WHY THIS MATTERS IN BRIEF
Cancer is still one of the world’s biggest killers but new personalised treatments seem to be working with staggering results for previously “terminal” patients.
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When Mark Lashway found out that his melanoma skin cancer had spread to his lungs, he immediately quit his job as a chemistry teacher in Hillsdale, New York, and prepared for the worst.
“I knew the survival rate was only 15 per cent and I was frightened. It was the realisation of like, ‘Holy cow, is this it?’,” he says.
Seven years later, the 67-year-old is now seemingly cancer-free after becoming one of the first people in the world to receive a personalised cancer vaccine – one that was designed just for him so that his immune system could attack and destroy the unique biology of his tumours. “I had these three lung tumours that were so big I could see them and feel them – one was protruding out of my back,” he says. “Then a few months later [after treatment], I’m waiting for my results and my oncologist comes in and says, ‘I’ve got the best news a doctor can tell you – you’ve had a 100 per cent response.’ The tumours were all gone.”
Lashway is now one of a few hundred cancer patients who have received personalised vaccines as part of several clinical trials. Other participants have also had remarkable responses, even some with cancers that would be hard to treat conventionally.
“I would say these vaccines are the next big thing,” says Adilia Hormigo at Mount Sinai Hospital in New York, who has used them to treat some people with a notoriously deadly brain cancer known as glioblastoma.
We have long known that the immune system naturally tries to fight cancer, but it is often outsmarted by cancer’s tricks. Many decades of research have tried to dial up this natural response. The first big breakthrough came in 2011 with the approval of “checkpoint inhibitors” – a class of drugs that boosts the anti-tumour activity of important parts of the immune system called T-cells. Thanks to checkpoint inhibitors, some people with cancer who would have been given months to live have survived more than a decade.
Checkpoint inhibitors, however, don’t work for everyone’s cancer: 50 per cent at best survive for five years in melanoma clinical trials. They also don’t work for every type of cancer – for example, they are powerless against most bowel cancers.
That is why researchers have continued to search for other ways to supercharge the immune system against cancer One strategy is vaccination, which aims to increase the number of T-cells that can fight tumours. If T-cells are thought of as an army, checkpoint inhibitors make the soldiers stronger and vaccination recruits extra soldiers. A combination of these strategies could be extremely powerful.
We normally think of vaccines as being used to prevent disease – like vaccines that protect against Covid-19 – but they can treat disease too. The idea of a vaccine is to help the immune system battle something harmful, be it a virus or a cancer cell. Our immune systems do this by pumping out substances that recognise a target part of a disease-causing entity, such as the proteins on the outside of a virus.
Unfortunately, cancer vaccines have previously failed to live up to their promise. One of the biggest challenges has been finding the right targets for these vaccines, as every individual’s cancer is genetically different. This means that a vaccine that works for one person is unlikely to work for another.
About 12 years ago, Eric Lander, one of the leaders of the human genome project and founding director of the Broad Institute in Cambridge, Massachusetts, wondered if a personalised approach would work best. With the cost of genetic sequencing falling to just hundreds of dollars, he thought it might be possible to analyse the DNA of a person’s tumours and design a vaccine to target their unique mutations.
Lander approached oncologists at Dana-Farber Cancer Institute in Boston to see if they would be interested in giving this a go. They agreed and applied for approval from the US Food and Drug Administration (FDA).
“It was kind of a big deal, because no one had done this before – the idea that every single participant would get a different vaccine was something the FDA wasn’t used to,” says Patrick Ott at Dana-Farber. “We had to convince them that we didn’t need to do animal studies beforehand because it wouldn’t make sense.”
After getting the FDA on board, Ott and his colleagues enrolled eight people with advanced melanoma, including Lashway, between 2014 and 2015, to test personalised cancer vaccines. They chose melanoma because it is an example of a “hot tumour,” one that is easily recognised by the immune system because of its many mutations.
First, they took samples of tumour cells and normal cells from each patient and genetically sequenced them. Next, they used powerful computers at the Broad Institute to compare the two so they could identify mutations in the tumour DNA. Some of these mutations caused abnormal proteins to be expressed on the tumours, making them look different to normal cells.
For each patient, the team then manufactured a vaccine that contained snippets of up to 20 of these abnormal proteins. The idea was to expose the immune system to these snippets so that many more T-cells could learn to recognise them. When this new army of T-cells then encountered the same abnormal proteins on tumour cells, they would know to attack them.
Lashway received seven shots of his bespoke vaccine over the course of six months. He experienced no side effects aside from some itchy blisters that broke out on his skin. “The fact that these vaccines are so tailored to each patient’s tumour makes them really safe,” says Ott. This is because the vaccines prompt the immune system to attack tumour cells while leaving other cells in the body alone.
At the end of the six months, Lashway began getting injections of a checkpoint inhibitor called Pembrolizumab – more commonly known as Keytruda – to give an extra boost to the newly recruited T-cells.
“It was like a one-two punch,” says Lashway. That was when his tumours started rapidly shrinking before his eyes. “I could actually see the one that was sticking out of my back getting smaller.”
It is hard to know how much of Lashway’s impressive recovery was due to the personalised vaccine and how much to the pembrolizumab. Ott believes the synergy between the two was key.
“It is possible that the Pembrolizumab did it alone, but it would be unusual to have such a profound response as quickly as he had it,” he says.
Of the seven other trial participants, most of whom received the vaccine without any Pembrolizumab, six are still alive and appear to be cancer-free.
