CANCER. Of all the maladies that afflict us, it is often the most feared. And with good reason: for most of history anyone discovering its unwelcome presence faced near-certain death. Even today it is either the number one or number two killer in many countries.
It’s fair to say our three main weapons against cancer are crude and brutal. We cut the tumour out, burn it with radiation, or give drugs that poison any rapidly dividing cells. All are undeniably effective, but they almost inevitably inflict collateral damage.
The latest new class of treatment to reach the clinic is targeted therapies, which act on molecular pathways active mainly in cancer cells, and therefore lack the harsh side effects of chemo. Yet despite all the fanfare about them, these drugs rarely cure anyone, because cancer cells’ high mutation rate allows them to dodge the pathway concerned. Targeted therapies usually only prolong life by a few months.
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That’s why cancer doctors are eagerly anticipating several new kinds of treatment, including killing cancer cells with RNA, nanoparticles, modified viruses and bacteria, as well as harnessing our own immune system to engage cancer in cell-to-cell mortal combat. “I believe we’re about to see a whole new wave of treatments with less toxicity and more efficacy,” says Christian Ottensmeier of the University of Southampton, UK.
When taking stock of the war on cancer, it is easy to overlook some of the gains that have been made. A diagnosis of some kinds of cancer is no longer a death sentence. In the past few decades, the cure rate for testicular cancer, for instance, has reached over 90 per cent, and for childhood cancers it is about 80 per cent. Still, when it comes to other cancers, such as those of the lung, stomach or pancreas, the prognosis is not so good. And for any kind of tumour, the later it is caught, the worse the odds.
So hopes for higher cure rates lie with alternative approaches, including the following strategies. These therapies are still only at early-stage clinical trials and are therefore many years from reaching the clinic. But if any one of them meets their promise, they would be the biggest development in the treatment of cancer since chemotherapy came on the scene seven decades ago.
RNA interference
At the turn of the millennium, RNA interference was being hailed as the next big thing in medicine. Discovered in the 1990s, it represents a natural cellular control mechanism that can be subverted to our own ends. RNA interference gives us the power to temporarily turn individual genes on and off. It “opens up a universe” of what you can do, says Judy Lieberman, a cancer specialist at Harvard Medical School, who helped pioneer the approach.
Translating that promise into effective medicines has not been easy, though. The technique involves making short stretches of RNA that switch off specific genes. But it turns out that our cells are very good at detecting and destroying short stretches of RNA, which may look similar to an invading virus. “Delivery is still a major obstacle,” says Lieberman.
A variety of cunning molecular tricks are being investigated to get round this hurdle. One is to hide the RNA inside lipid nanoparticles. A drug called ALN-VSP, made using this technique, is being tried out in cases of liver cancer; it targets two genes involved in cancer growth. , tumour growth stalled in 7 out of 37 people treated.
Lieberman reckons the first RNA-based cancer drug could reach the clinic within the next 10 years. “What’s amazing is that RNA-interference drugs are developing much faster than other types of drugs,” she says. “It’s only a decade since we knew this phenomenon even works in mammalian cells.”
Nanoparticles
The science of the small could prove to be our saviour. While not necessarily toxic to cancer by themselves, nanoparticles can boost the potency of existing chemotherapy drugs to new heights. “The ability to fundamentally change drug pharmacology allows you to look for the first time at biology you never could explore,” says Omid Farokhzad, head of nanomedicine and biomaterials at Brigham and Women’s Hospital in Boston, Massachusetts.
The problem with chemotherapy is that it poisons rapidly dividing cells, whether cancerous or not, so dosages are usually limited by toxicity to the gut, skin and immune system. Linking chemotherapy to nanoparticles allows the drugs to target the tumour selectively, so higher doses can be used. That’s because nanoparticles tend to accumulate in tumours, partly due to the fact that their blood vessels are more leaky than normal.
