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Scientists comment on an abstract of Phase 3 INTerpath-001 trial results of an individualised mRNA vaccine for resected stage IIB-IV melanoma, due to be presented at ESMO.
Dr Heather Shaw, Consultant Medical Oncologist, University College London Hospitals NHS Foundation Trust (UCLH), said:
“These are very encouraging results for people with high-risk melanoma. Although surgery and immunotherapy can be effective, some patients will still have their cancer return, and living with that uncertainty can be extremely difficult.
“This trial tested a personalised cancer vaccine, made using information from each patient’s tumour, alongside standard immunotherapy. The aim is to help the immune system recognise and attack any cancer cells left behind after surgery.
“At two years, 82% of patients receiving the combination were free from cancer recurrence, compared with 70% receiving immunotherapy alone. That means around 12 more people in every 100 remained free from recurrence. There was also a reduction in the risk of cancer spreading to other parts of the body.
“This is an important step forward, but we still need longer follow-up to understand whether the benefit lasts and whether patients live longer. The treatment also caused more side effects, particularly fever and tiredness.
“The vaccine remains an experimental treatment and is not currently available on the NHS. We are some way from being able to offer it routinely to patients, as further approval and assessment processes need to take place. There is currently no confirmed timeline for when this might happen.”
Professor Alan Melcher, Professor of Translational Immunotherapy, at The Institute of Cancer Research, London, said:
“These are very impressive results. Adding the personalised mRNA cancer vaccine intismeran to pembrolizumab reduced the risk of the melanoma returning or patients dying by 42 per cent compared with pembrolizumab alone in people whose high-risk melanoma had been removed by surgery. At two years, 82 per cent of patients receiving the combination were free from recurrence, compared with 70 per cent receiving pembrolizumab alone.
“Cancer vaccines have been researched for many years, but advances in genetic sequencing, immunotherapies and mRNA technology, including experience gained from Covid vaccines, have transformed what is possible. What is particularly exciting here is that this vaccine is personalised, using information from each patient’s own tumour to identify targets that are specific to their cancer. It essentially trains the immune system to recognise those cancer cells as a threat and attack them, while pembrolizumab helps release the brakes on the immune response.
“This is a large phase III trial, so it provides much stronger evidence than we have previously had that a personalised cancer vaccine can make a meaningful difference to patients. It is an important proof of principle for the field, although we shouldn’t get ahead of the evidence. We can’t assume from one melanoma trial that the same approach will work across all cancers, and longer follow-up will be important to understand the effect on overall survival.
“Melanoma is leading the way, but vaccines are being investigated in many other cancers, including cancers that are very difficult to treat and don’t respond well to current immune-based treatments. The challenge now is working out which cancers and which patients are most likely to benefit, and which are the best vaccine targets to go for.
“We’re closer to cancer vaccines becoming part of routine treatment than we’ve ever been, but they are not going to replace existing treatments across the board. The more realistic prospect is that they become another powerful tool that we can combine with treatments such as immunotherapy.”
Dr Lennard Lee, Associate Professor of AI and Cancer Vaccine Research at the University of Oxford, said:
“This is the Rolls-Royce of clinical trials. It is a large, randomised, double-blind, well-controlled study, representing the highest standard of clinical evidence. The results are compelling. When added to existing treatment, this personalised cancer vaccine reduced the relative risk of cancer returning or patients dying by 42%. This is a major breakthrough for cancer vaccine research. Although we await the full publication, the findings reported so far provide strong evidence that the vaccine can reduce cancer recurrence.”
“Melanoma is less common than many other cancers, yet it can be devastating when it spreads. Preliminary estimates suggest that around 3,000 to 4,000 patients in the UK each year could potentially be eligible for this approach, although the precise number will depend on clinical criteria. For these patients and their families, having another treatment that substantially reduces the risk of cancer returning could make an enormous difference.”
“The most exciting finding is what happens two years after surgery. Among patients receiving the cancer vaccine, 82.2% were alive and free from cancer recurrence, compared with 70% receiving standard treatment alone. That means that for every 100 patients treated, approximately 12 additional people were alive and free from cancer recurrence after two years. Put another way, we would need to treat approximately nine patients to prevent one additional recurrence or death over that period. That’s a remarkably encouraging result.”
