Immunotherapy: hype or hope?

It seems to make sense: don’t blast the symptoms of diseases with powerful drugs; instead, encourage the body’s own immune system to attack the problem.

That’s the theory behind medicine’s great new hope, immunotherapy, which has been predicted to be the future of cancer treatment – and of drug-company profits.

Early results from clinical trials have been off the charts, and share prices of the drug companies developing the new therapies have skyrocketed, with the big pharmaceuticals circling for a takeover feeding frenzy.

But it’s all been going terribly wrong of late. One of the pioneers, Juno Therapeutics, a biotech company in Seattle, has revealed that five of 20 patients with end-stage leukaemia, who were being treated with its immunotherapy cancer treatment CAR-T, have died. The five developed cerebral oedema, when fluids accumulate in the brain, and at least three of the victims were younger than 25.

America’s drugs regulator, the Food and Drug Administration (FDA), put the trial on hold and stopped Juno recruiting new participants. Juno’s stock price fell by 30 per cent when the FDA intervened, while the shares of one of its immunotherapy rivals, Kite Pharma, dropped by 14 per cent.

But despite the deaths, the share prices of both companies quickly bounced back, helped by the FDA’s decision to lift its ban after accepting assurances from Juno executives that the trial would be safer going forward.

Juno blamed the deaths on the chemotherapy drug fludarabine, which was being used to ‘condition’ the immune system before the patients’ own T cells were reintroduced into their bloodstream, having first been genetically modified to fight cancer cells.

Their protestations would have carried more weight had it not been for the deaths of two other patients in 2014 while taking part in a trial called ROCKET. They both died because of immune reactions to T cells and, on that occasion, the chemo drug wasn’t blamed.

Autoimmune alert

The US National Cancer Institute says that fatal allergic reactions to immunotherapy are rare, but researchers at the UT Southwestern Medical Center in Dallas, Texas, reckon these reactions might be common in patients who already have autoimmune conditions, such as rheumatoid arthritis, psoriasis and polymyalgia. More than half these patients could suffer severe and irreversible toxic reactions affecting many organs.

The researchers also reckon that up to 25 per cent of lung-cancer patients have an autoimmune disorder, making it far too dangerous for them to start immunotherapy treatment. The high rate could be due to the average age of lung-cancer sufferers and also because many of them are or have been smokers, the researchers say.

One of the researchers, Dr David Gerber, said their findings – based on data from 210,509 lung-cancer sufferers aged 65 and older – overturn the belief that immunotherapy is safe for people with an autoimmune disease. “While prior research has suggested that administering immune therapy to patients with autoimmune disease may be feasible, doing so carries the risk of making their disease worse, and requires careful monitoring.”1

It’s thought that up to 50 million Americans have some kind of autoimmune condition – in all, there are 80 different types – making them ineligible for immunotherapy. It’s also more prevalent in people with cancer, say researchers from the Roswell Park Cancer Institute, who have estimated that people with autoimmune disorders are 42 per cent more likely to also have cancer.

And now the good news

But these reports are unlikely to put a brake on a therapy that has won the American Society of Clinical Oncology (ASCO) Advance of the Year award for 2016. “There is now evidence that immunotherapy works against a range of cancers. Even for patients who have exhausted all traditional treatments, immunotherapy is able to halt cancer growth, often with only mild effects”, the accolade reads.

And the evidence does appear to be there – and very impressively it reads too.

• Immunotherapy might improve survival from pancreatic cancer, one of the more lethal forms of cancer, by as much as 75 per cent, say researchers at the Fred Hutchinson Cancer Research Center. Their estimates are based on studies of laboratory mice given modified T cells, which killed the cancer cells.2

• The immunotherapy drug nivolumab could be a “game-changer” for people with lung cancer not responding to conventional treatment. In a trial by researchers at UT Southwestern Medical Center, 292 lung-cancer patients were given nivolumab and 290 were given a chemotherapy drug. The one-year survival rate among the immunotherapy patients was 51 per cent vs 39 per cent in the chemo group.3

• Nivolumab could also improve survival from head and neck cancers. Patients taking the immunotherapy drug were more than twice as likely to still be alive a year later compared with patients receiving conventional treatment. In a trial by researchers at Ohio State University Comprehensive Cancer Center, 240 patients with head and neck cancer were given nivolumab and 121 others got a chemo drug. After a year, 36 per cent of the nivolumab group were still alive compared with 17 per cent of those on chemotherapy.4