Some conventional chemo drugs are already packaged up with nanoparticles. But it may be possible to enhance the homing instinct further by attaching a nano-sized drug package to antibodies that target cancer proteins, an approach that was shown to work . “We saw significant effects at very low doses,” says Farokhzad, who helped conduct the study. “Nanotechnology isn’t going to make a bad drug into a good drug,” he says. “But nanotechnology could make a good drug a great drug.”
Super-Bugs
My enemy’s enemy is my friend, so the saying goes. Infectious bacteria are not something we’d usually encourage into our bodies, but if they can be made to attack cancer cells, perhaps we should consider them our strategic allies.
Many strains of bacteria, including salmonella and E. coli, tend to migrate towards tumours and set up home inside. There they hide from the immune system in the low-oxygen zone in the tumour’s centre, feeding off metabolites made by the rapidly dividing tumour cells. As with virotherapy (see “Self-defence”), bacteria can be genetically engineered to release toxins or carry out “whatever activity you want to localise”, says Mark Tangney, principal investigator at the Cork Cancer Research Centre, Ireland.
Although this approach is at an earlier stage than virotherapy, with fewer trials in people so far, working with bacteria has certain advantages. They are easier to mass-produce than viruses and are more amenable to modification. And, unlike viruses, they can target the stroma, the non-cancerous supporting cells that comprise up to 80 per cent of a tumour.
In 2010, Tangney showed that a strain of harmless gut bacterium can , even when given orally. “Using microbes that don’t naturally cause disease, like probiotic bacteria, is exciting since our bodies don’t see these as toxic and permit them to go about their business – in this case, producing anti-cancer drugs inside tumours,” he says.
Immunotherapy
Of the many new cancer treatments in development, the biggest buzz is about the idea of harnessing our own immune system to seek out and destroy cancer cells, wherever they are in the body.
The idea of “immunotherapy” has a long history, arguably beginning in the 1890s, after a chance finding by New York surgeon William Coley. He noticed that a patient with neck cancer made a miraculous recovery after developing a nasty skin infection. Coley spent the next few decades brewing up concoctions of bacteria to inject into people’s tumours, with some success.
Though Coley could not have known it, our immune system is constantly on the watch for cancer cells. When we discover a cancerous lump, it’s because those defences have failed. Occasionally, people with cancer are lucky enough to see their tumours spontaneously shrink and disappear, presumably because their immune system has belatedly woken up to the danger.
Coley’s quest seemed to die with him in the early 20th century. But as our understanding of the immune system has grown, so the idea of harnessing its powers against cancer has been revived. After all, we routinely manipulate it any time we get vaccinated against infectious diseases. Unlike shots against measles and flu, however, this would be a “therapeutic vaccine”, one given to treat an existing illness as opposed to a preventive vaccine that stops us catching it in the first place. Yet it would still exploit the immune system’s key strengths of specificity and memory, targeting only cancer cells, and staying effective long after the shots are given.
Mimicking vaccines
Modern attempts to create a cancer vaccine began, perhaps predictably, by mimicking preventive vaccines against bacteria and viruses. Patients were injected with proteins unique to cancer cells, or with dead tumour cells still bearing their protein load, accompanied by an adjuvant, a chemical that waves a red flag at the immune system.
Over the past few decades there have been hundreds of trials of this approach in people and countless more in animals. All have failed. One hitch is that tumours make signals telling immune cells to back off. What’s more, cancer patients’ immune systems tend to be weakened from chemotherapy and radiotherapy. And there’s another, more fundamental, stumbling block. The immune system works via two main “arms”: immune cells and antibodies. It is the immune cells that destroy cancer cells. “When you make vaccines with protein, then you are really good at inducing antibodies,” says Christian Ottensmeier of the University of Southampton, UK. “They’re not so good at inducing immune cells.”
That’s why Ottensmeier’s group is one of many investigating ways to alert the immune cells. The most common one is to inject not a cancer protein, but the gene that codes for that protein. Once this DNA vaccine is injected into, say, the patient’s arm muscle, the muscle cells obey these new genetic instructions and start churning out the protein until it reaches the cells’ surface.
