A virus that kills cancer: the cure that's waiting in the cold

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dinsdag 18 september 2012

Sitting in a refrigerator in a Swedish laboratory is what promises to be a cheap and effective cancer treatment. So why are the trials to bring it to market not going ahead?

On the snow-clotted plains of central Sweden where Wotan and Thor, the clamorous gods of magic and death, once held sway, a young, self-deprecating gene therapist has invented a virus that eliminates the type of cancer that killed Steve Jobs.

'Not "eliminates"! Not "invented", no!' interrupts Professor Magnus Essand, panicked, when I Skype him to ask about this explosive achievement.

'Our results are only in the lab so far, not in humans, and many treatments that work in the lab can turn out to be not so effective in humans. However, adenovirus serotype 5 is a common virus in which we have achieved transcriptional targeting by replacing an endogenous viral promoter sequence by…'

It sounds too kindly of the gods to be true: a virus that eats cancer.

'I sometimes use the phrase "an assassin who kills all the bad guys",' Prof Essand agrees contentedly.

Cheap to produce, the virus is exquisitely precise, with only mild, flu-like side-effects in humans. Photographs in research reports show tumours in test mice melting away.

'It is amazing,' Prof Essand gleams in wonder. 'It's better than anything else. Tumour cell lines that are resistant to every other drug, it kills them in these animals.'

Yet as things stand, Ad5[CgA-E1A-miR122]PTD – to give it the full gush of its most up-to-date scientific name – is never going to be tested to see if it might also save humans. Since 2010 it has been kept in a bedsit-sized mini freezer in a busy lobby outside Prof Essand's office, gathering frost. ('Would you like to see?' He raises his laptop computer and turns, so its camera picks out a table-top Electrolux next to the lab's main corridor.)

Two hundred metres away is the Uppsala University Hospital, a European Centre of Excellence in Neuroendocrine Tumours. Patients fly in from all over the world to be seen here, especially from America, where treatment for certain types of cancer lags five years behind Europe. Yet even when these sufferers have nothing else to hope for, have only months left to live, wave platinum credit cards and are prepared to sign papers agreeing to try anything, to hell with the side-effects, the oncologists are not permitted – would find themselves behind bars if they tried – to race down the corridors and snatch the solution out of Prof Essand's freezer.

I found out about Prof Magnus Essand by stalking him. Two and a half years ago the friend who edits all my work – the biographer and genius transformer of rotten sentences and misdirected ideas, Dido Davies – was diagnosed with neuroendocrine tumours, the exact type of cancer that Steve Jobs had. Every three weeks she would emerge from the hospital after eight hours of chemotherapy infusion, as pale as ice but nevertheless chortling and optimistic, whereas I (having spent the day battling Dido's brutal edits to my work, among drip tubes) would stumble back home, crack open whisky and cigarettes, and slump by the computer. Although chemotherapy shrank the tumour, it did not cure it. There had to be something better.

It was on one of those evenings that I came across a blog about a quack in Mexico who had an idea about using sub-molecular particles – nanotechnology. Quacks provide a very useful service to medical tyros such as myself, because they read all the best journals the day they appear and by the end of the week have turned the results into potions and tinctures. It's like Tommy Lee Jones in Men in Black reading the National Enquirer to find out what aliens are up to, because that's the only paper trashy enough to print the truth. Keep an eye on what the quacks are saying, and you have an idea of what might be promising at the Wild West frontier of medicine. This particular quack was in prison awaiting trial for the manslaughter (by quackery) of one of his patients, but his nanotechnology website led, via a chain of links, to a YouTube lecture about an astounding new therapy for neuroendocrine cancer based on pig microbes, which is currently being put through a variety of clinical trials in America.

I stopped the video and took a snapshot of the poster behind the lecturer's podium listing useful research company addresses; on the website of one of these organisations was a reference to a scholarly article that, when I checked through the footnotes, led, via a doctoral thesis, to a Skype address – which I dialled.

'Hey! Hey!' Prof Magnus Essand answered.

To geneticists, the science makes perfect sense. It is a fact of human biology that healthy cells are programmed to die when they become infected by a virus, because this prevents the virus spreading to other parts of the body. But a cancerous cell is immortal; through its mutations it has somehow managed to turn off the bits of its genetic programme that enforce cell suicide. This means that, if a suitable virus infects a cancer cell, it could continue to replicate inside it uncontrollably, and causes the cell to 'lyse' – or, in non-technical language, tear apart. The progeny viruses then spread to cancer cells nearby and repeat the process. A virus becomes, in effect, a cancer of cancer. In Prof Essand's laboratory studies his virus surges through the bloodstreams of test animals, rupturing cancerous cells with Viking rapacity.

