The tumour on the man’s tonsil was the size of an egg; it bulged out from his neck and obscured so much of his throat that he could barely swallow. Emaciated and weak, no-one held out much hope that he would survive. Deliberately injecting him with bacteria that would cause his skin to blister and his temperature to soar might therefore have sounded like a cruel form of torture. But William Coley, the surgeon brandishing the syringe, hoped it would prove his salvation. Indeed, in the months following the injection in May 1891, the patient’s tumour began to break down, and by October it was gone.1 The man lived a further eight years before the cancer relapsed and ultimately killed him.
This was some of the first evidence that stimulating the immune system – in this case by triggering an infection – might cause cancers to regress. In the years that followed, Coley refined his technique and claimed to cure many more patients, although others struggled to replicate his results and following his death in 1936, Coley’s toxins were gradually forgotten. Today though, the idea of harnessing the immune system to fight cancer is firmly back on the agenda. A string of successful trials involving immune-based drugs called checkpoint blockers or inhibitors – not to mention the recovery of the former US president Jimmy Carter from melanoma – has seen pharmaceutical company investment in the field soar. Immunotherapy is also at the heart of the recently launched ‘Cancer MoonShot’ initiative in the USA, the goal of which is to find a vaccine-based cure for cancer by 2020.
A shape-shifting enemy
Is such excitement justified? History tells us that cancer is a shape-shifting enemy, and molecular therapies – previously hyped as a silver bullet for cancer – have been less successful than many had initially hoped. Yet there are several reasons to think immune-based therapies might do better. The first is immunological memory, which means that once cells of the immune system are engaged in fighting a tumour, they should continue to do so – even if the cancer disappears and then returns at a later date. The immune system is also capable of adapting to changes in its enemies through such phenomena as epitope spreading, in which immune cells diversify to attack multiple targets, as well as the one they started with. “This means even if tumour cells evolve and subclones emerge, it may be possible for the immune response to continue recognising them,” says Peter Johnson, Professor of Medical Oncology at the University of Southampton and Chief Clinician for Cancer Research UK. “The emergence of resistance is a problem for molecular therapies.”
Modern interest in harnessing the immune system has been building since the 1980s when experiments in mice revealed that it was possible to immunise them against developing a particular type of tumour, if the cancer cells were first mutagenised by exposing them to radiation or chemicals.2 Before this, many scientists had assumed that cancer cells were too similar to our own cells for the immune system to recognise them. One of the main issues seems to be transforming this initial recognition of the cancer cells into a full-blown immune attack on them.
The rise of monoclonal antibodies
A major turning point was the development of monoclonal antibodies, which can be raised against a protein of interest and then manufactured in large amounts. One of the first monoclonal antibodies to become available was rituximab, which binds to a molecule called CD20 on the surface of immune cells called B cells and destroys them. Since dysfunctional B cells are the cause of many lymphomas and leukaemias, it’s an excellent way of removing them from the body. “From the moment rituximab was introduced as a widespread treatment for lymphoma, we’ve seen a fall in mortality rates,” says Johnson. Other monoclonal antibodies to treat a variety of cancers soon followed, including trastuzumab (Herceptin) and bevacizumab (Avastin). However, the really big shift in the field – and the one currently generating all the excitement – was the use of antibodies to target, not the tumour cells themselves, but the immune system’s own control processes.
Taking the brakes off
Because of its destructive power, the immune system has evolved a whole repertoire of regulatory processes to ensure its full might is only unleashed in the appropriate circumstances. “It is a bit like driving a car with one foot on the accelerator and one on the brake at the same time; there are all these checks and balances, which mean the immune response can increase or decrease in a controlled manner,” says Dr John Maher, Clinical Senior Lecturer in Immunology at King’s College London.
Many of these interactions take the form of molecular handshakes between proteins on the surfaces of different immune cells – or even on the tumour itself. For instance, T cells possess a protein called PD-1 on their surface, which interacts with a different protein that some tumour cells produce in abundance called PD-L1. When this handshake occurs, a brake is applied to T cells, encouraging them to hold fire, rather than attack the tumour.
Pembrolizumab – the drug that Jimmy Carter attributes his recovery from melanoma to – is referred to as a checkpoint blocker. It binds to and blocks PD-1, effectively taking the brakes off T cells and enabling them to mount an effective anti-cancer response.
Lagging only slightly behind the checkpoint blockers in terms of development are antibodies designed to switch on specific immune responses, such those targeting CD40 on antigenpresenting cells (APCs). APCs are responsible for showing T cells the particular proteins (called antigens) that they should react against, thereby kicking off immune responses; antibodies that bind to CD40 seem to activate APCs.
However, such antibody-based therapies are not a panacea. Take checkpoint blockers: they seem to be most effective in cancers that have a high mutational load (i.e. lots of changes to the DNA) – things like skin or lung cancer that often arise following damage by UV light or carcinogens – but even then, only around 20–30% of people respond to them. “The sad reality is that checkpoint blockers do not work for the majority of patients, and so there is still a huge unmet need for additional approaches,” says Maher.
A combined response
One such approach involves a fundamental redesign of T cells. Once set in motion, T cells are highly effective cancer killers, but tumours have evolved many ways of hiding from them. Antibodies, on the other hand, are extremely good at locating tumours, but not so good at destroying them. Chimeric antigen receptor (CAR) T cells are hybrids of the two: T cells that researchers have extracted from a patient’s blood and issued with the genetic instructions to make cancer-hunting antibodies as well as their usual T cell receptor. Some of them also contain additional signalling elements, which amplify the T cell’s response once it binds to its target. These CAR T cells are then injected back into the patient and left to do their work.
