Pharmaceutical companies Moderna and Merck have announced preliminary successes in the Phase 3 trial of their personalised melanoma vaccine

This is significant news. The results are not being presented, as there is no scientific publication; instead, the interim results of a phase 3 trial are being announced. The announcement has been made ahead of the publication, and it is stated that the findings will be presented at a conference.

Why has this attracted so much attention? Firstly, it is a phase 3 trial involving more than a thousand melanoma patients, and secondly, because of the technology involved. These are personalised vaccines, tailored to each individual patient. This is achieved, firstly, by sequencing the DNA to identify mutations. Then, by sequencing both normal and tumour DNA; and subsequently, by sequencing at the RNA level, to determine how many of these alterations are expressed and which ones can be recognised by the immune system.

This is one part of the treatment. The other part involves combining it with pembrolizumab to reduce all the inhibitory mechanisms that cells employ within the immune system—their multiple defence mechanisms. Furthermore, the aim is to ensure that the immune system actively recognises the tumour. This is why this other component of the treatment is included, and the result is the identification of up to 34 factors that are altered and expressed in the tumour cell.

The trial was conducted as an adjuvant treatment, that is, following surgery. The tumours (primary tumours, lymph nodes, and it appears some metastases too) have been removed. What is measured is how long it takes for the tumour to reappear after surgery, disease-free survival and metastasis-free survival.

Why is this interesting? Because of the RNA technology. Until now, there was no way to identify 34 alterations in proteins specific to a particular patient, and they have combined this with this immunomodulator. The idea is to get the immune system to attack these tumour cells as much as possible.

What remains to be done? Well, first we need to see the final results. And what is perhaps a cause for concern is how widely applicable it will be, as this varies from patient to patient; and also the cost to healthcare systems – whether such a personalised treatment is affordable. Perhaps in the future, alterations that are very common may be identified, but at the moment it is personalised.

In principle, the prospects are very promising – albeit with caution – for a technologically very complex trial.”

Personalised cancer vaccine:

“The vaccine has been developed to target mutations specific to each patient’s cancer. This in theory makes the vaccine safer (as only cancer cells, rather than normal cells, should have these mutations) and potentially more effective. 

What we know about these results:

“We know that the addition of V940 (personalised vaccine) to a standard therapy of pembrolizumab is better than pembrolizumab alone at preventing melanoma from coming back after surgery for patients with high-risk disease. How much better is not yet known until more data is released and at what cost is this gain? For example, how much more toxicity and/or cost does this add to standard therapy? If the benefit of adding V940 is small (e.g. a few percentage points), whilst the increase in toxicity or cost is high, then the impact of this treatment may be diminished. From the earlier phase 2 trial though, we know the combination treatment does not add much more toxicity to standard therapy, so this is likely to be the case for the phase 3 trial. 

How significant are these findings?

“This is the first phase 3 study to demonstrate improved recurrence-free survival and distant metastasis-free survival for a combination adjuvant treatment over anti-PD-1 (e.g. pembrolizumab) adjuvant therapy in melanoma which is significant in itself. How significant will depend on the details to be released later.”

What is this personalised cancer vaccine and how does it work?

“A personalised cancer vaccine is designed by first identifying mutations in the DNA of a cancer and then working out which mutations encode for proteins that get presented to immune cells on the surface of the cancer cells. Over 30 such mutations can then be selected for vaccine manufacturing. As the selection is done for each individual cancer, it is a personalised product. The vaccine technology is very similar to many Covid vaccines which use RNA. RNA that encodes the identified mutations is then injected under the skin ever 3 weeks and at the same time patients received another immunotherapy called pembrolizumab. The idea is that the personalised neoantigen vaccine educates the immune cells to recognize the cancer cells whereas pembrolizumab takes the breaks off the immune cells and helps them to have maximum effect.    

What can we know from these results? What details are still to come?