“The UK is one of the world’s leading countries for cancer vaccine research. Through our NHS Cancer Vaccine Launch Pad, we have set out to help up to 10,000 patients access personalised cancer vaccine trials. What’s particularly encouraging is that British hospitals have demonstrated their ability to recruit patients and deliver these complex studies across the nation. At a time when clinical research faces enormous international competition, our NHS has shown that it can play a major role in accelerating the development of the next generation of cancer treatments.”
“Britain demonstrated what it could achieve through our vaccine research during the pandemic with the Oxford–AstraZeneca vaccine. We brought together universities, the NHS, scientists, industry and government to develop and deliver a vaccine at extraordinary speed. We now have another opportunity to harness that scientific expertise and infrastructure to tackle cancer. The ambition must be to scale up our efforts and make the UK a world leader, not just in discovering cancer vaccines, but in developing new treatments for many more types of cancer and, most importantly, getting them to the patients who need them.”
“The main limitation is that we don’t yet know whether the vaccine helps patients live longer. For every 100 patients treated, 12 more were alive and free from cancer recurrence after two years. That’s fantastic news. It’s a bit like buying a better car that breaks down less often, although it costs more. The question is whether more people ultimately reach their destination, because even if your car breaks down, roadside rescue might get you there anyway. Similarly, when cancer returns, further surgery or other treatments may still help patients. We know the vaccine reduces the risk of cancer coming back. We’re still waiting to find out whether it helps more people live longer and better lives.”
“There is also a trade-off. For every 100 patients receiving the vaccine combination, approximately six more experienced treatment-related side effects, including fever, fatigue and injection-site reactions. Reassuringly, the rates of severe treatment-related side effects were very similar, at 14.2% compared with 13.4%. These are important considerations, particularly because some patients would never have experienced a recurrence with existing treatment alone. We need to understand whether the additional benefits justify the extra side effects, complexity and costs.”
“Perhaps the biggest implication is that the future of cancer vaccines may be personalised. Every patient’s cancer is different. Every person’s immune system is different. Rather than giving everyone the same medicine, this trial demonstrates the potential of designing cancer vaccines around the unique genetic fingerprint of an individual patient’s tumour. This is a powerful demonstration of personalised medicine. Off-the-shelf cancer vaccines remain an important area of research, yet this trial provides compelling evidence for the personalised approach. We may be witnessing the beginning of an entirely new way of treating cancer.”
“One of the greatest challenges is manufacturing. Can we realistically make enough personalised cancer vaccines for patients around the world? Unlike conventional medicines, every vaccine must be individually designed and manufactured for one patient. Imagine an enormous factory in America producing hundreds of thousands of unique vaccines every week, each needing to be frozen, transported across the world and delivered to exactly the right hospital, for exactly the right patient, at exactly the right time. The logistics could make Amazon look simple.
“This is an extraordinarily complex and potentially expensive way to manufacture medicines. It might be achievable in wealthy countries like the United States, yet the bigger question is whether we could ever deliver these vaccines affordably to patients in Africa, South America or South Asia.
“We may need to fundamentally rethink how these vaccines are manufactured, potentially through smaller, local facilities producing vaccines close to patients. The risk is that we create a revolutionary cancer treatment that only wealthy self-pay patients and private healthcare systems can afford.
“A scientific breakthrough is only a true global breakthrough if patients around the world can benefit from it. We have demonstrated what is scientifically possible. The next challenge is to make it practically achievable and affordable for everyone affected by cancer, wherever they live.”
–Comments from the Aus SMC–
Professor Christopher Sweeney, Director of SAiGENCI – South Australian immunoGENomics Cancer Institute at Adelaide University, said:
“This mRNA personalised vaccine is a step-change approach for how to improve the body’s immune system to see cancer cells as foreign and then augment the ability to prevent the cancer cells growing and recurring.
“The study was conducted in patients who had no visible disease and a cancer ‘melanoma’ that is responsive to immune-enhancing drugs like pembrolizumab. Further research is needed to see if this approach is effective in patients who have cancer we can see and / or not responsive to the immune enhancer.”
