Exciting results from mRNA drug trials on melanoma here in WA are giving heart to patients and clinicians across the globe.
By Eric Martin
There is tantalising new hope for melanoma sufferers with West Australian researchers playing a significant role in the trial of a personalised, cancer vaccine therapy – the first of its kind in the world.
The drug trial is testing mRNA-4157, which uses the DNA from a patient’s tumour to help develop a unique treatment for that individual. It is currently being trialled at various hospitals around the world, and lead researcher, Clinical Professor Adnan Khattak, who is a consultant at Fiona Stanley Hospital as well as a private practice at Hollywood Private Hospital, said the trial was taking a personalised approach to melanoma treatment in the hope of improving survival rates over and above that offered by standard immunotherapy.
“Dealing with melanoma in WA is very challenging. Perth obviously has a lot of sunshine, our incidence of skin cancer is considerably higher, and the prognosis depends upon how targeted the melanoma is at the time of diagnosis – because it might be too late,” Professor Khattak explained.
“Men can seek medical help quite late because they either ignore their symptoms or do not do their regular skin checks, and their melanomas can become much more advanced before they are detected. Not to mention the fact that melanomas in men are often more aggressive.
“In contrast, women are usually more careful of their skin and makeup provides some level of protection from direct exposure to the sun, but no matter what happens, I think we need to raise awareness that while these drugs are good, nothing is better than not developing melanoma in the first place.”
The vaccine trial was a phase two study involving 157 patients and, while it was an international study, Australia contributed a significant number of participants, with Perth the leading site worldwide.
Trial intervention
“The intention was to take high-risk melanoma patients who had undergone surgery and immunotherapy and were at a significant risk of relapse. For example, most patients had stage three melanoma, which would carry a relapse risk over 70% within the next five years even after curative surgery,” he said.
“This means surgery is not curing almost two thirds of our patients, and standard immunotherapy is reducing this relative risk to about 30-35%, but that is still a significant risk. Despite surgery and immunotherapy for 12 months, you still stand a one in three chance of the melanoma coming back.
“It is quite an aggressive disease and we wanted to see if we could further shrink this relapse risk and increase the cure rate.
“Secondly, standard immunotherapy is a very generic treatment, where you give the same drug to the same group of patients. It’s not rocket science that it may work for some, but not for others.
“It’s a one-size-fits all approach, whereas what we did in the personalised cancer vaccine study was that patients would go through the same pathway, then start their treatment as per the standard protocol, but in addition to that, we also analyse the tumour tissue.”
The tumour removed during surgery was sent to Professor Khattak’s team along with a blood sample for genetic sequencing to identify the specific proteins, or neoantigens, of the cancer cells.
“Using a complex computing algorithm at Moderna, they identified up to 34 such neoantigens and using that data to design a custom-built mRNA vaccine for that individual patient’s tumour, which was different than any other vaccine for any other patient on that trial. If we get 10 patients, the tumours will be seen and there’ll be 10 different vaccines,” Professor Khattak said.
“In some cases, we identified 31 neoantigens, in some we had identified 32, and in others 34. However, in most instances, we identified certain mutations, then came up with a vaccine specifically designed for that patient’s tumour type, which was sent back to the treating institution.”
Moderna has been using AI based algorithms in conjunction with their bioinformatic system, allowing them to generate data for each group of patients that they treat – and with each new patient, more information is collected.
“The whole turnaround time was about six to eight weeks and in the interim, the patient had started the standard immunotherapy treatment so there was no disadvantage to them. When the vaccine arrived, we usually started it with the third dose of immunotherapy, for a total of nine doses,” he said.
“And when we followed them up, compared to what the standard immunotherapy offered, there was further improvement in terms of reducing the risk of distant relapse.
“Obviously, we didn’t know COVID was going to hit a year after starting this trial, but we used the same technology that Moderna then used for COVID vaccination where they studied the COVID genome, identified the spike protein and then produced an mRNA vaccine specifically for it.
COVID slowdown
“Moderna were too busy making COVID vaccines which meant the computerised random allocation was put on hold for three months, with patients manually allocated for treatment with only one drug.
“When the study reopened, most of my patients ended up receiving the two drugs and I am yet to see a single patient who has experienced disease relapse.”
Professor Khattak said that the single stranded mRNA were sequences of proteins encoded with a simple terminal and encased in a lipid formulation acting as a preservative. There was no toxicity as such and so far, researchers have not seen any long-term complications.
“In fact, standard immunotherapy can lead to many long-term side effects that we see daily, but those on the vaccine trial no one has had a long-term consequence of any sort. Only, short-term immune phenomena have been noted, and many of my patients are now to two to three years on,” he said.
“My personal experience, in terms of treating all these patients, data has shown that in high-risk patients, where 80% of the relapses would have happened by now, we have not seen a single one.