The Uppsala virus isn't unique. Since the 1880s, doctors have known that viral infections can cause dramatic reductions in tumours. In 1890 an Italian clinician discovered that prostitutes with cervical cancer went into remission when they were vaccinated against rabies, and for several years he wandered the Tuscan countryside injecting women with dog saliva. In another, 20th-century, case, a 14-year-old boy with lymphatic leukaemia caught chickenpox: within a few days his grotesquely enlarged liver and spleen had returned to ordinary size; his explosive white blood cell count had shrunk nearly 50-fold, back to normal.

But it wasn't until the 1990s, and the boom in understanding of genetics, that scientists finally learnt how to harness and enhance this effect. Two decades later, the first results are starting to be discussed in cancer journals.

So why is Magnus – did he mind if I called him 'Magnus'? – about to stop his work?

A reticent, gently doleful-looking man, he has a Swedish chirrup that makes him sound jolly whatever his actual mood. On the web, the first links to him proclaim the Essand Band, his rock group. 'Money,' he said. 'Lack of.'

'Lack of how much money? Give me a figure,' I pressed. 'What sort of price are we talking about to get this virus out of your freezer and give these people a chance of life?'

Magnus has light brown hair that, like his voice, refuses to cooperate. No matter how much he ruffles it, it looks politely combed. He wriggled his fingers through it now, raised his eyes and squinted in calculation, then looked back into his laptop camera. 'About a million pounds?'

More people have full-blown neuroendocrine tumours (known as NETs or carcinoids) than stomach, pancreas, oesophagus or liver cancer. And the incidence is growing: there has been a five-fold increase in the number of people diagnosed in the last 30 years.

In medical school, students are taught 'when you hear hoof beats, think horses not zebras' – don't diagnose a rare disease when there's a more prob-able explanation. It leads to frequent misdiagnoses: until the death of Steve Jobs, NETs were considered the zebras of cancer, and dismissed as irritable bowel syndrome, flu or the patient getting in a tizz. But doctors are now realising that NETs are much more prevalent than previously thought. In a recent set of post-mortem investigations, scientists cut open more than 30,000 bodies, and ran their hands down the intestines of the dead as if they were squeezing out sausage skins. One in every 100 of them had the distinctive gritty bumps of NETs. That's two people in every rush-hour tube carriage on your way home from work, or scaled up, 700,000 people in Britain, or roughly twice the population of the city of Manchester. The majority of these tumours are benign; but a small percentage of them, for reasons that no one understands, burst into malignancy.

Many other cancers, if they spread, acquire certain features of neuroendocrine tumours. The first person to own a successful anti-neuroendocrine cancer drug – it doesn't even have to cure the disease, just slow its progress as anti-retrovirals have done with Aids – will be not only healthy but also Steve Jobs-rich. Last year the pharmaceuticals giant Amgen bought a cancer-assassinating version of the herpes virus for $1 billion. That Magnus's virus could be held up by a minuscule £1 million dumbfounded me.

'That's a banker's bonus,' I said. 'Less than a rock star's gold toilet seat. It's the best bargain going. If I found someone to give you this money, would you start the clinical trials?'

'Of course,' replied Magnus. 'Shall I ask the Swedish Cancer Board how soon we can begin?'

I do not have a million pounds. But for £68 I flew to Uppsala. I wanted to pester Prof Essand about his work, face to face, and see this virus, face to petri dish. I wanted to slip some into my mittens, smuggle it back to England in an ice pack and jab it into Dido.

Magnus's work is already funded by the Swedish Cancer Society and the Swedish Children Cancer Society (neuroblastoma, the most common cancer in infants, is a type of neuroendocrine tumour). A virus that he previously developed (against prostate cancer) is about to enter human trials in Rotterdam, supported by a European Union grant.

The difficulty with Magnus's virus is not that it is outré, but that it is not outré enough. It is a modified version of an adenovirus, which is known to be safe in humans. It originates from humans, occurring naturally in the adenoids. The disadvantage is that it is too safe: the immune system has had thousands of years to learn how to dispatch such viruses the moment they stray out of the adenoids. It is not the fact that Magnus is using a virus to deal with cancer that makes his investigation potentially so valuable, but the novel way he has devised to get round this problem of instant elimination by the immune system, and enable the virus to spread through tumours in other parts of the body.

The closer you get to manipulating the cellular forces of human existence, the more you sound like a schoolboy babbling about his model aeroplane. Everything in the modern genetics lab is done with kits. There are no fizzing computer lights or fractionating columns dribbling out coagulations of genetic soup in Magnus's lab; not a single Bunsen burner. Each narrow laboratory room has pale, uncluttered melamine worktops running down both sides, wall units above and small blue cardboard cartons dotted everywhere. Even in their genetics labs, Swedes enjoy an air of flatpack-ness. The most advanced medical lab in the world, and it looks like a half-fitted kitchen.

