Why the immune system holds the key to cancer treatment

We’re going to examine how cancer develops; how it has traditionally been treated; and how these new cancer vaccines look set to become a revolutionary tool in the fight against this disease. Here’s Charlie Swanton. He’s Cancer Research UK's chief clinician, a principal group leader at the Francis Crick Institute, and a thoracic oncologist at University College London Hospital…

Charlie - Cancer refers to an uncontrolled proliferation of cells that ultimately derive from a single cell of clonal origin that, due to their uncontrolled proliferation, invade the tissues around them and ultimately invade and spread across the body.

Chris - What proportion of the population will have a run in with cancer? If I'm an average person, which I hope I am, what would be my lifetime risk of this happening to me?

Charlie - Cancer Research UK estimates that over a lifetime one's risk of cancer is somewhere between one in three and one in two.

Chris - Quite high, isn't it?

Charlie - It's high and it is a disease of ageing for the most part.

Chris - Why does it happen, though? Why is it that when I'm young you don't seem to see very many people who have a malignancy but, as we get older, it tends to occur more commonly?

Charlie - There are many theories. The first is that as we age we accumulate more mutations in our cells. But what has become apparent over the last five or six years is that actually our normal cells in our body, our normal tissues, are a patchwork of mutant clones. And actually, whilst mutations may be necessary for tumour initiation, they're not sufficient. And so other aspects are required, and that probably relates to chronic inflammation that's required to initiate the first tumour cell with mutations and possibly local tissue disorder, disruption of normal tissue architecture that can occur with ageing.

Chris - So it's a range of things that have got to go wrong, the odds of which increase as we get older. So it's almost like aligning all the holes in the Swiss cheese to get exactly an aligned hole that enables cancer to escape and become a problem.

Charlie - That's exactly right, Chris. Yes.

Chris - What sorts of other things are controlling cancers normally, then, that mean that a young person doesn't have a tumour?

Charlie - First of all, a young person has many fewer mutations than somebody like me in his mid fifties. Younger individuals just simply have fewer mutations in their normal cells. They're less exposed to the chronic inflammatory stimuli that I referred to. Their tissues are more ordered and more structured in a normal manner. But, in addition, the body's own immune system plays an important role in keeping malignant clones at bay. Indeed, it's been postulated that tumours are initiating much of the time in elderly individuals and are being controlled by the body's own immune system and being prevented from initiating and evolving.

Chris - That's fascinating. Many of us could have cancer at any one moment, but then the immune system stamps on it?

Charlie - The answer to that question is hard to prove. Where we have evidence for it, we can look at the archaeology of cancers that have evolved in patients and find very strong evidence for what's called immune editing. That is, a footprint, or a fossil record if you like, of prior immune activity against the tumour. That is, it has essentially annihilated malignant sub clones with what we call immunogenic potential. That is, the potential to alert themselves to the immune system. So we have evidence from looking at tumours that they have been predated upon, if you like, by a functioning immune system in the past.

Chris - Can I paraphrase that and say, basically, the body's trying to produce cancers from time to time because it develops changes in the DNA, mutations that make a tumour try to appear. The immune system responds and stamps it out, and you can see in the genetic record of the immune system, or in the tumour itself, the fact that has happened. But then, eventually, there's some kind of breakthrough that enables the tumour to occur. Is that because there's a loophole in our immune system and cancers are just basically probing our immunity until they find the chink in our armour?

Charlie - It's a very good question. The answer is that there are ways that the cancer cell evolves to evade alerting the immune system to its presence. That can occur from ways in which the tumour can mutate DNA: it can mutate specific genes that are required to be recognised by the immune system such that the cancer begins to evolve and develop below the radar, so to speak.

Chris - On the basis of what you've just told me, there is a precedent for expecting the immune system to be able to control cancer. We can see that it has done that in our own bodies in the past. Therefore, it's a question of when we have manifest malignancy. It's a question of making it work again, but this time work against that particular tumour. It's a bit like saying, we know fusion can work because the sun's doing it, but we've got to get it to work on Earth. We've got to get it to work in the body against a cancer that has broken through.

Charlie - Except that there is one caveat, which is we've already proven this works. There is very good evidence now that boosting the immune system by releasing the brakes on T cells can improve outcomes for many different tumour types, both in terms of progression-free survival, overall survival, and even cures in the context of, for instance, solid tumours like advanced melanoma.

Chris - Talk us through how this actually works, then. What is the approach to to trying to get the immune system to stop ignoring something that it had previously overlooked?

Charlie - The way in which this works is that there's a subgroup of cells in the immune system called T cells, and these T cells have evolved over billions of years of evolution to essentially recognise non-self. But what we discussed in the last few minutes is that tumours also develop mutations and can appear to the immune system as non-self, but the tumours also in their evolution adapt and suppress t-cell activation. What we've learned through some seminal work from Jim Allison and Honjo who won the Nobel Prize for medicine for this discovery, is that there are specific brakes on T cells that are activated by the cancer cells that one can intervene on and block. By doing so, you can release T cell activity to attract them to tumours and recognise tumours and essentially annihilate them.

Chris - And are you involved in any of them specifically?

Charlie - I'm very involved in lung cancer treatment with immunotherapy, either through vaccine developments, T cell therapies, or immunotherapies. So yes, very much so.

Chris - And the outcomes from these treatments, do they buy time or do we dare to use the 'c' word and say, well, we're actually looking at potentially curing people?

Charlie - Well, that's not a word I use terribly often in advanced lung cancer. That said, we do have a number of patients who have been on these drugs for a long time who are in long term remission. I haven't yet used the word cure openly but, privately, I'm thinking that for a small minority of patients treated with these drugs, probably. I'd say it's a small minority in which we're achieving long-term remissions and possibly cure. In melanoma, it's much higher. Upwards of 30, possibly 40% of patients with advanced melanoma can expect to be in long-term remission and even be cured with these drugs. We're in the very early chapters of this story, and I think over the next 50 years we're going to see continual improvements in outcomes as a result of immune therapies like vaccines, T cell adoptive therapies and checkpoints, inhibitor therapies.