“We showed that the personalised vaccines were safe and, excitingly, produced a very robust immune response, which was something that hadn’t been shown before with cancer vaccines,” says Ott.
Hormigo and her colleagues at Mount Sinai Hospital have since used a similar approach to make personalised cancer vaccines for people with glioblastoma. In a trial involving 12 people with the disease, they found that personalised vaccines, combined with another experimental treatment, induced strong immune responses. The average survival for people with glioblastoma is normally just 15 months, but nine of the trial participants are still alive more than two years after treatment and all but one appear to be cancer-free.
“I’m very pleased with the results we have so far because glioblastoma is such a difficult disease to treat,” says Hormigo.
Both Ott and Hormigo, however, caution that their trials were small and unable to show conclusively that personalised cancer vaccines are effective.
“Ultimately, we need large randomised controlled trials to show that this can actually work, but you can imagine that it’s not cheap. Each vaccine can cost $100,000 or more,” says Ott.
Fortunately, there are some companies that can afford this kind of research. These include BioNTech in Germany and Moderna in the US, which both began working on personalised cancer vaccines many years ago, but shot to fame for their Covid-19 jabs.
The two companies have taken a slightly different approach to Ott and Hormigo. Instead of making the vaccines out of protein snippets, they make them out of messenger RNA – or mRNA – that instructs cells to make the relevant protein snippets inside the body.
The BioNTech version trains each cancer patient’s immune system to recognise up to 20 unique markers on their tumours. Moderna’s does the same, but targets up to 34 unique markers. Both prompt the immune system to selectively kill tumour cells.
“The beauty is, we start with the patient. We learn from the patient. And we design a complete drug that is personalised in every way,” says Praveen Aanur, one of Moderna’s chief oncologists.
BioNTech and Moderna have both reported encouraging early results for their personalised cancer vaccines in small trials. For example, in a study of 10 people with metastatic head and neck cancer, Moderna’s personalised vaccines stopped the cancers from progressing for an average of 10 months when combined with a checkpoint inhibitor. This figure would normally be closer to two months with a checkpoint inhibitor alone.
And 8 of 16 people with pancreatic cancer who received BioNTech’s personalised vaccines and a checkpoint inhibitor shortly after their tumours were surgically removed were still cancer-free 18 months later.
Now, BioNTech and Moderna are both conducting larger randomised controlled trials in people with melanoma, enrolling more than 130 participants each. In both trials, melanoma patients have been randomly assigned to receive a personalised cancer vaccine and the checkpoint inhibitor pembrolizumab, or pembrolizumab alone. This should finally confirm whether personalised cancer vaccines do provide additional benefits on top of checkpoint inhibitors. The first results are expected towards the end of this year.
Not everyone is convinced that personalised cancer vaccines will live up to their promise, says Riccardo Dolcetti at the Peter MacCallum Cancer Centre in Melbourne, Australia.
“Many clinicians have memories of the failed cancer vaccines of the past, before they were personalised,” he says. “It can also be a challenging concept for regulators because it’s not like a traditional drug, it’s more like a process.”
However, if more positive clinical trial results roll in, “more and more clinicians should become convinced that this is the right thing to do”, says Dolcetti. One of the best things about vaccines is that their targeted nature means that, unlike chemotherapy, they don’t make patients sick, he says.
The two major drawbacks of personalised vaccines are the time it takes to make them and their enormous cost, says Dolcetti. Companies like Moderna and BioNTech can do everything in-house and make the process more streamlined. But it still takes between four and six weeks for them to make each vaccine. Aanur won’t reveal the cost, but he says that over time the process should become cheaper and faster.
A high level of quality control is also required so that patients’ vaccines don’t get mixed up, because they are all different, says Aanur. At Moderna, a digital barcoding system follows each vaccine’s production from start to finish and is checked every step of the way to make sure the right treatment ends up in the right patient, he says.
Although personalised cancer vaccines have shown promise in hot tumours, we still don’t know if they could be used against “cold tumours” – those that aren’t easily recognised by the immune system, including many forms of bowel, breast, and prostate cancer. In one small trial, Moderna found that its personalised cancer vaccines had no effect in people with bowel cancer. But Aanur says the company is working on ways to switch cold tumours to hot so that they become more susceptible to vaccine treatment.
“We want to open all the gates to the T-cells,” he says.
The ultimate goal will be to develop personalised cancer vaccines that stop people from developing cancer in the first place, rather than treating it when it is already established, says Dolcetti. For example, if genetic sequencing could identify an individual’s risk of developing certain cancers, it may be possible to custom-make a vaccine for them that prevents those cancers forming.
“The difficulty is knowing what to target, but several groups around the world are working on this,” says Dolcetti.
In fact, it is already possible to prevent some cancers using vaccines. These are cancers that we know are caused by viruses, so we can make vaccines to stop these viruses from infecting us. For example, vaccines against human papillomavirus can prevent cervical cancer and vaccines against hepatitis B virus reduce the risk of liver cancer. Personalised vaccines for preventing non-virus-induced cancers are the next frontier.
For Lashway, getting the opportunity to try a personalised cancer vaccine and having a 100 per cent response has transformed his outlook on life.
“I remember after I was diagnosed, I watched a woman on YouTube talking about how cancer can be a gift in disguise and I thought, “This is bullshit’, and turned it off,” he says. “But at the end of this, how it’s changed the way I approach life, I think she was right. I feel so lucky.”