To make and test their virus, Magnus buys cell lines pre-fab (including 'human foreskin fibro-blast') for $50-100 from a company in California; DNA and 'enzyme mix' arrive in $179 packets from Indiana; protein concentrations are tested 'according to the manufacturer's instructions' with a DIY kit ($117) from Illinois; and for $79, a parcel from Santa Cruz contains (I haven't made this up) 'horseradish peroxidase conjugated donkey anti-goat antibody'.

In a room next to Magnus's office, a chatty woman with a ponytail is putting DNA inside bacteria. This God-like operation of primal delicacy involves taking a test tube with a yellow top from a $146 Qiagen kit, squirting in a bit of liquid with a pipette and putting the result in a box similar to a microwave: 'turn the dial to 25 kilovolts and oophlah! The bacteria, they get scared, they let the DNA in. All done,' the woman says. As the bacteria divide, the desirable viral fragments increase.

What costs the £1 million (less than two per cent of the price of Francis Bacon's Triptych 1976) that Magnus needs to bring this medicine to patients is not the production, but the health-and-safety paperwork to get the trials started. Trials come in three phases. What Magnus was suggesting for his trifling £1 million (two Mont Blanc diamond-encrusted pens) was not just a phase I trial, but also a phase II, which, all being well, would bring the virus right to the point where a big pharmaceuticals company would pay 10 or 100 times as much to take it over and organise the phase III trial required by law to presage full-scale drug development.

'So, if Calvin Klein or Elton John or… Paris Hilton stumped up a million, could they have the virus named after them?'

'Why not?' Magnus nodded, showing me the bacteria incubator, which looks like an industrial clothes washer, only less complicated. 'We can make an even better one for two million.'

There are reasons to be cautious. A recent investigation by Amgen found that 47 of 53 papers (on all medical subjects, not just viruses) by academics in top peer-reviewed science journals contained results that couldn't be reproduced, even though company scientists repeated the experiments up to 50 times. 'That's why we have to have such a careful peer-review process,' Dr Tim Meyer, Dido's energetic, soft-spoken oncologist, warns. 'Everybody thinks that their new treatment for cancer is worth funding, but everybody is also keen that only good-quality research is funded.' Similar to Prof Essand in youth but less polite of hair, Dr Meyer is the co-director of the Experimental Cancer Medicine Centre at University College London. Beside his office, banks of white-coated researchers are bent over desks, busy with pipettes and microscopes. His team pursues an exciting brew of new anti-cancer ideas: antibody-targeted therapy, vascular therapy, DNA binding agents and photodynamic therapy. Each of these shows remarkable promise. But even for such a brilliant and innovative team as this, money is not flowing.

Everyone in cancer science is fighting for ever-decreasing small pools of cash, especially now the government has started tiptoeing into charities at night and rifling the collection boxes. It is big news that Dr Meyer and the UCL team won a grant of £2.5 million, spread out over the next five years, to continue his institute's cutting-edge investigations into cancers that kill off thousands of us every week: leukaemia; melanoma; gynaecological, gastrointestinal and prostate cancers. Without this money, he would have had to sack 13 members of staff. The sum of £2.5 million is roughly what Madonna earns in 10 days.

He peers at Magnus's pairs of photographs of splayed rodents with glowing tumours in one shot that have vanished in the next. He knows the Uppsala neuroendocrine team well and has great respect for them. 'It may be good,' he agrees. But until Magnus's findings are tested in a clinical trial, nobody knows how good the work is. Astonishing results in animals are often disappointing in humans. 'We all need to be subject to the same rules of competitive grant funding and peer review in order to use scarce resources in the most effective manner.'

Back at home with whisky and fags, I nursed my entrepreneurialism. There are currently about half a dozen cancer research institutes in Europe developing adenoviruses to treat cancer – all of them pathetically short of cash. Enter the Vanity Virus Initiative. Pop a couple of million over to Uppsala University, and you will go down in medical books as the kind heart who relieved Ad5[CgA-E1A-miR122]PTD of its hideous hump of a moniker, and gave it the glamour of your own name. What's the worst that can happen? Even if Magnus's innovations don't work in clinical trials the negative results will be invaluable for the next generation of viruses. For the rest of time, your name will pop up in the reference sections of medical papers as the (insert your name here) virus that enabled researchers to find the cure for cancer by avoiding Magnus's error.

On my third glass of whisky, I wrote an email to Dr Meyer suggesting that he issue a shopping list each year at the time that bankers receive their bonuses, which could be circulated in the City. The list would itemise the therapies that his Experimental Cancer Medicine Centre have selected for support, and quantify how much would be needed in each case to cover all outstanding funds and ensure that the work is branded with your name.

