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TOWARDS THETDNA DNARNARNARNASARSCVRNARNAVRNAVRNAVRNARNAYour browser does not support the element. end of the 19th century William Coley, a surgeon in New York, made a surprising observation. One of his patients, close to death with a neck tumour, recovered after catching a serious bacterial skin infection. Intrigued, Coley tried to replicate the finding, injecting patients with a cocktail of killed bacteria to get their cancers to regress. He ended up treating over a thousand patients in this way, often successfully.Coley’s reasoning was that infection could trigger the immune system to fight cancer. That idea, controversial during his lifetime, would not become more widely accepted by scientists until the 1950s. Today it is driving efforts to create a new generation of therapies known as that aim to train the immune system to recognise tumours and fight their spread. Trials are now under way against cancers found everywhere from the skin and ovaries to the brain and lungs. After half a century of disappointing dead ends, promising results are starting to emerge.Cancer can begin from almost any cell in the body. The immune system usually tries to prevent it from spreading by monitoring the body for abnormal cells. White blood cells known as -cells, for example, attack tumours by recognising foreign proteins known as non-self antigens on their surfaces. So-called natural killer cells and macrophages can also identify and destroy cancerous cells by searching for the unfamiliar molecules they carry, or after they are tagged by antibodies.If the cells in a cancer evolve to evade the immune system, however, they can then grow, replicate and spread around the body. This outflanking manoeuvre, however, is now offering oncologists new targets for their drugs. When scientists first began to sequence the of tumours, in 2008, they found that cancer cells contained hundreds, if not thousands, of mutations that distinguished them from their healthy neighbours. Some of these mutations in cellular cause cancer cells to produce abnormal proteins, known as neoantigens, which can set the immune system’s alarm bells ringing.The idea behind a cancer vaccine, then, is to introduce these neoantigens directly into the body, thereby training the immune system to see any cancer that carries them as a foreign body, ripe for elimination.To make such a vaccine, scientists first need to take a sample of a tumour, sequence its genome and find all its genetic mutations. This information is analysed to predict which neoantigens are likely to elicit the strongest immune response from the body. A vaccine can then be created that will trigger the immune system to create antibodies against those specific abnormal proteins. This is done by introducing a short-lived sliver of genetic information, known as , which, once injected, instructs the body’s cells to manufacture the neoantigens. The resulting immune response will then hopefully target the original tumour.The theory is solid, but creating such a bespoke vaccine quickly enough to be of use is a different matter. “Not many years ago,” says Alan Melcher, a clinical scientist at the Institute of Cancer Research in London, “I would have said, hang on, that’s never going to be technically possible.”The fact that this is now possible within as little as six weeks—albeit at a cost—is in no small part due to the accelerated development of m vaccines (which carry a molecule of messenger ) during the covid-19 pandemic. The vaccines that were used against covid-19 caused the body to build one of the constituent proteins of -o-2, which the immune system then used to create antibodies. Cancer vaccines would do something similar for the proteins that tumours produce.Some promising early results have been published. A personalised m cancer vaccine for melanoma (a type of skin cancer) developed by Moderna and Merck, two American pharma firms, known as m-4157 (940), recently completed phase 2 trials in patients who have had advanced tumours surgically removed. Three years after treatment, the risk of cancer recurrence or death had fallen by nearly half. This is a promising finding for a phase 2 trial, but a definitive answer on the vaccine’s usefulness will have to wait until the results of later-stage trials are known.Many think such vaccines could be most effective in combination with other immunotherapies—which work in a variety of ways to enhance or modulate the immune system’s response to cancer. “We are giving a lot of these cancer vaccines with immunotherapy to try and prime the immune system,” explains Sarah Danson, a specialist in early-phase cancer research at Britain’s National Institute for Health and Care Research. Indeed, m-4157 (940) was given alongside the current standard of care, which includes another form of immunotherapy, a drug known as Keytruda (pembrolizumab).Moderna and Merck announced in June 2024 that they had initiated further studies of m-4157 (940) in patients with non-small cell lung cancer, renal cell carcinoma (a type of kidney cancer), urothelial carcinoma (a cancer of the urinary lining) and cutaneous squamous cell cancer (a type of skin cancer) in order to test its effectiveness against different tumours. The firms BioNtech and Genentech are also jointly evaluating personalised vaccines in a range of cancers. There is already a hint in the data that their vaccine, known as autogene cevumeran, may reduce the risk of pancreatic cancer after surgery.Glioblastoma—the most common brain cancer, and one for which no useful treatments exist—is also being targeted. In work by academics at the University of Florida, an m-based cancer vaccine tested on only four people produced evidence that the vaccine had triggered a strong immune response to the tumour. Tests on dogs with brain tumours have also been promising: they lived a median of 139 days after treatment, compared with the more typical 30-60 days expected without. These results on humans and dogs also suggest that a personalised vaccine can trigger an immune response in a “cold” tumour—one that the immune system typically does not recognise or fight.The hope is that cancer vaccines will advance to the point where they reduce the need for more invasive treatments such as chemotherapy or surgery. For Dr Danson, it is even possible that therapeutic cancer vaccines could one day be used for prevention—with vaccines against neoantigens common in different cancers given to those most at risk of developing them. In October 2024 scientists at the University of Oxford were given funding to create a preventative ovarian cancer vaccine which aims to recognise and attack the earliest stages of this cancer.It will not all be plain sailing. Personalised cancer vaccines are complicated and expensive to make. Creating off-the-shelf cancer vaccines such as the ovarian-cancer vaccine could help. Another example—one that is further ahead—is BioNtech’s m vaccine candidate for non-small cell lung cancer. Again, this vaccine presents the immune system with common tumour markers found in various types of cancer. This work is still only in early safety trials.Important scientific questions also remain unanswered. For one thing, says Elad Sharon, a clinical and translational director at the Dana-Farber Cancer Institute in Boston, it remains unclear why the immune system will overlook a neoantigen if it is produced by a tumour, but will leap into action when it is delivered by vaccine. Pharma firms also need to rigorously evaluate their neoantigen-picking techniques, to ensure the best candidates are chosen.More than a century after he carried out his experimental treatments, Coley’s instincts have proved sound. But just how effective modern vaccine candidates will turn out to be remains unknown. A study published in 2009 assessed developments in the field and wondered whether that would be the year of the cancer vaccine. It was not. 2025, however, may be a different story.