• Twenty-seven of 29 leukaemia patients went into remission after they were given the CAR-T immunotherapy treatment, which consists of T cells modified to express chimeric antigen receptors (CAR) that identify and kill neoplasms (cancer) on B cells (immune cells that produce antibodies).5

• Immunotherapy is more effective than chemotherapy for treating patients with advanced lung cancer, say researchers at the University of California at Los Angeles (UCLA). They gave the immunotherapy drug pembrolizumab to 691 cancer patients, while another 343 patients were given a chemo drug. Those receiving the immunotherapy lived longer and also reported fewer treatment-related adverse effects, the researchers said.6

Nevertheless, leading cancer specialist Dr Karol Sikora warns against getting too carried away by the good news. He points to one study, presented at the 2015 ASCO meeting, which concluded that “terminally ill cancer patients have been ‘effectively cured’ by a game-changing new class of drugs [immunotherapy]”.

Immunotherapy could quickly become the new standard treatment for cancer, saving many tens of thousands of lives each year, the researchers say. Excited by the findings, Dr Roy Herbst, chief of medical oncology at Yale Cancer Center, said: “I think it’s huge. I think we are seeing a paradigm shift in the way oncology is being treated.”

But digging deeper and getting past the hype, it seems that patients – far from being cured – in fact only lived a further three months compared with those given chemotherapy. It’s also worth noting that the above study using pembrolizumab was sponsored by Merck, which happens to make the drug.

While such overhype is understandable for a genuine breakthrough in cancer treatment, it’s also fuelled by money, and the arena is often the annual ASCO meeting. Sikora describes it as “a sophisticated conspiracy to hype products being sold to bigger companies by small start-ups, to get more investment for the industry from the City or Wall Street, or simply to ramp up share prices and make short-term gains.”7

Immunotherapy may be conventional medicine’s best hope for combatting cancer, but longer-term trials need to be carried out before its true effectiveness can be known – and it’s certainly not for everybody.

What is immunotherapy?

Immunotherapy, or biological therapy, is a new type of medicine that boosts the body’s own natural defences to fight diseases. Although much of the
pioneering work has centred on cancer, it has also been tested on neurological problems like schizophrenia and Alzheimer’s disease.

Immunotherapy is an umbrella term covering five different approaches:

Monoclonal antibodies. Our immune system naturally produces proteins – called ‘antibodies’ – that fight infection. Monoclonal antibodies are produced in a laboratory and mimic the body’s own natural defences. They can be used as targeted therapy to block abnormal proteins in cancer cells or to ‘flag’ cancer cells to help the immune system ‘see’ and destroy them. Drugs like ipilimumab, nivolumab and pembrolizumab are all monoclonal antibodies.

Non-specific immunotherapies. These often augment chemo-/radiotherapy, but may also be used as the primary cancer-fighter. These therapies include interferon, a protein made in the laboratory, and interleukins, both of which boost the immune system by making more cancer-fighting cells.

Oncolytic virus therapy. This harnesses genetically modified viruses to kill cancer cells. The first oncolytic virus to treat melanoma, or skin cancer, was approved by the US FDA in 2015.

T-cell therapy. This takes T cells from the patient’s blood and then adds receptor (chemical-signalling) proteins to T cells to help them recognize cancer cells, before the modified cells are put back into the bloodstream. This is known as ‘chimeric antigen receptor T-cell therapy’, or CAR-T.

Cancer vaccines. These vaccines introduce antigens – which are released when
the cells die – into the body to help the immune system identify cancer cells and
kill them.

What are the risks?

Immunotherapy is far from risk-free. People with an autoimmune disorder like rheumatoid arthritis or psoriasis shouldn’t even begin such treatment.

Researchers have also reported an alarmingly high rate of deaths in early trials, sometimes as high as 25 per cent of all participants (see the
main story).

It’s not known if all the victims had autoimmune conditions, although they are commonly seen among cancer patients.

More common side-effects of immunotherapy include sensations of sickness and nausea so severe that people have had to stop the treatment, as well as fatigue, fever, chills, flu-like symptoms and pain, especially at the site of the immunotherapy injections.

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