“Much like we saw with COVID vaccination, patients usually get a sore arm, local redness at the site of injection, maybe a bit of a fever or body aches for 24 to 48 hours, and then it settles on its own.
“We also saw that by the time we had administered the third or the fourth vaccine, that was when the immune response really kicked in and then there were very encouraging results, but not practice-changing yet.”
At this stage, a person must have stage two or stage three melanomas with potentially resectable disease.
“The surgeons have already operated on these patients, and then we use those tumour samples to identify whatever microscopic elements of the disease were left behind – that’s what we want to mop up,” Professor Khattak explained.
Expectations
“These are the groups of patients that we really need to focus on, using a more precautionary treatment, because once they develop stage four metastatic disease, the number of patients that get potentially cured is small.
“It is a preventative vaccine in a sense that it is stopping the cancer from relapsing, but it is not a primary prevention vaccine that you could give to somebody to prevent them from developing melanoma – sadly, we are not there yet.”
Professor Khattak said that while the exact cost of the drug treatment was unknown at this stage, as it was administered in the context of a clinical trial, he predicted that it would be an expensive technology to rollout due to the length of the process involved.
“Standard immunotherapy, which is a very generic approach, costs somewhere between $100,000 and $150,000 a year,” he said.
“And if you are talking about personalised cancer vaccine therapy, there is a lot of logistical steps involved in terms of getting the tumour, sending it off for genetic testing, analysing the blood sample, differentiating normal from abnormal, and then feeding that data into cloud-based computing algorithms to identify the salient features in order to design a vaccine.
“The whole process takes so much time.”
Professor Khattak highlighted that his research group were now working in collaboration with Edith Cowan University to identify certain molecular markers, proteins and antibodies which can be isolated from blood samples taken from a melanoma patient.
“Once you can identify certain molecules, you can target those with specific vaccines and we want to see if we can predict if somebody’s going to develop melanoma using blood tests to identify high-risk groups. But I think we’re still a good decade away from that,” he said.
“We are about to start rolling out a bigger clinical research study at Hollywood Private Hospital soon and while we hope that will be the first site in the world to open – and it would be fantastic to get the first Western Australian patient on that study – most importantly, we need to follow the textbook and reproduce these results in the context of a much bigger study involving at least 1000 patients.
“Our upcoming study is likely to recruit fast, given how positive the feedback has been to the previous study globally. I think patients will seek out these studies as soon as possible, and while an average study takes two to three years to complete this sort of recruitment, I think our study will be able to recruit all the participants within
a year.
“I am the primary investigator, and we have got contact details on the Hollywood hospital website, under clinical research, so they can contact us or speak to their treating plastic surgeon who is reviewing the melanoma – most of them are aware of it.
GPs welcome
“They can also speak to their GPs who are more than welcome to contact me, and we are very happy to advise if their patient is eligible or not. But the study is not for all the melanoma patients. We are targeting stage two B or higher melanoma because the risk of relapse is high.
Professor Khattak pointed out that this new technology had the potential to revolutionise cancer treatment as we know it.
“Treating advanced melanoma is just the tip of the iceberg. For example, there was a good pancreatic cancer study published in Nature recently, and even though it was a small group of patients, it showed encouraging results.
“I am also in discussion with Merck and Moderna, trying to get some other studies based in WA as well, and we are proud to be able to offer those studies to our patients.
“Our study will also be rolled out to lung, kidney and bowel cancer, which is what has caused so much excitement in the world of cancer management. If you can identify your enemy, you can prepare to meet it better.”
Medical Forum asked Professor Khattak, why, if patients are regularly subjected to blood tests and blood pressure readings when they visit the GP, are skin checks – particularly important for West Australians – carried out so infrequently?
“I was just talking to a 41-year-old gentleman who is a landscape designer, and obviously, he must work outside,” he said.
We see a lot of farmers as well, this is their lifestyle, and they cannot avoid it, but we can at least identify the highest-risk professions and try to raise awareness about greater skin protection as well as insisting on regular skin checks,” he said.
“I’d also highly recommend that all the clinicians discuss participation in clinical trials with their patients because this is how we learn, this is how we find out what works and what doesn’t.”
Hopes rise
The patients who took part in the Moderna study accessed it in 2019 and 2020 – when the drug was a novel therapy and still not available to public – even though the trial had positive results.
“By the time we recruit phase three, and the results are still positive, we are really looking at 2026 or 2027 before the drug becomes available to the public,” Dr Khattak said.
“We strongly negotiated and lobbied that public patients should be given the opportunity to take part in these clinical trials. If somebody does not have the resources or private insurance, that does not mean that they are less important or their cancer is less severe, and I think they should be given the opportunity.
“I’m proud that nearly two thirds of our patients are public patients despite this being done in a private hospital.”