Dr Jessamy Tiffen, Acting Deputy Director and Head of the Centre for Cancer Innovations at the Centennary Institute, said:
“What is truly remarkable about this vaccine is the deeply personalised nature of the treatment – something cancer researchers have been striving to achieve for decades. Where previously oncologists could pick a targeted therapy based on a single driver gene mutation present in the melanoma – this bespoke mRNA vaccine targets up to 34 gene mutations, unique to each patient. This vaccine, in combination with another type of immunotherapy, then trains the immune system to recognise and eliminate the melanoma, and most importantly – stop it from coming back.
“However, it’s not good news for all melanoma patients. A significant portion (58%) do not respond to the vaccine in the first instance. Cancer cells also have an insidious ability to adapt and evade whatever treatment we throw at them. Only time will tell how effective the treatment is beyond five years, but the results are clear that the combination works better than immunotherapy alone, and that’s a very exciting development.
“And don’t throw away the sunblock just yet. This vaccine is in no way preventative and can only be used in advanced (stage III & IV melanoma patients) who have their melanomas surgically removed. The best way to prevent melanoma is still to protect yourself from the sun.
“Another angle – A real triumph of the Australian clinical trials landscape. More pharmaceutical companies are choosing to run clinical trials here because they can be done more cheaply and quickly without compromising rigour and safety, compared to other countries. We have great expertise and resources, and it’s a huge benefit to Australian patients.”
Declared interests
Dr Heather Shaw: “Financial Interests: AstraZeneca Invited Speaker, Personal , BMS Invited Speaker, Personal , CDR-Life Advisory Board, Personal , Eisai Invited Speaker, Personal , Immunocore Expert Testimony, Personal , MSD Invited Speaker, Personal , MSD Advisory Board, Personal , Novartis Invited Speaker, Personal , Regeneron Advisory Board, Personal , Sanofi Invited Speaker, Personal , Sanofi Writing Engagement, Personal , ScanCell Advisory Board, Personal , ScanCell Invited Speaker, Personal , Sun Pharma Advisory Board, Personal , Therakos/Mallinkrodt Advisory Board, Personal , Cleveland Clinic London Full or part-time Employment, Personal , Biontech GMBH Local PI, Institutional, Financial interest , BMS Steering Committee Member, Personal, No financial interest , Ideaya Coordinating PI, Institutional, Financial interest , Ideaya Biosciences Steering Committee Member, Personal, Financial interest , immunocore Local PI, Institutional, Financial interest , immunocore Coordinating PI, Institutional, Financial interest , immunocore Steering Committee Member, Institutional, No financial interest , Immunocore Funding, Institutional, Financial interest, Data manager funding , iOnctura Local PI, Institutional, Financial interest , iovance Coordinating PI, Institutional, Financial interest , MSD Local PI, Institutional, Financial interest , MSD Funding, Institutional, Financial interest, Immunotherapy nurse pilot project funding – JWP , MSD Coordinating PI, Institutional, Financial interest , NovalGen Local PI, Institutional, Financial interest , NuTide Local PI, Institutional, Financial interest , ScanCell Local PI, Institutional, Financial interest
Non-Financial Interests , Agenus Advisory Role , iOnctura Advisory Role , NovalGen Advisory Role, Non-remunerated advisory role”
Associate Prof Helen Petousis-Harris: “HPH has received research funding from industry for investigator led and collaborative projects, served on expert advisory boards for industry, WHO, NZ government, and on clinical trial DSMBs. She is co-founder of the Global Vaccine Data network who conducted safety studies on COVID-19 vaccines across over 30 countries.”
Professor Christopher Sweeney: “I have no financial conflicts of interest with Moderna but have had consulting payments from Merck manufacturer of pembrolizumab”
Dr Lennard Lee: “I lead the UK Cancer Vaccine AI Scientist & Supercomputing programme at the University of Oxford, supported by funding from the Advanced Research and Invention Agency (ARIA). I have also held national advisory and leadership roles supporting cancer vaccine research and clinical trial development in the NHS and UK government. I designed co-founded the NHS cancer vaccine launchpad”
For all other experts, no reply to our request for DOIs was received.