Choosing the right molecular target is crucial: get it wrong, and the T cells will start to attack healthy tissue. But finding targets that are only expressed on cancer cells is tough, because cancer cells derive from our own tissue. The biggest success story to date involves CAR T cells engineered to recognise a molecule called CD19, which is expressed on both malignant and healthy B cells. A pilot study of three patients with advanced chronic lymphoblastic leukaemia who were injected with these cells demonstrated that they could indeed hunt down and destroy their targets – and generate a population of memory cells that could potentially destroy cancerous cells if they returned.3 However, there’s a catch: they also destroy healthy B cells. That’s not such a problem, because we can replicate their main function by giving patients antibody replacement therapy; however, this wouldn’t be so easy with tumours that affect other tissues, such as the liver or brain.
“The Holy Grail for CAR T cells is the identification of target molecules which are expressed on a sizeable proportion of tumours or leukaemias, and can’t be detected on the surface of healthy cells,” says Maher. “But that’s a very, very short list.” Another potential hurdle faced by researchers developing CAR T cells is the possibility of cancer cells mutating, so that they no longer express the T cell’s target. In an attempt to combat this, Maher’s group is developing T cells that will recognise an entire group of proteins called the ErbB family, which is implicated in a number of different cancers. “It is a collection of eight different targets, which makes it difficult for the tumour just to take out one of them,” Maher says. ErbB proteins are also produced by healthy cells, but Maher is getting around this by injecting the T cells directly into the tumour rather than into the blood. His team is currently conducting a safety study in terminally ill patients with head and neck cancer. There’s no doubt that CAR T cells are an extraordinarily clever means of manipulating the immune system, but whether they will ever become a mainstream cancer therapy is less certain. “We are seeing tremendous efficacy in acute lymphoblastic leukaemia, which has caused a great deal of excitement,” says Maher. “However, this is a very toxic treatment.”
Engineering the immune cells of individual patients is also extremely labour intensive, and therefore costly. Far better would be to find a way of preventing cancers from developing in the first place. For one thing, it is easier to mount an immune response against a tumour when it is in its infancy, before it has grown a support tissue called the stroma, which largely protects it from the immune system. “Solid tumours put up a huge wall around themselves as they grow,” says Maher.
One such preventative cancer vaccine already exists. The HPV vaccine targets proteins made by the human papilloma virus – the main cause of cervical cancer worldwide. Other viruses including Epstein-Barr and hepatitis B are also associated with certain cancers, but the majority develop as a result of genetic mutations, which makes finding a vaccine target somewhat harder. “The difficulty is that if there is no virus, there is nothing foreign for the immune system to recognise,” says Professor Roy Bicknell, Head of the Cancer Research UK Angiogenesis Group at the University of Birmingham.
History tells us that cancer is a shape-shifting enemy, and molecular therapies have been less successful than many had initially hoped
One approach might be to pick on the mutated proteins that drive the growth of cancer cells, such as the protein KRAS, which is implicated in 95% of pancreatic cancers. But such proteins are often found in the cytoplasm of cells, rather than on their surface. Immune cells can still mount a response to them, but it will be against small fragments of the protein, rather than the whole thing. This means targeting T cells, rather than antibody-producing B cells as conventional vaccines do. “T cells can see small protein changes within the cell; antibodies only see a whole protein,” explains Professor Elizabeth Jaffee, Deputy Director of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, USA.
She is developing a preventative cancer vaccine based on Listeria , a bacterium which grows and replicates inside human cells, using it to deliver proteins such as mutated KRAS to the antibody-presenting cells that show protein fragments to T cells. This sort of approach might work for cancers that are strongly associated with a specific mutation, such as pancreatic cancer. But for many cancers it’s far harder to guess what the mutation might be, so it’s unlikely to result in a universal cancer vaccine.
Attacking the support system
But that might yet be possible. Rather than second-guessing what mutations might someday arise in the body and vaccinating against them, Roy Bicknell is instead focusing his efforts on something all solid tumours need to grow: a blood supply. “We know that the blood vessels in tumours are structurally and genetically very different from those in healthy tissues,” he says. For instance, he has identified four proteins that are highly expressed in the blood vessels of solid tumours. The same proteins are also produced by human embryos when they are first laying down a vascular system, but they don’t seem to be made by healthy adults. “That potentially means we can attack them,” Bicknell says.
His team has been developing CAR T cells against one of these proteins, called CLEC14a. But he is also working on a preventative vaccine that might destroy any blood vessels that a fledgling tumour begins to grow, therefore stopping it in its tracks. So far they’ve demonstrated that this is possible in mice.4 “We have shown that if you vaccinate mice against the tumour vessels, then you get a strong anti-tumour effect,” Bicknell says.
The real challenge with this, and other preventative cancer vaccines, will be proving that they work in humans. Most cancers take decades to develop; if you vaccinated subjects now, you’d have to wait a very long time to find out if the vaccine had actually prevented any cancers.
To describe the goal of curing cancer with the immune system as a ‘moonshot’ is an understatement. The challenges are manifold, and if we ever do succeed it’s likely to be the result of a combination of approaches – not all of them immunological – rather than a single one. But William Coley was right about one thing: given the correct stimulus, our bodies do have the capacity to reject cancer. We just have to learn the intricate sequence of buttons that need to be pressed.
This article was written by Linda Geddes as part of the BSI's report '60 years of immunology: past, present and future'. This article is licensed under Creative Commons Attribution-NoDerivative Licence (CC BY-ND 4.0). Additional permissions may need to be sort from image licence owners.
- Wiemann & Starnes 1994 Pharmacology & Therapeutics 64 529–564
- Van Pel & Boon 1982 Proceedings of the National Academy of Sciences of the USA 79 4718–4722
- Kalos et al. 2011 Science Translational Medicine 3 95ra73
- Zhuang et al. 2015 Angiogenesis 18 83–95