Is immunotherapy a cancer game changer?

Ron Walker has never been one to shy from a challenge. But at 72, the former lord mayor of Melbourne was thrown a curveball. A pea-sized lump on his forehead turned out to be a melanoma.

Once removed, and with the lymph nodes showing all clear, his surgeon was optimistic. Within a year tumours blossomed in his lungs, bones and brain.

Walker was given a few months to live. In a last-ditch attempt, he travelled to Los Angeles to enrol in a trial of a new drug, Keytruda. Every three weeks, Walker watched drug-laced fluid drain from the drip into his arm. After just four treatments, his tumours began shrinking. A year and a half later, his cancer was nowhere to be seen.

Similar stories of survival against the odds are found across the globe, given prominence by celebrity recipients such as former US President Jimmy Carter, who used the drug to great effect in his fight against melanoma.

Keytruda and similar drugs are heralded as game-changers in the cancer community. “It’s absolutely profoundly changed the way we think about cancer treatment,” says Grant McArthur, Walker’s oncologist at the Peter MacCallum Cancer Centre in Melbourne.

Unlike most cancer treatments, these new drugs do not kill cancer cells. Rather, they unleash the formidable forces of the immune system. The approach is dubbed “cancer immunotherapy”. Science magazine, normally conservative with its calls, crowned it the 2013 breakthrough of the year. Pharmaceutical companies are spending billions on the new drugs, some already approved and others being fast-tracked through the regulatory pipeline.

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Ron Walker lobbied for Keytruda to be approved by the government after he had success with it.
Credit: Michael Clayton-Jones / Fairfax

So is it time to sound the victory call in the war on cancer?

Well, no.

Victories like those of Walker or Carter are still exceptions. About 40% of melanoma patients show little response to Keytruda. And for other types of cancer, the figures are worse. These are deflating statistics for desperate patients and their battle-weary oncologists. “What we’ve seen so far are the stand-outs – the cancers which are clearly very, very sensitive to immunotherapy,” says Hui Gan, a brain cancer specialist at the Joint Austin Ludwig Oncology Unit in Melbourne. Why, then, is cancer immunotherapy exalted as a breakthrough?

Because the war on cancer, first declared by US president Nixon in 1970, has been fought long and hard. Until now the dominant strategy has been slash, burn and poison – surgery, radiation and chemotherapy. This scorched-earth approach destroys tumours but also causes a lot of collateral damage. And the tumour often returns. By contrast, the immune system is a smart army, designed by nature to identify and destroy only enemy cells, and to keep on destroying them.

What researchers now have in their sights is commanding this army, with its numerous divisions, communications systems and sophisticated weaponry. That’s why, even with the treatment’s limitations, hopes are so high.

“People use words like ‘game-changer’ – well it is a game-changer,” says Jonathan Cebon, medical director of Melbourne’s Olivia Newton-John Cancer Research Institute. “A lot of incurable cancers are now coming under control, often long‑term. It’s something that we’ve never seen before in the history of oncology.”

Not so long ago, medical wisdom held that the immune system could not be marshalled against cancer. It’s an army exquisitely trained to recognise foreigners like bacteria or viruses. It is also well-trained not to attack our own cells. And cancer cells are our own cells.

Yet there have long been hints that the immune system might be recruited to the cause.

In 1890 an astute young American surgeon by the name of William Coley noticed that in some patients, cancers melted away after a severe bacterial infection. He tried to replicate the effect by injecting patients with a bacterial brew known as Coley’s toxins. Despite some success the technique did not take hold, largely because there was no clear understanding of what the toxins were doing. Were they especially deadly to cancer cells or did they work some other way?

In more recent times, hints came from cancer patients who’d received bone marrow transplants. Bone marrow is one of those tissues that suffers huge collateral damage after cancer therapy. Cancer patients can’t survive long without the constant stream of fresh red and white blood cells that the transplanted bone marrow provides. But occasionally the transplant itself was deadly, turning on the patient’s tissues, a scenario known as graft-versus-host disease. To avoid it, doctors removed the most aggressive of the foreign bone marrow cells, white blood cells known as T-cells. They successfully reduced the risk of graft-versus-host disease; they also reduced the efficacy of the cancer treatment. It seems the foreign T-cells were obliterating the cancer cells.

Another major clue came from the AIDS epidemic. Patients’ immune systems were obliterated by the HIV virus. One of the first symptoms of their disease was tumours. And in some cancer patients, there was a compelling but perplexing finding: their tumours were often infiltrated with T-cells –evidence that the immune system had answered the call to battle. But clearly that wasn’t enough.

Throughout the 1980s researchers tried to boost the immune system in the time-honoured fashion – by developing a vaccine. For instance, the measles vaccine is made by taking a fragment of the virus, an “antigen”, and mixing it with an irritating chemical called an “adjuvant”. The adjuvant recruits the immune forces, which are trained to recognise the antigen – rather like teaching troops to recognise the stripes on an enemy uniform. These troops stand ready and waiting to nip any future incursion of the measles virus in the bud.

