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Techniques already used can be exploited to promote cancer cell death

Immunotherapy techiques for the treatment of hepatabiliary cancer offer the promise of new and exciting ways to kill these cancers, Dr Austin Duffy, Clinical Director of the Gastrointestinal Malignancies Section at National Cancer Institute, Washington DC told delegates to the Gathering Around Cancer 2016 meeting, which was held at Croke Park late last year.

Dr Duffy opened by making the point that he felt that everyone in the room, which was full of oncologists, would agree that the standard of care with hepatobiliary cancer types was not very good. “We need to do better and there are promising signs that I’d like to tell you about,” said Dr Duffy. 

Immune-suppressed

The liver could be categorised as an immune-suppressed organ, said Dr Duffy, and it makes sense that this is so because the liver is the first port of call for the ‘trash’ that comes through the gut, as well as gut borne pathogens, and drugs. This means, said Dr Duffy, that it is important that the liver is not “trigger happy” from an immunological point of view. The liver needs to act as a calming influence, said Dr Duffy, and not to react to everything it is in contact with.

The fact that the liver is an immune-suppressed organ, said Dr Duffy, means that it is fertile ground for cancer development, particularly when combined with the ‘ignition switch’ of chronic inflammatory conditions. “When you look at the risk factors of cholangiocarcinoma and hepatocellular carcinoma, they all have different etiologies, but the common underlying pathogenesis, which unites them all, is inflammation,” said Dr Duffy. It is no accident, Dr Duffy said, that chronic inflammation in an immune-suppressed organ will lead to cancers.

“The fact that the immune system is heavily implicated in the etiology of pretty much all these cancers is an argument for using immune based approaches to be part of the solution,” commented Dr Duffy. These cancers manipulate the immune system for their own benefit, and what doctors need to do is think of ways of manipulating back the other way to benefit patients, said Dr Duffy.

There is plenty of evidence that despite the fact that the immune system is suppressed in the liver, that the liver’s immune system remains capable of recognising these tumours. When researchers look in the blood for T-cell responses to antigens such as AMP or survivin, for example, said Dr Duffy, you can find antigen specific immune responses, which are spontaneous against the tumour in the peripheral blood of the patients.

There are many papers looking at the role of immune cells in tumours, and the impact that has on prognosis, said Dr Duffy. One of the most famous case reports, commented Dr Duffy, which was published in Science two years ago by a surgery branch of the National Cancer Institute, involved a patient with cholangiocarcinoma; a woman in her 40s who had a resection of the side of her metastasis. Then a T-cell clonal population, grown ex vivo was reinfused back into the patient and it produced an astonishing result. The woman went into remission, said Dr Duffy, and though this was two years ago, she remains in remission today.

There are many ways that immunotherapy can be applied to the treatment of hepatobiliary cancers, said Dr Duffy. The immune checkpoint inhibitors are where most of the research funds are going, he said, but there are also important studies looking at cytokin activated cells, engineered T-cells, oncolytic viruses – which are particularly exciting, he said – and small peptide-based vaccine studies. “There are a whole range of ways to target the immune system to try and get responses,” said Dr Duffy.

One question that has to be asked, said Dr Duffy, is why are the immune response rates to cancer so low in general? “The vogue term is whether a cancer is T-cell inflammed or not; this reflects whether the immune system is already wise to the cancer,” said Dr Duffy. When the immune system is already switched on, recognising and infiltrating the cancer, that is where the cancer begins to take evasive strategies such as PDL-1 upregulation.

However, PDL-1 is ‘druggable’, said Dr Duffy, and this is where you get the nice responses, he said, which is creating all the hype, excitement, and optimisim.

It is unfortunate that in the GI cancer world, most cancers are not T-cell inflammed and there is no PDL-1 upregulation going on, said Dr Duffy.

Big question

“The big question is how can we go from a non T-cell inflammed tumour to a T-cell inflammed tumour?” said Dr Duffy. There are lots of exciting, novel methods coming down the pipeline, which can achieve this, but many of the treatments already now in use regularly in the clinic – such as radiation, ablation and chemotherapy – can achieve the same result, which is fascinating, he said.

Ablation treatments, for example, are in daily use in the treatment of hepatocellular carcinomas and biliary tract carcinomas, said Dr Duffy. The ablations can be done with heat, by placing a probe directly into the tumour to burn it, or by freezing it, or injecting it with alcohol, or doing a procedure to cut off the blood supply to the tumour. What has been found over the last 10 years or so, said Dr Duffy, is that when you do these things, you stimulate the immune system to respond – presumably, he said, because the cancer cells are dying and in the process of dying they become visible to the immune system through ‘immunogenic cell death’.

Many patients with these type of cancers will have small, localised tumours, not metastatic disease. When there is an immune response a simple procedure is performed to burn the tumour, or block off its blood supply, and this can determine whether one is cured or not. It is not a question either of simple adaptive immunity where T-cells are being activated, said Dr Duffy. There is more to the story.

There is a gathering consensus that NK cells are crucial here, said Dr Duffy, as they have been shown to increase in number and functionality after an ablation procedure. There are more NK cells after the procedure and they are better able to attack and kill the cancer cells.

Oncolytic viruses

Dr Duffy said that he wanted to mention oncolytic viruses as he was “super excited” about their potential. The thing that really excites him, is that oncolytic viruses stimulate an adaptive immune response and he cited an interesting study published in Nature three years ago on the Vaccinia virus; the same virus Dr Duffy is preparing to use in his clinic.

In this study in patients with liver cancer, they took the Vaccinia virus and injected it locally into the tumour. This was performed by the interventional radiologist at two doses, a high dose and a low dose. The result was a load of shrinkage of the tumour, which presumably was from the direct lysis effect, he said. However, there were also distant effects which can be explained by the virus entering the bloodstream and travelling to infect other tumour types, said Dr Duffy. There is great potential to use this virus in combination with immune checkpoint inhibition in gastrointestinal tumours, said Dr Duffy, and this is what he has been working on recently.

Dr Duffy finished his talk by summarising a number of points that he wished to get across to the gathering.

“The main points I wanted to make is that the ‘standard of care’ I think we’ll all agree in this group of diseases we need to do better,” said Dr Duffy. “The liver is a unique organ from an immunological standpoint and we can exploit that and the fact the common underlying pathogenesis here is inflammation, so we can exploit that also.

“And I wanted to give a hint about the promise of the immune approaches that we are all super excited about. I think there is beginning to emerge encouraging provisional activity for monotherapy; it is very low, it is a small number of patients, but I think there is a proof of principle that we can build on and that is key.”

There are new ‘modalities’ coming, added Dr Duffy, including viruses, vaccines, and other checkpoint inhibitors, which can improve standard of care. However, he said that before we get to those agents there are things that we do everyday all around the world in terms of standard care, which can be really exploited.

“I showed you some exciting data on interventional radiologic procedures and the same applies for chemotherapy,” commented Dr Duffy.

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