The appearance of a cancer protein on the surface of living cells, rather than floating around freely in the bloodstream or on dead cancer cells, appears to be just what is needed to stir the immune cells into action. Several different DNA vaccines are now in small, early-stage trials in people.
But with cancer vaccines taking longer than expected to come to fruition, interest has grown in another approach, dubbed adoptive immunotherapy. This involves removing immune cells from someone with cancer, manipulating them in some way and putting them back. “This approach is far and away the most exciting right now,” says Steven Rosenberg of the US National Cancer Institute in Bethesda, Maryland, one of immunotherapy’s pioneers.
The first example of this treatment reached US clinics in 2010. Called Provenge, it is used to treat terminal prostate cancer, delivering an extra four months of life, on average. Each person’s course of treatment has to be tailor-made in the lab, which helps to explain its hefty price tag of $100,000.
But other kinds of adoptive immunotherapy may deliver more impressive results. Provenge is unusual in that the immune cells taken from the patient’s blood are of a type that do not kill cancer cells directly; instead they pick up cancer proteins and “display” them to T-cells, which do the killing.
Better results have been achieved by growing T-cells directly. One technique is to culture and reinject T-cells found in a tumour that has been surgically removed. The presence of T-cells within the tumour indicates they recognise it as foreign. Combining them with drugs and radiotherapy to get rid of any immune-suppressing cells has led to in late-stage melanoma; untreated, this cancer is almost invariably fatal. Could this be the breakthrough needed for hitherto incurable cancers? “We haven’t yet tapped the potential of the immune system,” says Ottensmeier. “If you can unleash that, then we’ll see quite dramatic effects.”
Cure in sight
It may be possible to do even better by turning the complexity level up a further notch. Instead of leaving things to nature, we can genetically engineer someone’s T-cells to attack their cancer. This can be done by introducing into the T-cells a gene for a receptor on their surface that recognises a known cancer protein. “We can create entirely new cell types,” says Rosenberg.
Combining adoptive immunotherapy with gene therapy in this way is the stuff of cutting-edge research, and it is too early to tell how well it might work. So far it has been performed at a handful of university-linked medical centres on a few dozen patients with apparently terminal illness. But some of the results suggest genetically engineered T-cells have . In published last year, for instance, two out of three leukaemia patients entered complete remission. “These are small experimental trials,” says Rosenberg. “But they’ve provided a lot of excitement.”
Indeed, after years of scepticism, many drug giants have various immunotherapies in the pipeline, including GlaxoSmithKline, Pfizer and Merck. “My personal slant is we are sitting at a time in medicine [similar to] the time we invented antibiotics,” Ottensmeier says. “The new antibiotics is going to be immunotherapy.”
Virotherapy
Destroying human cells comes naturally to viruses. Their life cycle often goes as follows: infect cell, then force cell to make more viruses until it dies, unleashing a torrent of new viruses primed to infect more cells.
The idea of harnessing this destructive force against cancer cells first arose in the 1950s. Various kinds of virus were injected into people’s tumours, sometimes with fatal results if the infection spread.
Today the focus is on using viruses that have been genetically modified so they can only infect tumour cells, and sometimes to make the virus more deadly too. “You get them to replicate like crazy inside the cell – basically they eat their way through a tumour,” says Mark Tangney of the Cork Cancer Research Centre, Ireland.
“You can get viruses to replicate like crazy inside a tumour cell – they eat their way through the tumour”
At least 10 different groups of viruses, with various genetic modifications, are being investigated as potential forms of “virotherapy”. The best result so far has been seen using a herpes virus to deliver a potent immune chemical, called GM-CSF, in people with melanomas that had metastasised. in eight of the 50 people taking the therapy. And virotherapy may not yet have reached its full potential: several ways of beefing up the viruses are still at the stage of animal research.