Thierry Boon and colleagues at the Brussels branch of the Ludwig Institute for Cancer Research took a similar approach to train an immune army against melanoma. They used a protein unique to melanoma cells as the antigen in a vaccine to boost immunity against the cancer.

“Overall the results were disappointing,” recalls Cebon, who devoted over 20 years of his career to pursuing a melanoma vaccine. The dismal story was repeated over and over for vaccines against different cancers. In the war against cancer, it was not a proud moment for the immunology brigade.

But some researchers were not ready to give up. They turned their attention to where there had been a flicker of promise: those T-cells found camped inside tumours. These T-cells had clearly recognised the enemy, yet failed to vanquish it. Were they just outnumbered? Steven Rosenberg, a surgeon at the US National Cancer Institute near Washington DC, decided to send in reinforcements.

From the tumours he had removed from his patients, he extracted T-cells and stimulated their growth with a natural booster called IL-2. The cells multiplied into an army of billions of tumour-recognizing T-cells, which Rosenberg returned to his patients. The technique, termed “adoptive cell therapy”, worked. In a 2011 trial of patients with advanced melanoma, more than half of the participants saw their tumours shrink; 40% underwent complete remission and some remained cancer-free for more than four years.

Meanwhile another group of researchers took a different tack. Harking back to the T-cells camped around the tumours, it seems there was more to their wimpiness than simply being outnumbered. T-cells are formidable killers that specialise in destroying cells infected by viruses. Once the viral infection is contained, it’s crucial to deactivate them lest they fire on innocent cells. So T-cells come with molecular muzzles to keep them in check. (In the jargon they are known as “checkpoints”.) Those muzzles have to be locked into place. Usually that’s the job of regulatory cells that act like military police. Astoundingly, cancer cells – consummate survivors that they are – have also learnt how to lock down the muzzles.

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How checkpoint inhibitor drugs work (press to zoom).

In 1997, immunologist James Allison, now at the University of Texas MD Anderson Cancer Centre, identified the first of these muzzles, called CTLA-4. Working in mice, he experimented with drugs that unmuzzled CTLA-4. “All we’d have to do was just give one, maybe two injections and the tumours would disappear,” he says. Another muzzle goes by the name of PD-1.

Certain contingents of the immune system possessed keys capable of locking down the muzzles on the T-cells. For instance, one of the keys for muzzling T-cells is known as PD-L1. Lieping Chen, now at Yale University, discovered some tumours possessed this same key. In other words, a tumour can direct T-cells to lay down their arms. Cracking these communication codes offered a whole new strategy for unleashing the immune system. Drugs (engineered antibodies) could be designed to interfere with the muzzling of T-cells by clogging up the CTLA-4 and PD-1 locks or the PD-L1 key.

Yervoy, the first drug to unmuzzle CTLA-4, yielded striking results in advanced melanoma patients. Some 11% of patients who received the drug saw some tumour shrinkage compared to 1.5% in the group who received a different treatment.

But the real excitement was the long survival tail. With previous melanoma treatments, the number of long-term survivors would drop to 5-10% of those treated. With Yervoy, 20% of patients shifted into the tail. Some of the first trial participants are alive today, 14 years after treatment.

Unlocking the PD-1 muzzle has produced even more impressive results. The miracle drug Keytruda, acts this way. In one head-to-head comparison published in the New England Journal of Medicine last year, 74% of melanoma patients on Keytruda were still alive after a year, compared with 58% on Yervoy. (Without immunotherapies, as few as 25% survive this long.) A small trial of Opdivo (another drug that unlocks PD-1) in patients with relapsed Hodgkin’s lymphoma saw a stunning 87% response rate.

Keytruda may have the edge over Yervoy because it strikes a better balance between unleashing killer cells while minimising collateral damage.

Drugs that block PD-L1, the key carried by tumour cells, are also being developed. Small trials suggest they are about as effective as those that unmuzzle PD-1 with similar rates of side effects.

Keytruda and Opdivo were initially approved in the US in 2014 to treat advanced melanoma, but in 2015, both drugs were approved for use in advanced non-small cell lung cancer and kidney cancer, where the response rates are about 25%.

Approvals are also in the pipeline for head and neck cancer, bladder cancer, and Merkel cell carcinoma, says Thomas Gajewski, a cancer immunologist at the University of Chicago who has pioneered immunotherapy trials. Small trials of 20-40 patients are also showing responses with gastric cancer, triple negative breast cancer, ovarian cancer, oesophageal cancer, mesothelioma and bladder cancer. “It’s not just a melanoma story,” says Cebon. “And it’s not just a matter of a couple of extra months. Some patients get complete remissions which last for years.”

