Gene therapy: A controversial cure

It sounds like something out of a science fiction novel. The body re-engineered to recognise and attack cancer, so that doctors do not have to battle the disease with conventional medicine. But thanks to a revolutionary new treatment, it has become a reality for hundreds of blood cancer patients, many of whom would be dead had they not undergone chimeric antigen receptor cell therapy or Car-T.

But with just months until the first Car-T products were expected to secure regulatory approval in the US and hit the market, the field has been rocked by the deaths of three patients who received the treatment in a clinical trial.

Juno Therapeutics, a Seattle-based biotech group developing several Car-T products, revealed two weeks ago that three patients on one of its trials had died from swelling on the brain related to the toxic side-effects of the therapy. The US Food and Drug Administration temporarily suspended the study, codenamed Rocket, but allowed the company to restart the trial and enrol new participants a few days later.

It is not uncommon for patients to die on cancer trials. The participants tend to be very sick, and such studies provide statistical evidence that a new drug or treatment can keep them alive for longer than the next best option. Yet in Juno’s case, the patients, all of whom were aged under 25, died not from their illness but from the treatment itself — the cure was worse than the disease.

The deaths have rekindled questions about whether Car-T treatments — which are being developed at a quicker pace than traditional drugs — are safe enough to go on sale. They have also drawn attention to efforts to shorten the 10-15-year timeline that it typically takes to bring a medicine to market.

Successive legislative efforts have allowed the FDA to approve drugs on an accelerated basis, especially in cases where patients are terminally ill and running out of options. In these instances, drugmakers are able to start selling treatments that have been tested over a shorter period of time as long as they continue to study the medicines after they go on sale.

“One of the things I’ve always been concerned about with Car-T is the development has happened very fast, and these companies are learning new things on a day-to-day basis,” says Brad Loncar, founder of the Loncar Cancer Immunotherapy exchange-traded fund, which holds shares in Juno. “If you have something that’s going this fast and you’re making tweaks as you go along, then it’s a recipe for something like this to happen.”

Re-engineering cells

When a patient undergoes Car-T therapy, doctors first extract millions of their T-cells, a type of white blood cell, and ship them to a laboratory where they are genetically modified to encourage them to attack cancer. The re-engineered cells are then returned and infused back into the patient in what is an expensive bespoke treatment.

Even in some of the most stubborn blood cancers, such as acute lymphoblastic leukaemia — the illness that patients on Juno’s Rocket trial are suffering from — the results have been dramatic. Without treatment, this form of leukaemia can kill within months. Patients tend to respond to chemotherapy at first but in most cases the cancer returns, and the only way of wiping out the disease is a type of bone marrow transplant — a dangerous, complex procedure that often proves fatal. The cure rate is low at 40 per cent.

Yet on some Car-T trials every patient has gone into remission, and as many as three-quarters were cancer-free a year later. This is an early sign that suggests they could effectively be cured although it will take years to be sure that the disease will not return. Each year, roughly 43,000 patients in the US and Europe are diagnosed with a type of blood cancer that could be treated by Car-T therapy, according to Reni Benjamin, a biotech analyst at Raymond James.

Patients are given a final round of chemotherapy before the genetically modified cells are dripped back into them. This is designed to make them more receptive to the treatment. The chemo wipes out their existing T-cells, allowing the re-engineered ones more space to multiply and attack the cancer.

It is this penultimate stage that Juno believes went wrong and ended up killing the patients. In the spring, the company changed the mixture of chemotherapy drugs it was administering, after a study of one of its other Car-T products suggested that doing so would improve long-term remission rates.

The change involved adding the drug fludarabine to an existing medicine, cyclophosphamide, to create a mixture known as FluCy. Something about the way the cocktail interacted with the Car-T cells caused so much toxicity that the patients experienced a fatal cerebral oedema, Juno believes.

The company told the FDA it wanted to switch back to the original chemotherapy and restart the trial as quickly as possible. Although not known for moving with such speed, the regulator took just three days to reach a decision and allowed the study to continue.

It is not unusual for the FDA to impose a “clinical hold” on a trial following patient deaths, but it is rare for the regulator to lift it so quickly. Last year it suspended trials of a cancer vaccine being developed by Advaxis, even though the company and the scientists conducting the study argued that a fatality had been caused by the illness, not the treatment. In that instance, it took two months for the FDA to allow trials to restart.

The speed took many in the industry by surprise. Jonathan Eckard, an analyst at Barclays, believes that the move reflects the “dire need of the patients”, and says it bodes well for swift approval.

Belén Garijo, head of healthcare at Germany’s Merck, which is also developing Car-T cells, praised the FDA. “[It] shows that the regulators are becoming much more agile,” she says. “I’m extremely encouraged by the evolution of the regulatory environment.”

But others believe that the FDA’s decision to lift the suspension so quickly is another sign that it is allowing the development of Car-T to evolve too quickly. “They are trying to referee a game while the rules are still being written. And it appears to be causing some deaths that should have been avoided,” says one buyside biotech analyst.

