The immune system analyses the world around it using molecular 'handshakes'
Last weekend, the world’s biggest cancer research conference – ASCO 2014 – took place in the US. Thousands of doctors and scientists from around the world gathered to discuss the results of ongoing trials of experimental cancer drugs.
This year, much of the pre-conference buzz has focused on immunotherapy – treatments that use the power of our immune system to fight cancer. In particular, the excitement focused on two new, related classes of drugs called anti-PD-1s and anti-PD-L1s, part of a wider class of drugs called ‘immune checkpoint blockers’.
Given so much interest, we thought we’d explain a bit about these drugs – where they came from, how they work, and how they fit in with other cancer treatments. But to do so, we first need to take a look at how our immune system works – not only in cancer, but also when we’re healthy.
Our immune system is an army of different types of cell, which exists to detect and destroy dangerous invaders, keeping us healthy. As a result it’s on constant look-out for foreign forces such as bacteria and viruses, many of which can cause serious diseases.
But it needs to be able to tell these apart from our own cells, and from the many harmless bugs that peacefully coexist in our guts and mouths, on our skin, and in many other nooks and crannies around our bodies.
In order to maintain this balance, the immune system has evolved a dazzlingly complex repertoire of sensing mechanisms, all aimed at ensuring it only gets primed to attack under certain circumstances, only unleashing its fearsome power at exactly the right place and time.
A key player in our response to invaders is a type of immune cell called a T-cell.
T-cells patrol our bodies, constantly scanning anything they bump into. Each time they encounter another cell, a whole array of molecules in their surface makes contact with others on the surface of the cell under scrutiny. Depending on the presence or absence of certain contacts, T-cells ‘decide’ whether to call in reinforcements, prime themselves for action, or stand down and move along to the next cell.
Working out the precise molecular switches and signals governing these processes has taken immunologists decades of hard, painstaking graft – and there’s still much we don’t understand. But we now know a significant amount about the molecules involved.
But the system isn’t perfect. Many invaders trick it, evading detection while growing and dividing. Certain viral infections – notably HIV – disguise themselves from the immune system’s patrols, as can various parasites and bacteria.
So, too, can cancer: one of the biggest mysteries in cancer research is why and how an entity so distorted and deranged as a tumour manages to escape the body’s defences. As an example of how cancer confuses the immune system, tumours are often jam-packed full of T-cells, primed and ready to act… and yet they somehow fail to recognise the cancer as a threat. It’s as if tumour cells have developed a ‘secret handshake’ that they use to trick our T-cells into holding fire.
Understanding how cancers do this is vital to unleashing the immune system’s lines of attack, and getting better results for patients.
Researchers have made significant strides in decoding these ‘handshakes’. In 1992, Japanese researchers found a molecule on the surface of T-cells they named ‘programmed death 1’, or PD-1, which subsequently turned out to be a key part of their molecular handshake.
In 1999, a lab in Minnesota isolated a molecule on our other cells that forms the other ‘hand’ of the handshake, which they called PD-L1 (for ‘programmed death ligand 1′). Researchers then discovered that cancers often produced large amounts of PD-L1 – this was one of the key ways in which they were tricking the body’s defences. This fired the starting gun on a race to develop drugs to disrupt the handshake by targeting either PD-1 and PD-L1 – and pretty much every major pharma company joined in.
By 2006, a lab in Atlanta, Georgia, had proved, in mice, that disrupting the PD-1 – PD-L1 handshake could cure chronic viral lung infections – blocking this process could be relevant for a wide range of other diseases. The pressure to bring these drugs through trials began to build.
Neck and neck
Wind forward to the present decade. There are now at least eight drugs in clinical trials that target either PD-1 or PD-L1. Most of them are modified antibodies but a few of them are more exquisitely engineered biomolecules. Results to date have been extremely encouraging.
In 2012, two early-stage phase I trials run by the company Bristol Myers Squibb – one of an anti-PD-1 drug called nivolumab, and another of an anti-PD-L1 drug called BMS-936559 – caused a stir at that year’s ASCO conference, when they both showed signs of working against a range of cancers.
A year later, another catchily named anti-PD-1 drug, Merck’s lambrolizumab – now known as pembrolizumab – showed encouraging signs against advanced melanoma and hit the headlines this week following new results presented at the ASCO Conference.
In recent months AstraZeneca’s PD-L1 drug, MEDI4736, has been garnering some rather over-excited headlines, notably in the treatment of lung cancer. Another runner is Roche’s MPDL3280A, which was in the news yesterday thanks to a bladder cancer trial run out of our own Experimental Cancer Medicine Centre network.
(Edit: there’s now an excellent summary of some of the recent trial results, with some added insight and commentary, over at Dr Len’s Cancer Blog).
But researchers have seen the most eye-catching results when the drugs are used in combination with another very similar immune therapy, which targets part of a completely different T-cell ‘handshake’ – a molecule called CTLA4.
CTLA4 ‘handshakes’ take place in our lymph glands, where T-cells meet up with other immune cells called ‘antigen-presenting cells’, or APCs. Here, APCs alert the T cells to invaders (or tumour cells) and signal to the T cells to gear up for action and start dividing rapidly – into an army of clones, primed to recognise and zap that invader wherever it resides in the body (this is what causes swollen glands when you’re ill).
But CTLA4 ‘handshakes’ switch off this process, preventing the eager army from growing, and hampering their ability to march out and fight the enemy. In a parallel story, researchers have already developed drugs that target CTLA4, and in doing so, have proved that unleashing the immune system, rather than targeting the cancer itself with drugs, is hugely promising.
Now we’re discovering that when PD-1 blockers and CTLA4 blockers are used together, they have a much greater impact than either alone: knocking out CTLA4 allows the body to create an army of anti-cancer T-cells, and knocking out PD-1 or PD-L1 allows this army to attack. Preliminary trial results, again, have been extremely promising.
Not yet ready for prime time
And now, as so often is the case, we get to the caveats.
While these drugs – alone or in combination – are hugely promising, they’re still being tested in clinical trials. And until the results are in, we should be wary of hailing them as ‘cancer cure breakthroughs’, as the media are wont to do.
Aside from ipilimumab, none has yet been proven to prolong life (the gold standard of cancer drug development). And because they activate your immune system, they can also cause some pretty fearsome side-effects – particularly a nasty inflammatory bowel condition called colitis, which leads to diarrhoea and stomach cramps.
Even if they do make it through regulatory hurdles, they’re likely to be very expensive (although we hope the companies making them will set realistic prices that the NHS can afford).
So there’s still a fair way to go, and a lot of questions to answer, before these potentially exciting new drugs are approved for routine use.
But as a concept, targeting the subtle molecular interactions between our immune system and cancer looks like a breakthrough that’s here to stay. In fact, some experts even think that the idea will eventually replace ‘traditional’ chemotherapy and radiotherapy, and become a new paradigm for treating the disease.