Nevertheless, while some patients see their cancers melt away, others have tumours that stubbornly persist, meaning most trials show only a modest few months of life extension on average. And for the common types of breast and colon cancer, responses are rare, says Cebon. So can these resistant cancers be tackled by the immune system?

Yes, believes Gajewski. He points out that T-cells are straitjacketed through multiple locks. The hope lies in steadily identifying them, and unpicking them. For instance a recent advance came from identifying another muzzle called IDO. A trial where both PD-1 and IDO were unmuzzled, saw the response rate to melanoma climb over 50%. “These developments are occurring at breathtaking speed compared to the sloth-like pace of typical oncology drug development,” says Gajewski.

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While one group of researchers was busy learning how to unleash T-cells, another was trying to develop an immune special ops force. If the search and destroy capability of T-cells is limited, why not give them tailor‑made guidance systems and sustained blast power? When Michel Sadelain at the Memorial Sloan Kettering Cancer Centre in New York mooted the concept in the 1980s, he says, “It was perceived as … science fiction”.But it’s an idea whose time has come.

The guidance on a T-cell comes from a T-cell receptor, which can be genetically engineered to recognise antigens on the surface of specific types of cancer cells. Alternatively, a completely artificial receptor known as a chimeric antigen receptor (CAR) can be engineered. The destructive power of these receptors can also be enhanced by adding modules that ensure T-cells stay switched on. To deliver these engineered receptors into T-cells, the cells are removed from a patient and infected with a virus that carries the receptor DNA. The engineered T-cells are called CAR T-cells.

Between 2011 and 2013, promising results in a handful of leukaemia patients silenced the sceptics. In most cases, the leukaemia melted away after a single infusion of the engineered cells, followed by complete remission in just three weeks. “There’s no doubt that when these cells go into the body, they mean business,” says Sadelain, who refers to them as “living drugs”.

The great promise of these cells is that they can be engineered to attack cancers that normally fly under the radar of the immune system. Clinical trials of T-cells engineered to attack brain, breast, liver, ovarian, pancreatic and ovarian cancers are already underway.

But there’s a rub. If any non-cancerous tissue contains the same antigens recognised by the modified T-cells, it too will be marked for destruction. Finding targets specific to each cancer is key. But sometimes researchers have been fooled. In a tragic 2011 case of a 39 year old woman with colon cancer, CAR T-cells were targeted at an antigen – ERBB2 – known to be abundant on the surface of colon cancer cells. But it also turned out to be present at low levels in her lung tissue. Within 15 minutes of being infused with the suped-up cells, she went into severe respiratory distress and died five days later. Clinicians are now on high alert to an immune system going haywire, and can usually keep things under control using corticosteroids and other drugs.

The other challenge in using CAR T-cells is to make the technology accessible on a large scale, given that each patient needs their own batch of T-cells engineered, a process that takes several weeks. Companies are rising to both challenges. Immunocore in Abingdon, UK, is using gene databases to screen cancer targets to ensure they do not appear in vital tissues. Sadelain believes robotics could speed up the engineering of patients’ T-cells and co-founded a biotech start-up, Juno Therapeutics, to commercialise CAR therapies. In an illustration of the frenzy that surrounds this field, Juno went public in 2014 and within a month was valued at a record US$4.7 billion.

In Australia, Alan Trounson, former president of the California Institute of Regenerative Medicine has founded a cancer immunotherapy start-up, Cartherics Pty Ltd, based at the Monash Health Translation Precinct in Melbourne. Rather than engineering T-cells for individual patients, the company aims to make broadly compatible “off‑the‑shelf” CAR T-cells. The idea is to start with donors whose blood cell types represent about half the population.

As with any war, the winning strategy for immunotherapy will be one that coordinates the different elements of the immune army: the regular fighting forces and special ops, the communication codes, the weaponry. To that end, trials that involve a mind-boggling number of combinations of the old and new are underway. For instance, radiotherapy which rouses the immune system (what we call inflammation) is being combined with cancer vaccines. Other trials are combining Keytruda and Yervoy, or adding in vaccines or battalions of T-cells.

Tailoring the treatment to each patient is crucial, because each cancer, in effect, requires a different type of battle plan. “We are just scratching the surface of what can be achieved,” says Cebon.

Cancer immunotherapy does not yet mean a cure-for-all, but there’s no doubt researchers have begun an entirely new type of war against cancer. And as they master the command of the immune forces, many are confident that a lasting victory may be within reach.

David Bowtell, a geneticist at the Peter McCallum Cancer Centre, sums up the views of many: “The history of cancer medicine has been one of excitement subsequently tempered by reality. We’ve been hampered because what occurs in one cancer doesn’t necessarily apply to the many. However, medicine is also characterised by gaining a ‘beachhead’ and then ‘invading inland’. My money would be on this being a D-Day rather than a Gallipoli experience.” 

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