Toxicity concerns

Investors initially responded to the news of the deaths by sending Juno’s stock down 30 per cent in a single day, July 8, wiping more than $1bn from the value of the company. There was also concern that the FDA would begin a broader investigation of Car-T therapies, which would have hindered Juno’s main competitors — Novartis, the Swiss drugmaker, and Kite Pharma, another biotech. After learning that the FDA had lifted the suspension, shares in Juno recovered some of their losses.

Despite the FDA’s swift decision, some investors and analysts remain worried that its chemotherapy hypothesis is just that: a hypothesis. They fear that there could be some other reason, as yet unapparent, for the fatal build-up of toxicity. Others wonder whether Juno was right to alter the chemotherapy partway through the trial. “I just don’t know, and I don’t think they really know either,” says Maxim Jacobs, a healthcare analyst at Edison. “I don’t know that you can rush to blame the chemotherapy.

“If this had happened at Genentech back in the day, they would probably have spent two years looking into this — not a week,” he says, referring to the biotech company set up to explore genetic medicine in 1976.

The deaths have served to underline the limited testing of Car-T therapies. Traditional drugs tend to be studied in more than a thousand patients, meaning there is enough time and critical mass for problems to emerge.

Juno started studying Car-T treatments shortly after it was founded in 2013 and has tested them in about 130 patients. Yet it hopes to have the therapy on the market in 2018.

“All of the products are at an early stage and no one knows the rules yet,” says Dr Stephan Grupp, an oncologist at the Children’s Hospital of Philadelphia, who has run Car-T trials for Novartis.

Dr Grupp says the “jury is out” on whether chemotherapy was to blame for the Rocket deaths, but he agrees it was right to quickly restart the trial. “The only way to be sure is to get rid of the fludarabine, take the next 10 patients and see what happens next.”

Hans Bishop, the British chief executive of Juno, describes the experience of the past couple of weeks as “truly humbling”, but insists the company has made the right calls since the deaths.

“While we’ve experienced a setback, the promise of Car-T cells and their potential to be curative is still very real,” he says. “These therapies are potent and we’re still on the learning curve.”

Working out the risks

Some investors and analysts, however, believe it is inappropriate to still be learning while seeking regulatory approval. They argue that the deaths in the Rocket trial are a sign that the field is moving too quickly, and point to another fatality on a separate Juno trial last year as well as deaths in some of the very early studies in academic centres.

“I’m really surprised with how quickly the FDA has let all this go through,” says Mr Jacobs, making a criticism that is rarely levelled at a regulator that has a reputation for being cumbersome. “I feel if this were another treatment that were not so hot and in the news, then they would still be trying to work out the risks.”

The FDA’s haste is perhaps best understood in the context of just how unwell people have to be to qualify for the Rocket trial. Juno is testing the Car-T treatment in the sickest patients, all of whom have failed to respond to other drugs or relapsed. Left untreated, many of them could die within weeks.

Suspending the trial for a longer period would not only have denied future participants the chance to receive a potentially life-saving treatment, but also have delayed the eventual approval, and the point at which ordinary patients can access Car-T.

Assuming that Juno’s hypothesis is correct, and the Rocket trial proceeds without any further fatalities, there are still concerns over whether Car-T treatments will ever be scaleable.

Unlike a drug, which tends to be a one-size-fits-all proposition, Car-T products are bespoke therapies that are tailored to each individual. Every time a new patient is treated, their cells must be extracted, genetically modified and reinserted, at great time and expense. Juno and its rivals have not revealed the cost of the treatment, but some analysts have estimated the price tag will be in excess of $500,000 per patient.

Even if cash-strapped healthcare systems can absorb the cost, a big logistical challenge remains. Transporting cells from a Midwestern US state to a Seattle laboratory capable of re-engineering them is hard enough, let alone doing the same from a far-flung country.

It is perhaps no coincidence that Amazon founder Jeff Bezos, an early backer of the company, is so keen on developing delivery drones.

“How is this going to work in real life if it gets approval,” asks Mr Jacobs. “The cost is going to be outrageously high. In the end, you’ve got to wonder how marketable this is.”

Mr Bishop disagrees. He believes that any commercial and logistical issues will be figured out once the therapy has been approved. “These diseases are truly awful, and while this has been a really difficult time, it does not change our sense of urgency one bit,” he says. “We’ve got to figure it out, and we will.”

Chimeric antigen receptor cell therapy — the process

1
White blood cells are collected via ‘apheresis’, a process that withdraws blood and removes one or more blood components.

2
T-cells, which can attack cancerous cells, are isolated from the white blood cells in a lab and ‘activated’ or woken up by scientists.

3
The T-cells are engineered to produce chimeric antigen receptors on the surface. Cars are proteins that recognise tumour cells.

4
Laboratory scientists grow and freeze millions of the modified Car-T cells. When there are enough they are sent to the hospital.

5
Chemotherapy wipes out a patient’s existing T-cells, giving the modified ones more space to multiply for a more effective treatment.

6
At the hospital, the Car-T cells are then infused into the patient. The cells multiply and can recognise and kill cancerous cells.

This process results in an expanded number of tumour-specific Car-T cells that systemically target and kill cancer cells, including those that have metastasised.