



Four things we’ve learnt about immunotherapy for pancreatic cancer
The findings from our Grand Challenge award have increased our knowledge of the potential of immunotherapy for treating pancreatic cancer and laid vital groundwork for the development of more effective treatments. Here we take a look at what our researchers have achieved.
Better treatments save lives. At present the only potentially curative treatment for pancreatic cancer is surgery, however only around 20% of patients are eligible for this at the time of diagnosis. Sadly, over 70% of people with pancreatic cancer receive no treatment at all. We desperately need new and more effective treatment options for pancreatic cancer to improve survival rates and allow patients to spend more time with their loved ones.
An emerging new treatment option for cancer is immunotherapy, which aims to boost the power of the body’s own immune system to recognise and destroy cancer cells. Scientists have recently learnt how to modify immune cells called T cells so that they specifically attack cancer cells without also destroying normal healthy cells, reducing unwanted side-effects of treatment. These customised cancer-fighting cells are called CAR-T cells. CAR-T cell therapy has revolutionised the treatment of some cancers including leukaemia, which was previously hard to treat, however it has so far not been effective for pancreatic cancer.
In 2017 we funded the Pancreatic Cancer UK Grand Challenge award, led by Professor Nick Lemoine, Professor John Marshall, Professor Yaohe Wang and a team of researchers at Barts Cancer Institute (Queen Mary University of London) and King’s College London. This award focussed on trying to overcome some of the challenges in using immunotherapy for pancreatic cancer and working out the best way to combine immunotherapy with other promising therapies, such as viruses that selectively destroy tumour cells, to develop an effective new approach to treating this devastating disease.
Last month, the most recent outcomes from this research award were published in the journal Cancers.
Eight years on, how has this award advanced our knowledge and moved us closer to improving the treatment of the deadliest common cancer?
Here we take a look at four things we’ve learnt from our Grand Challenge Award.
1. Immunotherapies designed to specifically attack pancreatic cancer cells can increase survival
One of the challenges in CAR-T cell therapy is identifying target molecules that are only found on cancer cells, so that treatment does not also damage normal healthy tissue. Our researchers identified two new targets for CAR-T cell therapy that are specific to pancreatic cancer cells.
These two promising targets are proteins called CEACAM7 and αvβ6 which are found at much higher levels in pancreatic cancer tumour cells than in normal healthy cells. αvβ6 had first been suggested as a promising target in previous Pancreatic Cancer UK-funded research led by Dr John Maher at King’s College London, and here the research team build upon these findings. They produced CAR-T cells that targeted each of these protein in mice with pancreatic cancer and showed that that both were able to reduce tumour growth of the tumours and increase survival.
2. Tumour-targeting viruses are able to shrink pancreatic cancer tumours
Viruses that can selectively infect cancer cells and cause the immune system to specifically destroy these cells rather than normal cells represent another promising new class of treatment for pancreatic cancer.
Our researchers created and tested a large number of different tumour-targeting viruses which were modified so that they were only able to infect cancer cells. The tumour-targeting viruses also contained a gene that is able to alter the pancreatic cancer immune environment to make CAR-T cell therapy more effective. This work built on previous Pancreatic Cancer UK-funded research led by Professor Yaohe Wang.
Excitingly, when these viruses were used to treat a mouse model of pancreatic cancer the results were promising, with some doses stopping tumours from growing and reducing the tumour size. These findings now need to be tested further in order to find out whether they have the same effect in human pancreatic cancers. The research team secured a large grant of £3.42 million from the Medical Research Council to explore these results further.
3. Combining CAR-T cells and tumour-targeting viruses is more effective than using therapies individually
Pancreatic cancer tumours are surrounded by a tough outer layer of scar-like tissue, which makes it hard for treatments such as CAR-T cell therapy to get inside the tumour and destroy cancer cells. The research team tested whether combining CAR-T cell therapy and cancer-targetting viruses is a more effective treatment for pancreatic cancer rather than used individually. They also included a drug targeting a protein called TGFbeta which research has shown can make CAR-T cell therapy more effective.
Our researchers tested the triple treatment of αvβ6 CAR T-cells, a cancer-targeting virus and a drug targeting TGFbeta in a mouse model of pancreatic cancer. Excitingly, they found that this trio of therapies improved the ability of CAR-T cells to enter the tumours, slowed tumour growth and reduced the spread of cancer to other organs. The triple therapy was more effective than using either of the treatments individually. Overall survival only showed a small improvement, but these promising results lay vital groundwork for further research.
“The challenge is that solid tumours like pancreatic cancer create an environment that powerfully suppresses the immune system and blocks immune cells from entering. Finding those T cells inside the tumours was such a fantastic observation…these findings represent a promising first step. They set the scene for us to move forward.”
Professor John Marshall
4. New techniques can be used to produce large numbers of CAR-T cells
To carry out their Grand Challenge experiments, our researchers needed large numbers of CAR-T cells – more than they had ever produced before. To obtain enough cells for their research, they had to come up with new ways of making large numbers of CAR-T cells. This proved a challenge, but ultimately they were able to successfully generate 10x more cells they had before.
It was also crucial that the research team were able to store the cells until they needed them, and so they developed a way of freezing the cells in liquid nitrogen at extremely cold temperatures where they could be safely stored until they were needed, without damaging the cells or making them less effective at killing cancer cells.
These new methods will be valuable for other researchers working in CAR-T cell research and will benefit future research not only for pancreatic cancer but for other cancers as well.
"After more than 30 years working in pancreatic cancer research, I am more optimistic than ever that we can develop an effective therapy for this dreadful disease. This award has given us the launchpad to take a novel biotherapeutic into the clinic to explore its effectiveness and safety in patients. This is a very exciting time - thank you to all the supporters who have given us this opportunity!"
What happens next?
Overall, the findings from the Grand Challenge award have increased our knowledge of the potential of CAR-T cell and tumour-targeting viruses for treating pancreatic cancer and laid some vital groundwork for future work in this area which could ultimately lead to the development of new and more effective treatments for pancreatic cancer.
Following the completion of the Grand Challenge award, the researchers are now considering how to translate their findings for use in people and have so far leveraged further funding of over £3.6 million to continue this research.