An experimental vaccine, created individually for each patient from his or her own tumour, has shown that it may significantly reduce the risk of melanoma returning after surgical removal. In a clinical trial involving more than a thousand people, adding the personalised mRNA vaccine to standard immunotherapy reduced the likelihood of relapse or death by 42% compared with immunotherapy alone.
Even after surgeons remove a melanoma, individual malignant cells may remain in the body. They are too few to detect on a scan, but over time they can cause a relapse. Two years after treatment began, 82.2% of patients in the group receiving the new drug combination were alive and showed no signs of the disease returning. In the group receiving standard treatment, the figure was 70%.
The vaccine is called intismeran autogene and was developed by Moderna and Merck. Unlike conventional vaccines, which protect healthy people from infections, this one is designed to help those who already have cancer. The drug is made separately for each patient, using genetic information from their removed tumour.
These results represent a fundamental shift in our approach to cancer: we are using the immune system in a more personalised way to reduce the risk of melanoma recurrence or death.
— Georgina Long, medical director of the Melanoma Institute Australia
As it grows, any tumour accumulates genetic mutations. Some of them lead to abnormal proteins that are absent from healthy cells — scientists call them neoantigens. Sometimes the immune system recognises these proteins as a sign of cancer and attacks it, but cancer cells can suppress such a response. The vaccine helps the immune system learn to recognise the neoantigens of a specific tumour and attack any cancer cells bearing the same markers that remain after surgery.
To create the drug, researchers analyse the patient's removed tumour and compare its genetic material with a sample of healthy tissue, usually blood. Computer algorithms identify the mutations that can produce the most recognisable neoantigens. Scientists then select up to 34 such targets and encode instructions for making them into a molecule of mRNA — messenger ribonucleic acid.
The vaccine delivers these instructions into the body, prompting cells to temporarily produce harmless fragments of the abnormal proteins. This gives immune cells, in particular T-cells, which destroy cancer, the chance to learn exactly what to attack. However, the vaccine does not work on its own. Patients also receive pembrolizumab, a well-known immunotherapy drug that blocks the molecular signal cancer cells use to suppress immune attacks. Put simply, the vaccine teaches the immune system what to look for, while pembrolizumab helps release the "brakes" that stop it from attacking.
The study involved patients from 157 medical centres around the world. All had undergone surgery to completely remove a high-risk melanoma. 757 patients were randomly assigned to the group receiving intismeran and pembrolizumab; the other 380 received pembrolizumab and a placebo. Patients received up to nine vaccine injections at three-week intervals, and pembrolizumab treatment lasted about a year. The benefits of the combined treatment became apparent after six months, which points to the time the immune system needs to respond to the vaccine.
Producing a personalised vaccine is a complex task. Each patient requires tumour sequencing, computer analysis, the design of an individual mRNA, its production and delivery. In the study, the vaccine was manufactured for more than 99% of the patients who were scheduled to receive it. On average, 64 days passed before the first dose. However, analysis requires a sufficient amount of tumour tissue. Of the 1,749 patients initially screened for the study, 302 could not take part because their tumour samples were inadequate.
Merck and Moderna are discussing the results with regulators in order to make the drug available to patients. Researchers are also studying whether the technology can help with other cancers, including lung, kidney and bladder cancer.
Letters