“The press release only announced that the study is positive, and we don’t have any details yet. The main aim of the study was to show that recurrence free survival improves when patients receive the vaccine. This has been achieved but we don’t know yet how much lower the recurrence rate for example at 3 years is. These results may be presented at one of the big oncology conferences in autumn. How much long-term survival improves is almost certainly not know yet as the patients will need to be followed for longer but recurrence free survival correlates well with this. 

How significant are these findings?

“I think it is fair to call it a breakthrough in the development of new cancer immunotherapies as it is the first phase 3 study that shows that a vaccine can protect against recurrences of one of the deadliest cancer types. This is certainly good news for patients with melanoma, but the study has much wider implications. It provides proof of principle that personalised cancer vaccines work. This is important as they can be designed against many different cancer types. I am hopeful that we will see similar successes of this technology in a range of cancer types such as colon cancer where a large study has been performed.“

What is this personalised  cancer vaccine and how does it work?

“Personalised cancer vaccines are a fundamentally different way of thinking about cancer treatment. Rather than giving every patient the same medicine, a treatment is designed specifically for the individual patient and the unique genetic fingerprint of their cancer.

“A sample of the patient’s tumour is analysed to identify mutations that distinguish the cancer cells from healthy cells. These mutations can generate abnormal proteins, known as neoantigens, which can potentially be recognised by the immune system. The vaccine uses mRNA to provide instructions corresponding to selected neoantigens, with the aim of training the patient’s immune system, particularly its T cells, to recognise and attack cancer cells carrying them.

“In this trial, each personalised treatment encodes up to 34 neoantigens and is given alongside pembrolizumab, an established immunotherapy. In simple terms, one treatment helps show the immune system what to look for, while the other helps release the brakes on the immune response.

What can we know from these results, and what details are still to come?

“What we know today is important. This was a large Phase III randomised trial involving 1,137 patients with surgically removed, high-risk melanoma, and the trial met its primary endpoint.

“According to the topline announcement, patients receiving the personalised mRNA cancer vaccine alongside pembrolizumab had a statistically significant and clinically meaningful improvement in recurrence-free survival compared with pembrolizumab alone. The study also met the important secondary endpoint of distant metastasis-free survival.

“That is very encouraging. We should now look forward to seeing the complete data. We do not yet have the magnitude of the Phase III benefit, the detailed subgroup analyses, quality-of-life data or mature overall-survival results. Those details will allow the scientific and clinical community to understand precisely how large the benefit is, which patients benefit most, and ultimately where this treatment might sit within routine melanoma care.”

How significant are these findings?

“These findings are significant. This is the first positive Phase III trial of an individualised neoantigen therapy and an mRNA-based cancer treatment. That makes this an important moment for a field that scientists have been working towards for many years. Within 6 years of the pandemic, we have mRNA vaccines to treat cancer. 

“There is also a wider story here about what happened after the pandemic. In 2020, enormous global investment accelerated mRNA technology, vaccine science and manufacturing, and it started in the United Kingdom. The question afterwards was whether that capability could be redirected towards other major diseases.

“In 2022, the UK made an early strategic decision to pursue that opportunity in cancer, launching a national cancer vaccine advance to accelerate clinical trials of mRNA cancer vaccines. It forms part of our AI For Science Plan, our 10-year cancer plan, and our modern industrial strategy. Since then, the UK has developed into one of the world’s leading environments for cancer vaccine trials. Nearly 50 cancer centres have contributed to this national effort, including through programmes such as the NHS Cancer Vaccine Launch Pad and Vaccine Innovation Pathway, alongside expert contributions to the MHRA. We have even made a major push into AI, using our AI Supercomputer to significantly improve design of these vaccines.”

“These results are encouraging because they suggest treatments made for an individual patient, even in common conditions, may be moving closer to everyday clinical use. They indicate that highly personalised treatments can be developed, tested and potentially delivered on a much larger scale than previously thought. While this research focuses on cancer, the lessons could have implications far beyond this field, helping build confidence in more tailored approaches to treatment, including for rare conditions that are often driven by unique genetic mutations.”