The corridors connecting the different research departments of the Uppsala medical campus are built underground, in order to protect the staff from death during the Swedish winters. Professors and lab technicians zip back and forth along these enormous rectangular tunnels on scooters, occasionally scratching their heads at the tangled intersections where three or four passageways meet at once, then pushing off again, gowns flying, one leg pounding the concrete floor like a piston, until they find the right door, drop the scooter and rise back upstairs by lift. Suspended from the ceiling of these corridors is a vacuum tube that schluuuuups up tissue samples at top speed, and delivers them to the appropriate investigative team. Magnus led me along these tunnels to the Uppsala University Hospital, to visit the chief oncologist, Kjell (pronounced 'Shell') Oberg – the man who will run the trial once the money is in place.

'The trouble with Magnus's virus is Magnus is Swedish,' he says, wincing and clutching the air with frustration.

'It is so,' Magnus agrees sorrowfully. Swedishly uninterested in profiteering, devoted only to the purity of science, Magnus and his co-workers on this virus have already published the details of their experiments in leading journals around the world, which means that the modified virus as it stands can no longer be patented. And without a patent to make the virus commercial, no one will invest. Even if I could raise the £2 million (I want only the best version) to get the therapy to the end of phase II trials, no organisation is going to step forward to run the phase III trial that is necessary to make the therapy public.

'Is that because pharmaceuticals companies are run by ruthless plutocrats who tuck into roast baby with cranberry sauce for lunch and laugh at the sick?' I ask sneerily.

'It is because,' Kjell corrects me, 'only if there's a big profit can such companies ensure that everyone involved earns enough to pay their mortgage.'

There is no ready source of public funds, either. For reasons understood only by Wotan and Thor, the Swedish government refuses to finance clinical trials in humans, even when the results could potentially slash the country's health bill by billions of kronor.

All is not lost, however. Kjell does not have to wait until the end of the trials – which could take as much as 10 years – for the full, three-phase process before being able to inject Magnus's virus into his patients, because as soon as the test samples are approved and ready for use, he can by European law start offering the medicine, on an individual basis, to patients who sign a waiver confirming that they're prepared to risk experimental treatments. Within 18 months he could be starting his human case-studies.

At several moments during my research into this cancer-delaying virus from the forests of Scandinavia I have felt as though there were someone schlocky from Hollywood operating behind the scenes. The serendipitous discovery of it on the internet; the appalling frustration of being able to see the new therapy, to stand with my hand against the freezer door knowing that it is three inches away, not well-guarded, and that it might work even in its crude current state, but that I may not use it; the thrill of Kjell Oberg's powerful
support; the despair over the lack of such a silly, artificial thing as a patent. Now, Dr Leja steps into the narrative: she is the virologist whose brilliant doctoral thesis first put me on to the cancer-eating-virus-left-in-a-freezer, and whose name heads all the subsequent breakthrough research papers about this therapy. She turns out to be 29, to look like Scarlett Johansson and to wear voluptuous red lipstick.

Justyna Leja slinks up from her chair, shakes my hand and immediately sets off into a baffling technical discussion with Magnus about a good way to get the patent back for the virus, by a subtle manipulation that involves something called a 'new backbone'. She also has in mind a small extra tweak to the new-backboned microbe's outer coat, which will mean that the virus not only bursts the cancer cells it infects, but also provokes the immune system to attack tumours directly. It will be easy to see if it works in animals – but is it worth lumbering the current virus with it for use in humans, who tend to be less responsive? The extra preparatory work could delay the phase I and II trials for a further year.

Back at his lab, Magnus opened up the infamous freezer. I took a step towards the plastic flasks of virus: he nipped the door shut with an appreciative smile.

'What would you do,' I asked bitterly, returning my hand to my pocket, 'if it were your wife who had the disease, or one of your sons whose photograph I saw on your desk?'

He glanced back at the freezer. Although his lab samples are not made to pharmaceutical grade, they would be only marginally less trustworthy than a fully-sanctioned, health-and-safety certified product that is between 1,000 and 10,000 times more expensive.

'I don't know,' he groaned, tugging his hair in despair at the thought. 'I don't know.'

To donate money to Professor Magnus Essand's research on viral treatments for neuroendocrine cancer, send contributions to Uppsala University, The Oncolytic Virus Fund, Box 256, SE-751 05 Uppsala, Sweden, or visit www.uu.se/en/support/oncolytic. Contributions will be acknowledged in scientific publications and in association with the clinical trial. A donation of £1 million will ensure the virus is named in your honour

Bron: telegraph.co.uk

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