD-1 on immune cells that already target cancer cells.
To do this they turned to specialised gene editing tools called TALENs, which can be engineered to precisely cut a DNA molecule wherever a researcher wishes.
This technology made headlines around the world last year as scientists and doctors at London’s Great Ormond Street Hospital used the technique to edit immune cells to treat a young girl with leukaemia. And newer, easier to use gene editing tools – such as one called CRISPR – are already creating a buzz in the research world.
In their latest study, Quezada and his team used TALENs to make precise breaks in the PD-1 gene inside immune cells, causing it to make the PD-1 switch incorrectly – a bit like building flat-pack furniture using instructions with a page missing. As a result the modified immune cells were no longer able to present PD-1 on their surface.
In theory, this should deny cancer cells the ability to switch the immune cells off.
So what were the results?
First, the team worked with mice that develop melanoma, characterised by a known molecular target on the cancer cells’ surface, called Pmel-1.
Then the researchers grew specific immune cells called T cells that recognised the Pmel-1 target.
They then used TALENs to disrupt these cells’ PD-1 gene, so they could no longer carry an off switch.
Finally, they infused these heavily modified cells back into mice with melanoma.
Within just a few days, many of these modified immune cells found their way to mice’s tumours and began attacking them.
After three weeks, tumours from mice who had received the modified immune cells were about half the size of those that didn’t. Furthermore, the act of removing PD-1 from these T cells didn’t in any way impair their ability to multiply and attack.
Read more about gene editing
This was a really exciting result – demonstrating that modifying the T cells could make them more effective at killing cancer cells, and that this didn’t seem to have any unintended consequences. But this experiment doesn’t exactly mirror how a tumour develops, or how the immune system spots a tumour. The T cells, for example, were already engineered to go after the cancer.
The team next needed to test whether this technique would work in a setting much closer to how cancer develops in people – where the ‘flag’ that alerts the immune system isn’t so obvious.
So the researchers turned to mice with sarcoma, a type of cancer that affects the body’s supporting tissues. But this time, rather than picking out the T cells they already knew could recognise the cancer, the team used a cocktail of different T cells extracted from the mice’s tumour. These would likely contain a handful of cells able to target the cancer, but which had had their PD-1 off-switch flipped.
Importantly, this mixture they edited contained a whole variety of different forms of T-cell, including both ‘killer’ and ‘helper’ T cells.
‘Killer’ T cells are the immune cells that cancer scientists usually work with. They recognise cancer cells directly and deliver chemical signals that trigger their destruction. ‘Helper’ T cells pile the pressure on cancer cells by releasing chemical signals that call for reinforcements, pushing other cancer-fighting immune cells into a higher gear.
“The reason we avoided selecting specific T cells was to keep it as close to the clinic as possible,” explains Quezada. “We mostly wanted to check how well this approach would work when we simply used whatever T cells were available to us, rather than spending time trying to identify the best ones.
“We also couldn’t guarantee that PD-1 was completely removed from all of the cells we used.
“But we wanted to see if we could still boost the cancer-fighting prowess of these cells, despite these drawbacks.”
And the results they got were remarkable. More than 70 per cent of the mice that received modified immune cells were still alive after 70 days. But for mice that didn’t receive the modified immune cells, survival dropped to less than 20 per cent in the same amount of time.
What do these results mean?
The immediate implication of this work is that this potentially provides an entirely new approach for immunotherapy.
Getting such striking responses in mice from a random mix of immune cells, rather than painstakingly selecting for a preferred cell type, could make this easier to translate into the clinic.
It also has the potential to dramatically reduce side effects, as only cells which were found inside tumours were unleashed, rather than using a drug which takes the brakes off the entire immune system.
I suspect that this type of modification will be adopted very quickly for anyone trying to use modified T cells
– Dr Sergio Quezada
And although we don’t yet know how well removing PD-1 from immune cells might work in people, the results from these early experiments are very encouraging. And they offer a starting point that could lead to trials in the future.
Furthermore, if successful, disabling PD-1 in T cells could be combined with other treatments that involve re-engineering immune cells out of the body.
“I suspect that this type of modification will be adopted very quickly for anyone trying to use modified T cells,” says Quezada. “We are already experimenting with how we can better target cancer cells – this allows us to also pre-rig the brakes.”
And PD-1 is simply one of many similar ‘checkpoint’ molecules that are found on T cells, and according to Quezada: “This work could provide the tools for knocking out any number of these brakes. As we understand the signals cancer is using to keep the immune system at bay, we can begin to remove these avenues of escape, and box cancer in.”
With our growing understanding of how cancers avoid the immune system, and our increasing ability to get around these obstacles, we are coming closer to the precision immunotherapies that cancer patients need.
Menger, L., et al. (2016). TALEN-Mediated Inactivation of PD-1 in Tumor-Reactive Lymphocytes Promotes Intratumoral T-cell Persistence and Rejection of Established Tumors Cancer Research, 76 (8), 2087-2093 DOI: 10.1158/0008-5472.CAN-15-3352